Predictive mirnas for response to lung cancer therapy

Abstract

The present invention relates to a method of predicting a response to lung cancer immunotherapy of a patient suffering from lung cancer. Further, the present invention relates to a method of providing a survival prognosis to a patient suffering from lung cancer who is eligible to immunotherapy. Furthermore, the present invention relates to a method of determining whether to treat a patient suffering from lung cancer with immunotherapy. In addition, the present invention relates to a method of selecting a patient suffering from lung cancer to benefit from immunochemotherapy or immunotherapy. Moreover, the present invention relates to a kit for carrying out these methods.

Description

[0001] Our Ref.: 505-102 PCT

[0002] Hummingbird Diagnostics GmbH

[0003] PREDICTIVE MIRNAS FOR RESPONSE TO LUNG CANCER THERAPY

[0004] The present invention relates to a method of predicting a response to lung cancer immunotherapy of a patient suffering from lung cancer. Further, the present invention relates to a method of providing a survival prognosis to a patient suffering from lung cancer who is eligible to immunotherapy. Furthermore, the present invention relates to a method of determining whether to treat a patient suffering from lung cancer with immunotherapy. In addition, the present invention relates to a method of selecting a patient suffering from lung cancer to benefit from immunochemotherapy or immunotherapy. Moreover, the present invention relates to a kit for carrying out these methods.

[0005] BACKGROUND OF THE INVENTION

[0006] Cancer is the uncontrolled growth of abnormal cells anywhere in a body. The abnormal cells are termed cancer cells, malignant cells, or tumor cells. Cancer cells can proliferate uncontrollably and form a mass of cancer cells.

[0007] Lung cancer or bronchogenic carcinoma refers to tumors originating in the lung parenchyma or within the bronchi. It is one of the leading causes of cancer-related deaths in Europe and in the United States. Since 1987, lung cancer has been responsible for more deaths in women than breast cancer. It is estimated that there are 225,000 new cases of lung cancer in the United States annually, and approximately 160,000 die because of lung cancer. It is interesting to note that lung cancer was a relatively rare disease at the beginning of the 20th century. Its dramatic rise in later decades is attributable primarily to the increase in smoking among both males and females.

[0008] Cancer therapy such as lung cancer therapy, includes, but is not limited to, immunotherapy, chemotherapy, radiation therapy, vaccination therapy, stem cell therapy, anti-hormonal therapy, immunosuppressive therapy, antibody therapy, and surgical therapy. Standard clinical parameters such as tumor size, grade, lymph node involvement and tumor-node-metastasis (TNM) staging may correlate with outcome and severity to stratify patients with respect to cancer therapy regimens. However, stage-matched tumors grouped by histological subtypes may respond differently to the same treatment regimen.

[0009] Immunotherapy has recently gained recognition as a highly effective therapy in late-stage cancers. Drugs used in immunotherapy work by blocking the mechanisms by which tumors commonly evade detection and unleashing the immune system to fight the cancer. Alongside the remarkable benefits, immunotherapies can be associated with characteristic (and sometimes severe) side effects. For this reason, it is required to administer immunotherapies only to those patients in which the benefits are predicted to outweigh the risks. The mainstay of response prediction to immunotherapies in the PD-1 inhibitor class (Nivolumab and Pembrolizumab) is the quantification of tumor PD-L1 expression. However, still only approximately 30% of patients will achieve a positive response.

[0010] In addition, in late-stage cancers, immunotherapy (IO) alone or immunotherapy in combination with chemotherapy (i.e. immunochemotherapy (ICT)) are recommended as treatment options in major international guidelines. However, there remains uncertainty as to the ideal therapeutic choice in individual patients.

[0011] A positive response to immunotherapy is dependent both on local interactions between malignant and immune cells in the tumour microenvironment as well as more distal interactions between the tumour and the peripheral immune system. The latter has the potential to provide non- invasive therapy guidance, but no blood-based biomarkers have yet entered routine clinical use.

[0012] There is, thus, a pressing need for more accurate biomarkers for cancer therapy, such as lung cancer therapy, in particular immunotherapy, response prediction, and survival prediction. In addition, there is a pressing need for new biomarkers which can identify which patients will benefit from chemotherapy in addition to immunotherapy.

[0013] Multiple lines of evidence suggest that information held in peripheral blood may be predictive of the immune response within the localized tumor microenvironment. Associations have been found between immunotherapy response and peripheral blood counts and peripherally expanded T-cell clones.

[0014] The present inventors identified response and survival predictive miRNAs from whole blood for lung cancer therapy, specifically immunotherapy. These new miRNAs allow a quick and accurate clinical response prediction and survival prognosis in lung cancer diseases. Said miRNAs can, thus, be used as companion or complementary diagnostics in lung cancer therapy. As an additional advantage, repeated liquid biopsies reduce procedural risks and are more feasible than serial tumor biopsies (as required by the methods of the prior art) to perform longitudinal monitoring and investigate the dynamic processes, e.g. of tumor PD-L1 expression. In addition, these new miRNAs allow to select a patient suffering from lung cancer to benefit from immunochemotherapy or immunotherapy.

[0015] SUMMARY OF THE INVENTION

[0016] In a first aspect, the present invention relates to a method of predicting a response to lung cancer immunotherapy of a patient suffering from lung cancer comprising the step of: determining the level of at least one miRNA in a blood sample of a patient suffering from lung cancer, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR- 143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

[0017] In a second aspect, the present invention relates to a method of providing a survival prognosis to a patient suffering from lung cancer who is eligible to immunotherapy comprising the step of: determining the level of at least one miRNA in a blood sample of a patient suffering from lung cancer, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR- 143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

[0018] In a third aspect, the present invention relates to a method of determining whether to treat a patient suffering from lung cancer with immunotherapy comprising the steps of:

[0019] (i) carrying out the method of the first aspect, thereby identifying the patient as patient who will respond to lung cancer immunotherapy, or carrying out the method of the second aspect, thereby identifying the patient as patient having a good survival prognosis under immunotherapy, and

[0020] (ii) assigning the patient to (said) lung cancer immunotherapy.

[0021] In a fourth aspect, the present invention relates to a method of selecting a patient suffering from lung cancer to benefit from immunotherapy or immunochemotherapy comprising the step of: determining the level of at least one miRNA in a blood sample of a patient suffering from lung cancer, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR- 342-3 p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa- miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 14 (hsa- miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

[0022] In a fifth aspect, the present invention relates to a method of determining whether to treat a patient suffering from lung cancer with immunochemotherapy or immunotherapy comprising the steps of:

[0023] (i) carrying out the method of the fourth aspect, thereby identifying the patient as patient who will benefit from immunochemotherapy or immunotherapy, and

[0024] (ii) assigning the patient to said therapy.

[0025] In a sixth aspect, the present invention relates to a method of treating a patient suffering from lung cancer with immunochemotherapy or immunotherapy comprising the steps of:

[0026] (i) carrying out the method of the fourth aspect, thereby identifying the patient as patient who will benefit from immunochemotherapy or immunotherapy, and

[0027] (ii) treating the patient with said therapy.

[0028] In a seventh aspect, the present invention relates to the (in vitro) use of at least one miRNA or at least one polynucleotide allowing the detection of said at least one miRNA for predicting a response to lung cancer immunotherapy of a patient suffering from lung cancer, for providing a survival prognosis to a patient suffering from lung cancer who is eligible to immunotherapy, or for determining whether to treat a patient suffering from lung cancer with immunotherapy, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155- 5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

[0029] In an eight aspect, the present invention relates to the (in vitro) use of at least one miRNA or at least one polynucleotide allowing the detection of said at least one miRNA for selecting a patient suffering from lung cancer to benefit from immunotherapy or immunochemotherapy, or for determining whether to treat a patient suffering from lung cancer with immunochemotherapy or immunotherapy, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR- 342-3 p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa- miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 14 (hsa- miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

[0030] In a ninth aspect, the present invention relates to a kit for predicting a response to lung cancer immunotherapy of a patient suffering from lung cancer, for providing a survival prognosis to a patient suffering from lung cancer who is eligible to immunotherapy, or for determining whether to treat a patient suffering from lung cancer with immunotherapy, wherein said kit comprises: means for determining the level of at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192- 5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR- 576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

[0031] In a tenth aspect, the present invention relates to a kit for selecting a patient suffering from lung cancer to benefit from immunotherapy or immunochemotherapy, or for determining whether to treat a patient suffering from lung cancer with immunochemotherapy or immunotherapy, wherein said kit comprises: means for determining the level of at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155- 5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 16 (hsa-miR- 199b-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

[0032] This summary of the invention does not necessarily describe all features of the present invention. Other embodiments will become apparent from a review of the ensuing detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0033] Definitions

[0034] Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0035] Preferably, the terms used herein are defined as described in “A multilingual glossary of biotechnological terms: (TUPAC Recommendations)”, Leuenberger, H.G.W, Nagel, B. and Kolbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

[0036] Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, GenBank Accession Number sequence submissions etc.), whether supra or infra, is hereby incorporated by reference in its entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. In the event of a conflict between the definitions or teachings of such incorporated references and definitions or teachings recited in the present specification, the text of the present specification takes precedence.

[0037] The term “comprise” or variations such as “comprises” or “comprising” according to the present invention means the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. The term “consisting essentially of’ according to the present invention means the inclusion of a stated integer or group of integers, while excluding modifications or other integers which would materially affect or alter the stated integer. The term “consisting of’ or variations such as “consists of’ according to the present invention means the inclusion of a stated integer or group of integers and the exclusion of any other integer or group of integers.

[0038] The terms “a” and “an” and “the” and similar reference used in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0039] As used herein, the term “about” indicates a certain variation from the quantitative value it precedes. In particular, the term “about” allows a ±5% variation from the quantitative value it precedes, unless otherwise indicated or inferred. The use of the term “about” also includes the specific quantitative value itself, unless explicitly stated otherwise. For example, the expression “about 80°C” allows a variation of ±4°C, thus referring to range from 76°C to 84°C.

[0040] The term “biomarker”, as used herein, refers to a biological molecule found in blood, other body fluids, or tissues that is an indicator of a normal or abnormal process, or of a condition or disease. A biomarker may be used to foresee how well the body responds to a treatment for a disease or condition or may be used to associate a certain disease or condition - or outcome of disease - to a certain value of said biomarker found in e.g. a blood sample. Biomarkers are also called molecular markers and signature molecules. If the biomarker is used to predict the probable course and outcome of a disease, it may be called a prognostic biomarker. The biomarkers described herein are miRNAs. Said miRNAs are predictive and prognostic biomarkers.

[0041] The term “miRNA” (the designation “microRNA” is also possible), as used herein, refers to a single-stranded RNA molecule of at least 10 nucleotides and of not more than 45 nucleotides covalently linked together. Preferably, the polynucleotides used in the present invention are molecules of 10 to 45 nucleotides or 15 to 35 nucleotides in length, more preferably of 16 to 28 nucleotides or 18 to 23 nucleotides in length, i.e. 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 nucleotides in length, not including optionally labels and / or elongated sequences (e.g. biotin stretches).

[0042] The miRNAs regulate gene expression and are encoded by genes from whose DNA they are transcribed but miRNAs are not translated into protein (i.e. miRNAs are non-coding RNAs). The genes encoding miRNAs are longer than the processed mature miRNA molecules. The miRNA is initially transcribed as a longer precursor molecule (>1000 nucleotides long) called a primary miRNA transcript (pri-miRNA). Pri-miRNAs have hairpin structures that are processed by the Drosha enzyme (as part of the microprocessor complex). After Drosha processing, the pri-miRNAs are only 60-100 nucleotides long, and are called precursor miRNAs (pre-miRNAs). At this point, the pre-miRNA is exported to the cytoplasm, where it encounters the Dicer enzyme. Dicer cuts the miRNA in two, resulting in duplexed miRNA strands. Traditionally, only one of these miRNA arms was considered important in gene regulation: the arm that is destined to be loaded into the RNA-induced silencing complex (RISC) and occurs at a higher concentration in the cell. This is often called the “guide” strand and is designated as miR. The other arm is called the “minor miRNA” or “passenger miRNA” and is often designated as miR*. It was thought that passenger miRNAs were completely degraded, but deep sequencing studies have found that some minor miRNAs persist and in fact have a functional role in gene regulation. Due to these developments, the naming convention has shifted. Instead of the miR / miR* name scheme, a miR-5p / miR-3p nomenclature has been adopted. By the new system, the 5’ arm of the miRNA is always designated miR-5p and the 3’ arm is miR-3p. The present nomenclature is as follows: The prefix “miR” is followed by a dash and a number, the latter often indicating order of naming. For example, hsa- miR-16 was named and likely discovered prior to hsa-miR-342. A capitalized “miR-” refers to the mature forms of the miRNA (e.g. hsa-miR-16-5p and hsa-miR-16-3p), while the uncapitalized “mir-” refers to the pre-miRNA and the pri-miRNA (e.g. hsa-mir-16), and “MIR” refers to the gene that encodes them. However, as this is a recent change, literature will often refer to the original miR / miR* names. After processing, the duplexed miRNA strands are loaded onto an Argonaute (AGO) protein to form a precursor to the RISC. The complex causes the duplex to unwind, and the passenger RNA strand is discarded, leaving behind a mature RISC carrying the mature, single stranded miRNA. The miRNA remains part of the RISC as it silences the expression of its target genes. While this is the canonical pathway for miRNA biogenesis, a variety of others have been discovered. These include Drosha-independent pathways (such as the mirtron pathway, snoRNA-derived pathway, and shRNA-derived pathway) and Dicer-independent pathways (such as one that relies on AGO for cleavage, and another which is dependent on tRNaseZ).

[0043] The term “miRBase”, as used herein, refers to a well-established repository of validated miRNAs. The miRBase (www.mirbase.org) is a searchable database of published miRNA sequences and annotation. Each entry in the miRBase Sequence database represents a predicted hairpin portion of a miRNA transcript (termed mir in the database), with information on the location and sequence of the mature miRNA sequence (termed miR). Both hairpin and mature sequences are available for searching and browsing, and entries can also be retrieved by name, keyword, references and annotation. All sequence and annotation data are also available for download.

[0044] The miRNAs described herein have a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 19, a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, or still even more preferably at least 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto.

[0045] Residues in two or more polynucleotides are said to “correspond” to each other if the residues occupy an analogous position in the polynucleotide structures. It is well known in the art that analogous positions in two or more polynucleotides can be determined by aligning the polynucleotide sequences based on nucleic acid sequence or structural similarities. Such alignment tools are well known to the person skilled in the art and can be, for example, obtained on the World Wide Web, for example, ClustalW or Align using standard settings, preferably for Align EMBOSS: rneedle, Matrix: Blosum62, Gap Open 10.0, Gap Extend 0.5. The term “disease”, as used herein, refers to an abnormal condition that affects the body of an individual. A disease is often construed as a medical condition associated with specific symptoms and signs. In humans, the term “disease” is often used more broadly to refer to any condition that causes pain, dysfunction, distress, social problems, or death to the individual afflicted, or similar problems for those in contact with the individual. In this broader sense, it sometimes includes injuries, disabilities, disorders, syndromes, infections, deviant behaviors, and atypical variations of structure and function, while in other contexts and for other purposes these may be considered distinguishable categories. Diseases usually affect individuals not only physically, but also emotionally, as contracting and living with many diseases can alter one’s perspective on life, and one’s personality.

[0046] The term “cancer”, as used herein, refers to or describes a physiological condition in an individual that is typically characterized by unregulated cell growth. The cancer specifically referred to herein is lung cancer.

[0047] In the context of the present invention, the term “lung cancer” refers to a disease which consists of uncontrolled cell growth in tissues of the lung. This growth may lead to metastasis, which is the invasion of adjacent tissue and infiltration beyond the lungs. Most primary lung cancers are carcinomas of the lung, derived from epithelial cells. Lung cancer is the most common cause of cancer-related death in men and women. The most common symptoms are shortness of breath, coughing (including coughing up blood), and weight loss. The lung cancer may be latestage lung cancer, in particular lung cancer of stage IV. The main types of lung cancer are nonsmall cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC). Preferably, lung cancer is NSCLC. More preferably, the lung cancer such as NSCLC is late / advanced stage lung cancer, e.g. lung cancer of stage IV.

[0048] The term “early-stage lung cancer”, as used herein, refers to lung cancer that is early in its growth. It has not grown deeply into nearby tissues. In addition, it has not spread to other parts of the body of a patient. No metastases have been formed. Specifically, early-stage lung cancer is lung cancer of stage I.

[0049] The term “late / advanced-stage lung cancer”, as used herein, refers to lung cancer that is progressed lung cancer. It has grown deeply into nearby tissues. In addition, it has spread to other parts of the body of a patient. Metastases have been formed. Specifically, locally advanced lung cancer is lung cancer of state III and late / advanced-stage lung cancer is lung cancer of stage IV.

[0050] Lung cancer can be staged as follows:

[0051] Stage I means that the cancer is small. It hasn’t spread to the lymph nodes or other distant organs. Stage I belongs to the early lung cancer stages. Stage I can be divided into IA and IB. Stage IA means the cancer is 3 cm or smaller. Stage IB means the cancer is between 3 cm and 4 cm. It might also be growing into structures such as: the main airway of the lung (main bronchus) or the membrane covering the lung (visceral pleura).

[0052] Stage II still belongs to the early lung cancer stages. Stage II can be divided into stage IIA and IIB. Part of the affected lung might have collapsed.

[0053] Stage IIA means that the cancer is between 4 cm and 5 cm in size but there are no cancer cells in any lymph nodes.

[0054] Stage IIB means that the cancer is up to 5 cm in size and there are cancer cells in the lymph nodes close to the affected lung. Alternatively, it is between 5 cm and 7 cm but there are no cancer cells in any lymph nodes. Alternatively, the cancer is not in any lymph nodes but has spread into one or more of the following areas: the chest wall (ribs, muscle or skin), the nerve close to the lung (the phrenic nerve), or the layers that cover the heart (mediastinal pleura and parietal pericardium). Alternatively, the cancer is less than 7 cm but there is more than one tumor in the same lobe of the lung.

[0055] Stage III can be divided into stage IIIA, IIIB and IIIC. It is sometimes called locally advanced lung cancer.

[0056] In stage IIIA, the cancer is up to 5cm in size and has spread to the lymph nodes in the center of the chest on the same side as the tumor. Alternatively, the cancer is between 5 cm and 7 cm and there is more than one tumor in the same lobe of the lung. Alternatively, the cancer has spread into one or more of the following areas just outside the lung: the chest wall (ribs, muscle or skin), the nerve close to the lung (the phrenic nerve), the layers that cover the heart (mediastinal pleura and parietal pericardium), or lymph nodes in the lung or close to the lung. Alternatively, the cancer is larger than 7 cm. It hasn't spread into lymph nodes but has spread into one or more of the following areas: the muscle under the lung (diaphragm), the center area of the chest (mediastinum), the heart, a main blood vessel, the wind pipe (trachea), the nerve that goes to the voice box (larynx), the food pipe (oesophagus), a spinal bone, or the area where the wind pipe divides (the carina). Alternatively, the cancer is in more than one lobe of the same lung and there might also be cancer cells in lymph nodes close to the affected lung.

[0057] Stage IIIB can also mean different things. The cancer is less than 5 cm and has spread into lymph nodes in one of these places: the opposite side of the chest from the affected lung, the neck, or above the collarbone. Alternatively, the cancer is between 5 cm to 7 cm and has spread into lymph nodes in the center of the chest. Alternatively, the cancer is any size, has spread into lymph nodes in the center of the chest, and has spread into one or more of the following areas: the chest wall, the muscle under the lung (diaphragm), or the layers that cover the heart (mediastinal pleura and parietal pericardium). Alternatively, the cancer has spread into the lymph nodes in the center of the chest. The lung tumor is more than 7 cm or it has spread into a major structure in your chest such as: the heart, the wind pipe (trachea), the food pipe (oesophagus), or a main blood vessel.

[0058] Stage IIIC means the cancer is between 5c m and 7 cm in size or has spread into one or more of the following: the nerve close to the lung (phrenic nerve) or the covering of the heart (parietal pericardium) and it has spread into lymph nodes: in the center of the chest on the opposite side from the affected lung or at the top of the lung on the same side or opposite side or above the collar bone. Alternatively, there is more than one tumor in a different lobe of the same lung. Alternatively, stage IIIC can mean the cancer is bigger than 7 cm or it has spread into one of the following: the muscle under the lung (the diaphragm), the center of the chest (mediastinum), the heart, a major blood vessel, the wind pipe (trachea), the nerve going to the voice box (the recurrent laryngeal nerve), the food pipe (oesophagus), a spinal bone, or the area where the windpipe divides (the carina) and it has spread into lymph nodes: in the center of the chest on the opposite side from the affected lung or at the top of the lung on the same side or opposite side or above the collar bone. Alternatively, there are tumors in more than one lobe of the lung.

[0059] Stage IV means that lung cancer has spread. It can be designated as advanced lung cancer. It is divided into stage IVA and IVB.

[0060] Stage IVA can mean any of the following: there is cancer in both lungs, the cancer is in the covering of the lung (the pleura) or the covering of the heart (pericardium), or there is fluid around the lungs or the heart that contains cancer cells. Alternatively, it can mean that there is a single area of cancer that has spread outside the chest to a lymph node or to an organ such as the liver or bone.

[0061] Stage IVB means that the cancer has spread to several areas in one or more organs.

[0062] The term “tumor”, as used herein, refers to a lesion and neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues resulting in abnormal tissue growth.

[0063] The term “therapeutic treatment / therapy”, as used herein, relates to any treatment / therapy which improves the health status and / or prolongs (increases) the lifespan of a patient. Said treatment / therapy may eliminate the disease in a patient, arrest, inhibit, or slow the development of a disease in a patient, decrease the frequency or severity of symptoms in a patient, and / or decrease the recurrence in a patient who currently has or who previously has had a disease.

[0064] As used herein, the term “lung cancer therapy” refers to any protocol, method, and / or agent that can be used in the prevention, management, treatment, and / or amelioration of lung cancer cancer. In particular, the term “lung cancer therapy”, as used herein, means accomplishing one or more of the following: (i) tumor growth inhibition and / or tumor cell death, (ii) reduction of tumor marker(s), (iii) reduction of tumor lesions and metastases, (iv) reduction of tumor burden as evidenced by imaging studies (e.g. computer tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), etc.), and (v) reduction of tumor burden as evidenced by clinical appraisal or self-report by the patient. Specifically, lung cancer therapy includes, but is not limited to, drug therapy, supportive therapy, and / or other therapy useful in the prevention, management, treatment, and / or amelioration of lung cancer known to one of skill in the art, such as medical personnel. More specifically, lung cancer therapy includes, but is not limited to, immunotherapy, chemotherapy, immunochemotherapy, radiation therapy, vaccination therapy, stem cell therapy, anti-hormonal therapy, immunosuppressive therapy, antibody therapy, and / or surgical therapy. Even more specifically, the lung cancer therapy is immunotherapy or immunochemotherapy .

[0065] The term “chemotherapy”, as used herein, relates to a type of cancer treatment that uses one or more anti-cancer drugs, also known as chemotherapeutic agents, as part of a standardized chemotherapy regimen. Chemotherapy may be given with a curative intent (which preferably involves combinations of drugs), or it may aim to prolong life or to reduce symptoms (palliative chemotherapy). Preferably, chemotherapy is platinum doublet chemotherapy.

[0066] The term “chemotherapeutic agent”, as used herein, refers to any agent which directly or indirectly inhibits the uncontrolled growth and proliferation of cancer cells. The chemotherapeutic agent includes, but is not limited to, an alkylating agent, an antimetabolite, folinic acid, a folate antagonist, a mitotic inhibitor, an anthracycline, a topoisomerase inhibitor, an antibody, a signal transduction inhibitor, an inhibitor of angiogenesis, and / or an inhibitor of histone deacetylase. Preferably, the chemotherapeutic agent is a platinum doublet, Cisplatin (CDDP), Carboplatin (CBDCA), or Nedaplatin (CDGP).

[0067] The term “radiation therapy”, as used herein, relates to a type of cancer treatment using ionizing radiation to control or kill cancerous / malignant cells. Ionizing radiation is normally delivered by a linear accelerator. Radiation therapy may be curative in several types of cancer if they are localized to one area of the body. It may also be used as part of adjuvant therapy, to prevent tumor recurrence after surgery to remove a primary malignant tumor. Radiation therapy is synergistic with chemotherapy, and can be used before, during, and after chemotherapy in susceptible cancers.

[0068] The term “immunotherapy” refers to any therapy in which one or more components of a human’s or animal’s immune system is (are) deliberately modulated in order to directly or indirectly achieve some therapeutic benefit, including systemic and / or local effects, and preventative and / or curative effects. Immunotherapy can involve administering one or more immunotherapeutic drugs or agents, either alone or in any combination, to a human or animal subject by any route (e.g. orally, intravenously, dermally, by injection, by inhalation, etc.), whether systemically, locally or both. Immunotherapy can involve provoking, increasing, decreasing, halting, preventing, blocking or otherwise modulating the production of cytokines, and / or activating or deactivating cytokines or immune cells, and / or modulating the levels of immune cells, and / or delivering one or more therapeutic or diagnostic substances to a particular location in the body or to a particular type of cell or tissue, and / or destroying cells or tissue. Immunotherapy can be used to achieve local effects, systemic effects, or a combination of both. Immunotherapy can also be used to reduce or eliminate side effects that may have been caused by other anti -cancer therapies.

[0069] Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress an immune response are classified as suppression immunotherapies.

[0070] Antitumor immunotherapy has broad potential and can be used to treat many different types of advanced- stage cancer owing to the durable and robust responses it elicits across a diverse spectrum of malignancies.

[0071] Immunotherapy encompasses the administration of an immunotherapeutic agent.

[0072] The term “immunochemotherapy”, as used herein, refers to the combination use of immunotherapy and chemotherapy in the treatment or control of a disease such as cancer.

[0073] The term “immunotherapeutic agent”, as used herein, refers to any drug, compound, or biologic that indirectly or directly restores, enhances, stimulates, or increases the body's immune response against cancer cells and / or that decreases the side effects of other anticancer therapies. Examples of common immunotherapeutic agents known in the art include, but are not limited to, checkpoint inhibitors, cytokines, cancer vaccines, antibodies such as monoclonal antibodies, and / or non-cytokine adjuvants. Alternatively, or additionally, the immunotherapeutic treatment comprises the administration of immune cells (e.g. T cells, NK, cells, dendritic cells, B cells, etc.) to the patient. Especially, said immune cells are antigen-presenting cells and / or chimeric antigen receptor T cells.

[0074] Immunotherapeutic agents can be non-specific, i.e. boost the immune system generally so that the human body becomes more effective in fighting the growth and / or spread of cancer cells, or they can be specific, i.e. targeted to the cancer cells themselves. Immunotherapy regimens may combine the use of non-specific and specific immunotherapeutic agents.

[0075] Non-specific immunotherapeutic agents are substances that stimulate or indirectly improve the immune system. Non-specific immunotherapeutic agents have been used alone as a main therapy for the treatment of cancer, as well as in addition to a main therapy, in which case the non-specific immunotherapeutic agent functions as an adjuvant to enhance the effectiveness of other therapies (e.g. cancer vaccines). Non-specific immunotherapeutic agents can also function in this latter context to reduce the side effects of other therapies, for example, bone marrow suppression induced by certain chemotherapeutic agents. Non-specific immunotherapeutic agents can act on key immune system cells and cause secondary responses, such as increased production of cytokines and immunoglobulins. Alternatively, the agents can themselves comprise cytokines. Non-specific immunotherapeutic agents are generally classified as cytokines or non-cytokine adjuvants. Several cytokines have found application in the treatment of cancer either as general non-specific immunotherapies designed to boost the immune system, or as adjuvants provided with other therapies. Suitable cytokines include, but are not limited to, interferons, interleukins, and / or colony-stimulating factors. Interferons (IFNs) include, for example, IFN-alpha (IFN-a), IFN-beta (IFN-P), and / or IFN-gamma (IFN-y). Interleukins include, for example, IL-2, IL-4, IL- 11, and / or IL-12. Colony-stimulating factors (CSFs) include, for example, granulocyte colony stimulating factor (G-CSF or filgrastim), granulocyte-macrophage colony stimulating factor (GM- CSF or sargramostim), and / or erythropoietin (epoetin alfa, darbopoietin).

[0076] In addition, immunotherapeutic agents can be active, i.e. stimulate the body's own immune response including humoral and cellular immune responses, or they can be passive, i.e. comprise immune system components such as antibodies, effector immune cells, antigen-presenting cells etc. that were generated external to the body. Passive immunotherapy involves the use of one or more monoclonal antibodies that are specific for a particular antigen found on the surface of a cancer cell or immune cell or that are specific for a particular cell growth factor. Monoclonal antibodies may be used in the treatment of cancer in a number of ways, for example, to enhance a subject's immune response to a specific type of cancer, to interfere with the growth of cancer cells by targeting specific cell growth factors, such as those involved in angiogenesis, or by enhancing the delivery of other anticancer agents to cancer cells when linked or conjugated to agents such as chemotherapeutic agents, radioactive particles or toxins.

[0077] It is known that tumors evade immune-mediated recognition through multiple mechanisms of immune escape. On chronic tumor antigen exposure, T cells become dysfunctional / exhausted and upregulate various checkpoint inhibitory receptors (IRs) that limit T cells’ survival and function. Thus, immunotherapy particularly encompasses an approach of treating cancer by stimulating T- cell function and preventing T-cell death. This approach is based on the striking finding that stimulation of T-cell function with compounds that block or activate regulatory receptors, e.g. antibodies, can be sufficient to cause the regression of tumors. Checkpoint blockade is, for example, a method by which T-cell function is stimulated with compounds that block their inhibitory receptors, whereas T-cell co-stimulation is a method that aims at activating T-cell function with compounds that target their stimulatory receptors. The immunotherapy described herein specifically encompasses the administration of a checkpoint inhibitor. In one embodiment of the present invention, the immunotherapeutic agent is a PD-1 / PD-L1 inhibitor. In one preferred embodiment of the present invention, the PD-1 / PD-L1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplima, durvalumab, and atezolizumab. In this respect, it should be noted that pembrolizumab and nivolumab specifically target the PD-1 protein, while atezolizumab, durvalumab, and avelumab specifically target the PD- L1 ligand. PD-1 means programmed cell-death protein 1 and PD-L1 means programmed cell-death ligand 1. PD-1 is the receptor for the ligand PD-L1.

[0078] As used herein, the term “immune checkpoint inhibitor” refers to any compound that totally or partially reduces, inhibits, interferes with or modulates one or more immune checkpoint proteins. Inhibition includes reduction of function and full blockade. Several immune checkpoint inhibitors are known and in analogy of these known immune checkpoint protein inhibitors, alternative immune checkpoint inhibitors may be developed in the (near) future. The immune checkpoint inhibitor includes, but is not limited to, a peptide, an antibody, a nucleic acid molecule, and / or a small molecule. Preferably, the immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting programmed cell-death protein 1 (PD-1), programmed celldeath ligand 1 (PD-L1), programmed cell-death ligand 2 (PD-L2), cytotoxic T-lymphocyte- associated Protein 4 (CTLA-4), LAG3 (Lymphocyte Activation Gene-3), TIGIT (T cell immunoreceptor with immunoglobulin and ITIM domain), CD73 (an ecto-5 '-nucleotidase (NT5E)), and intrinsic checkpoint blockades. More preferably, the inhibitor targeting PD-L1 is selected from the group consisting of atezolizumab, durvalumab, and avelumab and the inhibitor targeting PD-1 is selected from the group consisting of pembrolizumab and nivolumab.

[0079] The term “prediction”, as used herein, refers to a prognosis whether a patient will respond to a cancer therapy or achieve a clinical outcome in response to a cancer therapy. In some embodiments, a positive response to cancer therapy is predicted. In some alternative embodiments, a negative response to cancer therapy is predicted. The prediction of a response of a patient to a cancer therapy is usually carried out before treating the patient with the cancer therapy. If the predicted outcome is positive, the patient will receive cancer therapy. If the predicted outcome is negative, the patient will receive no cancer therapy or alternative cancer therapy. For example, if it is predicted that the patient suffering from cancer will not respond to immunotherapy, the patient may be treated with another therapy than immunotherapy such as radiotherapy and / or chemotherapy. However, the prediction of a response to a cancer therapy may also be carried out after the start of a cancer therapy. If the predicted outcome is positive, the cancer therapy is continued. If the predicted outcome is negative, the cancer therapy is changed or stopped. Specifically, the therapy is lung cancer therapy. In particular, the method of predicting a response to lung cancer therapy of a patient suffering from lung cancer, as described herein, is suitable for discriminating patients who will respond to lung cancer therapy from patients who will not respond to lung cancer therapy. Typically, the characterization of a patient as responder or non-responder can be performed by reference to a standard or training set. The standard may be the profile of subjects who are known to be responders or non-responders or alternatively may be a numerical value / reference level. Predetermined standards may be provided in any suitable form, such as a printed list or diagram, computer software program, mathematical algorithm, or other media. When the patient is predicted to be a responder, the physician can take the decision to administer the lung cancer therapy, e.g. immunotherapy, to the patient. When the patient is predicted as being a non-responder, the physician can take the decision not to administer lung cancer therapy, e.g. immunotherapy, but instead administer an alternative lung cancer therapy, e.g. immunochemotherapy. In this case, any further adverse sides effects may be avoided.

[0080] The present inventors have identified new miRNA biomarkers allowing the prediction of a response to lung cancer immunotherapy of a patient suffering from lung cancer. Said miRNAs have a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 19, a fragment thereof, and a sequence having at least 80% sequence identity thereto.

[0081] The term “response”, as used herein, refers to an alteration in a patient’s condition that occurs because of or correlates with cancer treatment. In some embodiments, a response is or comprises a beneficial response. In some embodiments, a beneficial response may include stabilization of the condition (e.g. prevention or delay of deterioration expected or typically observed to occur in the absence of treatment), amelioration (e.g. reduction in frequency and / or intensity) of one or more symptoms of the condition, and / or improvement in the prospects for cure of the condition, etc. Particularly, the cancer is lung cancer and the response is the response of the patient suffering from lung cancer to immunotherapy.

[0082] Specifically, a cancer patient or (control) subject suffering from cancer who has been treated with a cancer therapy is considered to “respond”, have a “response”, have “a positive response” or be “responsive” to the cancer therapy, if the individual shows evidence of an anti-cancer effect according to an art-accepted set of objective criteria or reasonable modification thereof, including a clinically significant benefit, such as the prevention, or reduction of severity, of symptoms, or a slowing of the progression of the cancer. It will be understood that the aforementioned terms may also be used in regard to cancer. Specifically, the cancer patient or (control) subject suffers from lung cancer and the lung cancer therapy is immunotherapy.

[0083] A variety of different objective criteria for assessing the effect of anti-cancer treatments on cancers are known in the art. The World Health Organization (WHO) criteria (Miller, A B, et al., Cancer 1981; 47(l):207-14) and modified versions thereof, the Response Evaluation Criteria in Solid Tumors (RECIST) (Therasse P, et al., J Natl Cancer Inst 2000; 92:205-16), and revised version thereof (Eisenhauer E A, New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45(2):228-47) are sets of objective criteria, based on imaging measurements of the size and number of tumor lesions and detection of new lesions, e.g. from computed tomography (CT), magnetic resonance imaging (MRI), or conventional radiographs. Dimensions of selected lesions (referred to as target lesions) are used to calculate the change in tumor burden between images from different time points. The calculated response is then categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). CR is the complete disappearance of tumor (-100%), and PD is an increase of about 20%-25% or greater (depending on criteriaeria) and / or the appearance of new lesions. PR is a significant reduction (of at least about 30%) in size of tumor lesions (without emergence of new lesions) but less than a complete response. SD is in between PR and PD.

[0084] However, in some cases, anatomic imaging alone may be not sufficient. For example, meaningful tumor responses to immunotherapy, e.g. with immune checkpoint inhibitors, may occur after a delay, in some cases following the above described WHO or RECIST criteria. Immune-related response criteria (irRC) were defined to capture additional favorable response patterns observed with immune therapies (Wolchok, J D, et al. (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin. Care Res. 15, 7412-7420.). The developers of the irRC based their criteria on the WHO Criteria but modified it: In the irRC, tumor burden is measured by combining 'index' lesions with new lesions. Ordinarily tumor burden would be measured simply with a limited number of 'index' lesions (that is, the largest identifiable lesions) at baseline, with new lesions identified at subsequent timepoints counting as 'Progressive Disease'. In the irRC, by contrast, new lesions are simply a change in tumor burden. The irRC retained the bidirectional measurement of lesions that had originally been laid down in the WHO Criteria. In the irRC, an immune-related Complete Response (irCR) is the disappearance of all lesions, measured or unmeasured, and no new lesions; an immune-related Partial Response (irPR) is a 50% drop in tumor burden from baseline as defined by the irRC; and immune-related Progressive Disease (irPD) is a 25% increase in tumor burden from the lowest level recorded. Everything else is considered immune-related Stable Disease (irSD). The thinking here is that even if tumor burden is rising, the immune system is likely to 'kick in' some months after first dosing and lead to an eventual decline in tumor burden for many patients. The 25% threshold allows this apparent delay to be accounted for.

[0085] The irRC are applicable to immune checkpoint inhibitors and other immunotherapeutic agents. One of ordinary skill in the art will appreciate that additional response criteria are known in the art, which take into consideration various factors such as changes in the degree of tumor arterial enhancement and / or tumor density as indicators of tumor viable tissue, with decreased arterial enhancement and decreased tumor density being indicators of reduced viable tumor tissue (e.g. due to tumor necrosis).

[0086] By contrast, a cancer patient or (control) subject suffering from cancer who has been treated with a cancer therapy is considered “not to respond”, “to lack a response”, to have “a negative response” or be “non-responsive” to the cancer therapy, if the therapy provides no clinically significant benefit, such as the prevention, or reduction of severity, of symptoms, or increases the rate of progression of the cancer. Specifically, the cancer patient or (control) subject suffers from lung cancer and the lung cancer therapy is immunotherapy.

[0087] The term “prognosis”, as used herein, means the likelihood of recovery from a disease or the prediction of the probable development or outcome of a disease, including but not limited to, predicting the survival, in particular overall survival, of the patient, the likelihood of reappearance of cancer in a patient, and the likelihood of tumor metastasis.

[0088] The term “survival prognosis”, as used herein, refers to the prediction of the likelihood / probability of death of a patient suffering from cancer. In particular, the term “providing a survival prognosis to a patient suffering from cancer”, as used herein, means determining whether the patient has a good prognosis (low probability of death) or a poor prognosis (high probability of death) with respect to cancer. The patient is preferably a patient to whom cancer therapy will be, is, or has been administered. The survival prognosis may be defined as the predicted overall survival (OS) and / or survival at 2- or 5-years follow-up. A survival chance / probability can be expressed in a value of between 0% and 100%, where 100 % is a high chance / probability of surviving an indicated time (good prognosis) and 0% is a low probability / chance of surviving an indicated time (poor prognosis). The indicated time may be (at least / at most) 3 months, 6 months, 9 months, 12 months (1 year), 2 years, 3 years, 4 years, 5 years,

[0089] 6 years, 7 years, 8 years, 9 years, or 10 years.

[0090] Specifically, a good survival prognosis is associated with a high chance / probability of surviving for a certain time. More specifically, a patient having a good prognosis has a chance / probability of greater than 50%, preferably of greater than 60%, more preferably of greater than 70%, even more preferably of greater than 80%, still even more preferably of greater than 90%, or most preferably of greater than 95% to survive a certain time. A certain time is preferably a time of (at least) 3 months, 6 months, 9 months, 12 months (1 year), 2 years, 3 years, 4 years, 5 years, 6 years,

[0091] 7 years, 8 years, 9 years, or 10 years.

[0092] Specifically, a poor survival prognosis is associated with a low chance / probability of surviving a certain time. More specifically, the patient having a low prognosis has a chance / probability of equal to or lower than 50%, preferably lower 40%, more preferably of lower than 30%, even more preferably of lower than 20%, still even more preferably of lower than 10%, and most preferably of lower than 5 % to survive a certain time. A certain time is preferably a time of (at most) 3 months, 6 months, 9 months, 12 months (1 year), 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years.

[0093] Alternatively, it is predicted that the patient suffering from cancer has a short or long survival time. The term “short survival time”, e.g. (at most) 3 months, 6 months, 9 months, or 12 months (1 year), indicates that the patient will have a survival time that will be lower than the median (or mean) observed in the general population of (control) subjects suffering from said cancer. When the patient has a short survival time, it means that the patient has a “poor prognosis”. Inversely, the term “long survival time”, e.g. (at least) 2 years, at least 5 years, at least 8 years, or at least 10 years, indicates that the patient will have a survival time that will be higher than the median (or mean) observed in the general population of (control) subjects suffering from said cancer. When the patient has a long survival time, it means that the patient has a “good prognosis”. For example, a patient who will have a predicted short survival time will not be alive at a 2- or 5-years followup anymore, while a patient who will have a predicted long survival time will still be alive at 2- or 5-years follow up.

[0094] Those of skill in the art will recognize that an “overall survival (OS)” time is generally based on and expressed as the percentage of people who survive a certain type of cancer for an indicated time. Cancer statistics often use an overall 2-year or 5-year survival rate. In a specific embodiment, patients having a good prognosis will survive a time of 2-years or 5-years. Patients having a poor prognosis will not survive a time of 2-years or 5-years.

[0095] The method of providing a survival prognosis to a patient suffering from cancer is a valuable tool in predicting whether (overall or long-term) survival of the individual, e.g. following therapy, is likely. This method can also be used clinically to make treatment decisions by choosing the most appropriate treatment modalities for any patient suffering from cancer. The treatment modalities may be selected from the group consisting of immunotherapy or immunochemotherapy.

[0096] The Kaplan-Meier analysis is the recommended statistical technique for survival analysis. It is applied by analyzing the distribution of patient survival times following their recruitment to a study. The analysis expresses these in terms of the proportion of patients still alive up to a given time following recruitment. In graphical terms, a plot of the proportion of patients surviving against time has a characteristic decline (often exponential), the steepness of the curve indicating the efficacy of the treatment being investigated. The shallower the survival curve, the more effective the treatment. Kaplan-Meier analysis can be used to test the statistical significance of differences between the survival curves associated with two different treatments. The present inventors have identified with this kind of analysis new miRNA biomarkers allowing the provision of a survival prognosis to a patient suffering from lung cancer. These miRNAs have a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 19, a fragment thereof, and a sequence having at least 80% sequence identity thereto. The present inventors have found that said miRNAs are discriminators of lung cancer patients regarding their survival time. They are prognostic indicators allowing to stratify / classify high and low risk patients. In the context of the present invention, it may be decided that low-risk patients suffering from lung cancer may be treated with immunotherapy such as PD-(L)1 inhibitor immunotherapy alone, while high-risk patients suffering from lung cancer may require immunotherapy such as PD-(L)1 inhibitor immunotherapy with additional chemotherapy.

[0097] The term “PD-L1 Tumor Proportion Score (TPS)”, as used herein, refers to the percentage of PD-L1 positive tumor cells out of all vital tumor cells. Thus, in case of determining the PD-L1 Tumor Proportion Score (TPS), all tumor cells that stain membrane-bound positive for PD-L1 are counted and divided by the total number of tumor cells (percentage value of positive tumor cells). The PD-L1 TPS may be a decision criterion in the selection of a treatment regimen. Particularly, the treatment regimen of a patient suffering from cancer such as lung cancer having a PD-L1 TPS of > 50% may differ from the treatment regimen of a patient suffering from cancer such as lung cancer having a PD-L1 TPS of < 1%, and / or from the treatment regimen of a patient suffering from cancer such as lung cancer having a PD-L1 TPS of between 1 to 49%.

[0098] In late-stage lung cancer such as stage IV NSCLC, for example, patients having a PD-L1 TPS of < 1% are usually treated with chemotherapy and patients having a PD-L1 TPS of between 1 to 49% are usually treated with immunochemotherapy.

[0099] Currently, both immunotherapy and immunochemotherapy are recommended as treatment options for patients with late-stage lung cancer such as stage IV NSCLC and PD-L1 TPS > 50%. Some of the approximately 60% of patients who will fail to respond to immunotherapy may benefit from immunochemotherapy, as the chemotherapy component can sensitise the tumour to concurrent immunotherapy. This additional therapeutic burden, however, comes at the cost of increased frequency and severity of toxicity, with grade 3-4 adverse events noted in approximately 70% of patients. The choice of either immunotherapy or immunochemotherapy remains largely based on clinical judgement. Factors that may be considered include general health status, number of metastatic sites and disease aggressiveness. However, the optimal therapy is still often unclear. The present inventors have solved this problem. They have defined a (miRisk) cut-off score which allows to identify a patient who will benefit from treatment with immunochemotherapy as opposed to immunotherapy. In this way, a patient only must undergo immunotherapy in combination with chemotherapy and the associated high physical stress if the patient really needs it. This (miRisk) cut-off score, thus, allows treatment decisions as a complementary diagnostic.

[0100] The term “patient”, as used herein, refers to any individual suffering from cancer for whom it is desired to know whether she or he will respond to cancer therapy. It may be predicted whether the patient suffering from cancer will respond to cancer therapy or will not respond to cancer therapy. If the patient is identified as a patient who will respond to cancer therapy, the patient is assigned to said cancer therapy. If the patient is identified as a patient who will not respond to cancer therapy, the patient is not assigned to said cancer therapy but may be assigned to an alternative cancer therapy.

[0101] The term “patient”, as used herein, also refers to any individual suffering from cancer for whom a survival prognosis is desired to know. It may be determined that the patient suffering from cancer has a good or poor survival prognosis.

[0102] The term “patient”, as used herein, also refers to any individual suffering from cancer for whom it is desired to know how cancer develops in the patient. This patient may be monitored, e.g. in the form of a longitudinal monitoring. Thus, the course of cancer (particularly after or during treatment) may be observed in the patient.

[0103] The term “patient”, as used herein, also refers to any individual suffering from cancer for whom it is desired to know whether the patient will (likely) benefit from immunotherapy or immunochemotherapy (i.e. patient selection / stratification).

[0104] The patient may be any mammal, including both a human and another mammal, e.g. an animal such as a rabbit, mouse, rat, or monkey. Human patients are particularly preferred.

[0105] Specifically, the cancer is lung cancer, and the lung cancer therapy is immunotherapy or immunochemotherapy .

[0106] The term “(control) subject”, as used herein, refers to an individual suffering from cancer who is a known responder or non-responder of cancer therapy. The term “(control) subject”, as used herein, also refers to an individual suffering from cancer having a known good or poor survival prognosis.

[0107] The (control) subject may be any mammal, including both a human and another mammal, e.g. an animal such as a rabbit, mouse, rat, or monkey. Human control subjects are particularly preferred. Specifically, the cancer is lung cancer, and the lung cancer therapy is immunotherapy or immunochemotherapy .

[0108] The term “blood sample”, as used herein, encompasses whole blood or a blood fraction. Preferably, the blood fraction is selected from the group consisting of a blood cell fraction, plasma, and serum. In particular, the blood fraction is selected from the group consisting of a blood cell fraction and plasma or serum. For example, the blood cell fraction encompasses erythrocytes, leukocytes, and / or thrombocytes. More preferably, the blood cell fraction is a fraction of leukocytes. Specifically, leukocytes encompass myeloid cells and / or lymphocytes. More specifically, the myeloid cells are selected from the group consisting of granulocytes, monocytes, macrophages, and dendritic cells (DCs), or are a combination thereof.

[0109] It is preferred that the blood sample has a volume of between 0.01 and 20 ml, more preferably of between 0.1 and 10 ml, even more preferably of between 0.5 and 8 ml and most preferably of between 1 and 5 ml.

[0110] Said blood sample may be provided by removing blood from a patient or (control) subject but may also be provided by using a previously isolated sample. For example, a blood sample may be taken from a patient or (control) subject by conventional blood collection techniques.

[0111] The blood sample may further be obtained from a patient or (control) subject prior to the initiation of a therapeutic treatment, during the therapeutic treatment, and / or after the therapeutic treatment. If the blood sample is obtained from at least one (control) subject, e.g. from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 500, or 1,000 (control) subject(s), it is designated as “reference blood sample”. Preferably, the reference blood sample is from the same source than the blood sample of the patient to be tested, e.g. both are whole blood samples or blood cell fractions. It is further preferred that both are from the same species, e.g. from a human. It is also (alternatively or additionally) preferred that the measurements of the reference blood sample of the (control) subject and the blood sample of the patient to be tested are identical, e.g. both have an identical volume. It is particularly preferred that the reference blood sample and the blood sample are from (control) subjects / patients of the same sex and similar age.

[0112] The whole blood sample may be collected by means of a blood collection tube. It is, for example, collected in a PAXgene Blood RNA tube, in a Tempus Blood RNA tube, in an EDTA-tube, in a Na-citrate tube, Heparin-tube, or in an ACD-tube (Acid citrate dextrose). Alternatively, the whole blood sample may be collected in a blood collection tube containing cell-free nucleic acid stabilizing chemical agents, such as glutaraldehyde, formaldehyde, or similar (e.g. Streck cfRNA BCT tube, Streck cfDNA BCT tube), and others, or cellular crowding agents, such as polyethyleneglycol (PEG) (e.g. Norgen cfDNA / cfRNA preservation tube), and others.

[0113] The whole blood sample may also be collected by means of a bloodspot technique, e.g. using a Mitra Microsampling Device. This technique requires smaller sample volumes, typically 45-60 pl for humans or less. For example, the whole blood may be extracted from the patient via a finger prick with a needle or lancet. Thus, the whole blood sample may have the form of a blood drop. Said blood drop is then placed on an absorbent probe, e.g. a hydrophilic polymeric material such as cellulose, which can absorb the whole blood. Once sampling is complete, the blood spot is dried in air before transferring or mailing to labs for processing. Because the blood is dried, it is not considered hazardous. Thus, no special precautions need be taken in handling or shipping. Once at the analysis site, the desired components, e.g. miRNAs, are extracted from the dried blood spots into a supernatant which is then further analyzed. This technique is suitable for monitoring patients having cancer at home (on a home care / home sampling basis) or for screening purposes.

[0114] In the methods described herein, the level of a miRNA is determined in a blood sample of a patient. The term “level”, as used herein, refers to an amount (measured for example in grams, mole, or ion counts) or concentration (e.g. absolute or relative concentration, e.g. reads per million (RPM) or NGS counts) of the miRNA. The term “level”, as used herein, also comprises scaled, normalized, or scaled and normalized amounts or values (e.g. RPM). In particular, the level of the miRNA is determined by sequencing, preferably next generation sequencing (e.g. ABI SOLID, Illumina Genome Analyzer, Roche 454 GS FL, BGISEQ), nucleic acid hybridization (e.g. microarray or beads), nucleic acid amplification (e.g. PCR, RT-PCR, qRT-PCR, or high- throughput RT-PCR), polymerase extension, mass spectrometry, flow cytometry (e.g. LUMINEX), or any combination thereof. Specifically, the level of the miRNA is the expression level of said miRNA.

[0115] Those of skill in the art will appreciate that, in many embodiments described herein, the determined miRNA level is compared with an appropriate miRNA “reference level”. Specifically, the level of the miRNA is compared to a reference level of said miRNA. More specifically, the reference level of a miRNA is determined in a blood sample of (control) subjects. Even more specifically, the reference level is determined empirically by measuring a number of reference blood samples from subjects suffering from cancer, specifically lung cancer, known to be responders or non-responders to cancer therapy, specifically lung cancer therapy, or by measuring a number of reference blood samples from subjects suffering from cancer, specifically lung cancer, having a known good or poor survival prognosis. Typically, as would be understood by those skilled in the art, the reference level is determined under conditions comparable to those utilized to determine or analyze the miRNA level in a blood sample of a patient.

[0116] The reference level may also be a cut-off or threshold level of the miRNA. Typically, a cut-off or threshold level can be determined experimentally, empirically, or theoretically. A cut-off or threshold level can also be arbitrarily selected based upon the existing experimental and / or clinical conditions, as would be recognized by a person of ordinary skilled in the art. The cut-off or threshold level must be determined to obtain the optimal sensitivity and specificity according to the function of the test and the benefit / risk balance (clinical consequences of false positive and false negative). Typically, the optimal sensitivity and specificity (and so the threshold level) can be determined using a Receiver Operating Characteristic (ROC) curve based on experimental data. For example, after determining the miRNA level in a group of a reference, one can use algorithmic analysis for the statistic treatment of the measured miRNA level in samples to be tested, and thus obtain a classification standard having significance for sample classification. The full name of ROC curve is receiver operator characteristic curve, which is also known as receiver operation characteristic curve. It is mainly used for clinical biomarker tests. The ROC curve is a comprehensive indicator that reflects the continuous variables of true positive rate (sensitivity) and false positive rate (1 -specificity). It reveals the relationship between sensitivity and specificity with the image composition method. A series of different cut-off or threshold levels are set as continuous variables to calculate a series of sensitivity and specificity values. Then sensitivity is used as the vertical coordinate and specificity is used as the horizontal coordinate to draw a curve. The higher the area under the curve (AUC), the higher the accuracy of a prediction / prognosis / diagnosis. On the ROC curve, the point closest to the far upper left of the coordinate diagram is a critical point having both high sensitivity and high specificity values. The AUC value of the ROC curve is between 1.0 and 0.5. When AUC > 0.5, the predicted / prognosed / diagnosed result gets better and better as AUC approaches 1. When AUC is between 0.5 and 0.7, the accuracy is low. When AUC is between 0.7 and 0.8, the accuracy is moderate. When AUC is higher than 0.8, the accuracy is high. When AUC is higher than 0.9, the accuracy is very high.

[0117] The term “classifier”, as used herein, refers to a prediction / prognostic model which allows to distinguish between or characterize samples by classifying a given sample into a predetermined class based on certain characteristics of said sample. For example, a classification, as used herein, can predict with a relatively high sensitivity and specificity if a blood sample of a patient of unknown response prediction belongs to the class of one of two given classes: each class representing a predicted estimated response. The output may be given as a probability of belonging to either class of between 0-1. A classification, as used herein, is also capable of predicting with a relatively high sensitivity and specificity if a blood sample of a patient of unknown survival prognosis belongs to the class of one of two given classes: each class representing a predicted estimated survival. The output may be given as a probability of belonging to either class of between 0-1. Specifically, a classifier allows to distinguish responders to cancer therapy, specifically lung cancer therapy, from non-responders to cancer therapy, specifically lung cancer therapy. A classifier may also allow to distinguish patients having a poor survival prognosis from patients having a good survival prognosis. In addition, a classifier may also allow to distinguish whether the patient should be assigned to and / or treated with immunotherapy or immunochemotherapy. Especially, the cancer is lung cancer.

[0118] The term “pharmaceutically effective amount”, as used herein, refers to an amount which achieves a desired reaction or a desired effect alone or together with further doses. In case of the treatment of a particular disease, the desired reaction preferably relates to an inhibition of the course of the disease. This comprises slowing down the progress of the disease and interrupting or reversing the progress of the disease. The desired reaction in a treatment of a disease may also be a delay of the onset or a prevention of the onset of the disease. An effective amount described herein will depend on the condition to be treated, the severeness of the disease, the individual parameters of the patient, including age, physiological condition, size, and weight, the duration of treatment, the type of an accompanying therapy (if present), the specific route of administration, and similar factors. Accordingly, the doses may depend on various of such parameters. In case that a reaction in the patient is insufficient with an initial dose, higher doses (or effectively higher doses achieved by a different, more localized route of administration) may be used. The disease described herein is cancer, preferably lung cancer.

[0119] In the context of the present invention, the term “kit of parts (in short: kit)” is understood to be any combination of at least some of the components identified herein, which are combined, coexisting spatially, to a functional unit, and which can contain further components.

[0120] Embodiments of the invention

[0121] The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. Any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous, unless clearly indicated to the contrary.

[0122] The present inventors identified response and survival predictive miRNAs from whole blood for lung cancer therapy, specifically immunotherapy. These new miRNAs allow a quick and accurate clinical response prediction and survival prognosis in lung cancer diseases. Said miRNAs can, thus, be used as companion or complementary diagnostics in lung cancer therapy. In addition, these new miRNAs allow to select a patient suffering from lung cancer to benefit from immunochemotherapy or immunotherapy.

[0123] Thus, in a first aspect, the present invention relates to a (an) (in vitro) method of predicting a response to lung cancer immunotherapy of a patient suffering from lung cancer comprising the step of: determining the level of at least one miRNA(e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 miRNA(s)) in a blood sample of a patient suffering from lung cancer, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR- 125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto.

[0124] In one embodiment, at least one further miRNA (e.g. 1, 2, 3, 4, 5, or 6 miRNA(s)) having a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR- 150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto is determined in the above method.

[0125] Specifically, the level of at least one miRNA having

[0126] (i) a nucleotide sequence according to SEQ ID NO: 1 to SEQ ID NO: 19,

[0127] (ii) a nucleotide sequence that is a fragment of the nucleotide sequence according to (i), preferably, a nucleotide sequence that is a fragment which is between 1 and 12, more preferably between 1 and 8, and most preferably between 1 and 5 or 1 and 3, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, nucleotides shorter than the nucleotide sequence according to (i), or

[0128] (iii) a nucleotide sequence that has at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity to the nucleotide sequence according to (i) or nucleotide sequence fragment according to (ii) is determined in a blood sample of a patient suffering from lung cancer.

[0129] Preferably, the at least one miRNA whose level is determined in a blood sample of a patient suffering from lung cancer

[0130] (i) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 13 (hsa-miR- 23a-3p), SEQ ID NO: 12 (hsa-223-3p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 2 (hsa-miR-let-7f-5p), a fragment thereof, and a sequence having at least 80%, more preferably at least 85%, even more preferably at least 90%, and still even more preferably at least 95% or 99%, e.g. 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto,

[0131] (ii) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR- 223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), a fragment thereof, and a sequence having at least 80%, more preferably at least 85%, even more preferably at least 90%, and still even more preferably at least 95% or 99%, e.g. 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto,

[0132] (iii) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR- 223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a- 3p), and SEQ ID NO: 5 (hsa-miR-192-5p), a fragment thereof, and a sequence having at least 80%, more preferably at least 85%, even more preferably at least 90%, and still even more preferably at least 95% or 99%, e.g. 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto,

[0133] (iv) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR- 342-3 p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa- miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR- 199b-5p), and / or

[0134] (v) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR- 342-3 p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa- miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR-30e-3p).

[0135] More preferably, the miRNAs whose levels are determined in a blood sample of a patient suffering from lung cancer

[0136] (i) have a nucleotide sequence according to SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO:

[0137] 12 (hsa-223-3p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 2 (hsa-miR-let-7f-5p),

[0138] (ii) have a nucleotide sequence according to SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO:

[0139] 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), (iii) have a nucleotide sequence according to SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p),

[0140] (iv) have a nucleotide sequence according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa- miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 12 (hsa- miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR-199b-5p), and / or

[0141] (v) have a nucleotide sequence according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa- miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa- miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR-30e-3p).

[0142] It should be noted that in cases where the levels of 2 or more miRNAs are determined, said miRNAs are designated as miRNA set or signature.

[0143] The level of the at least one miRNA is associated with or correlated to response prediction. In one preferred embodiment, the level of the at least one miRNA is compared to a reference level of said at least one miRNA. In this case, the (in vitro) method of predicting a response to lung cancer immunotherapy of a patient suffering from lung cancer comprises the steps of:

[0144] (i) determining the level of at least one miRNA (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 miRNA(s)) in a blood sample of a patient suffering from lung cancer, and

[0145] (ii) comparing the level of the at least one miRNA (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 miRNA(s)) to a reference level of said at least one miRNA, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155- 5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto.

[0146] The level of at least one further miRNA (e.g. 1, 2, 3, 4, 5, or 6 miRNA(s)) having a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto may also be determined.

[0147] In particular, the reference level is the level of the at least one miRNA determined empirically by measuring a number of reference blood samples from subjects suffering from lung cancer who are non-responders to lung cancer immunotherapy. For example, the reference level is determined from at least 2, at least 10, at least 50, at least 100, at least 200, at least 300, at least 400, at least 500, at least 1000, at least 1500, at least 2000 at least 5000 reference samples from subjects suffering from lung cancer who are non-responders to lung cancer immunotherapy.

[0148] In one more preferred embodiment, the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 17, a fragment thereof, and a sequence having at least 80% sequence identity thereto below the reference level indicates that the patient will respond to lung cancer immunotherapy, or the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 15, SEQ ID NO: 18, SEQ ID NO: 19, a fragment thereof, and a sequence having at least 80% sequence identity thereto above the reference level indicates that the patient will respond to lung cancer immunotherapy.

[0149] Additionally, or alternatively, the reference level is the level of the at least one miRNA determined empirically by measuring a number of reference blood samples from subjects suffering from lung cancer who are responders to lung cancer immunotherapy. For example, the reference level is determined from at least 2, at least 10, at least 50, at least 100, at least 200, at least 300, at least 400, at least 500, at least 1000, at least 1500, at least 2000 at least 5000 reference samples from subjects suffering from lung cancer who are responders to lung cancer immunotherapy.

[0150] In one more preferred embodiment, the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 17, a fragment thereof, and a sequence having at least 80% sequence identity thereto above the reference level indicates that the patient will not respond to lung cancer immunotherapy, or the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 15, SEQ ID NO: 18, SEQ ID NO: 19, a fragment thereof, and a sequence having at least 80% sequence identity thereto below the reference level indicates that the patient will not respond to lung cancer immunotherapy.

[0151] It is practicable to take one reference blood sample per subject for analysis. Said reference level may be an average reference level. It may be determined by measuring reference levels of subjects and calculating the “average” value (e.g. mean, median or modal value) thereof. It is preferred that the reference blood sample is from the same source (e.g. whole blood or blood fraction) than the blood sample of the patient. It is further preferred that the reference level is of a subject of the same gender (e.g. female or male) and / or of a similar age / phase of life (e.g. adults or elderly) than the patient to be tested.

[0152] Preferably, the level of the at least one miRNA is at least 0.6-fold or 0.7-fold, more preferably at least 0.8-fold or 0.9-fold, even more preferably at least 1.2-fold, 1.5-fold, or 2.0-fold, and still even more preferably at least 3.0-fold or 4.0-fold below / above the reference level. For example, the level of the at least one miRNA is at least 0.6-fold, at least 0.7-fold, at least 0.8-fold, at least 0.9- fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, at least 3.0-fold, at least 3.1-fold, at least 3.2- fold, at least 3.3-fold, at least 3.4-fold, at least 3.5-fold, at least 3.6-fold, at least 3.7-fold, at least 3.8-fold, at least 3.9-fold, or at least 4.0-fold below / above the reference level.

[0153] In one (altemative / additional) preferred embodiment, the method further comprises the step of determining a score by summarizing the weighted levels of at least two miRNAs, e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 miRNAs.

[0154] Particularly, the score is compared to a cut-off score which allows to determine whether the patient will respond to lung cancer immunotherapy or will not respond to lung cancer immunotherapy. In other words, the cut-off score allows to classify / stratify the patient as patient who will respond to lung cancer immunotherapy or as a patient who will not respond to lung cancer immunotherapy. In this case, the (in vitro) method of predicting a response to lung cancer immunotherapy of a patient suffering from lung cancer comprises the steps of:

[0155] (i) determining the levels of at least two miRNAs (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 miRNA(s)) in a blood sample of a patient suffering from lung cancer,

[0156] (ii) determining a score by summarizing the weighted levels of the at least two miRNAs (e.g.

[0157] 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 miRNAs), and

[0158] (iii) comparing the score to a cut-off score which allows to determine whether the patient will respond to lung cancer immunotherapy or will not respond to lung cancer immunotherapy, or which allows to classify / stratify the patient as patient who will respond to lung cancer immunotherapy or who will not respond to lung cancer immunotherapy, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155- 5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto.

[0159] The level of at least one further miRNA (e.g. 1, 2, 3, 4, 5, or 6 miRNA(s)) having a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto may also be determined.

[0160] More particularly, the score above the cut-off score indicates that the patient will not respond to lung cancer immunotherapy, or the score below or equal to the cut-off score indicates that the patient will respond to lung cancer immunotherapy.

[0161] In one more preferred embodiment, the score is determined by summarizing the weighted levels of 5 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 12 (hsa-223-3p), SEQ ID NO: 16 (hsa-miR-199b- 5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 2 (hsa-miR-let-7f-5p). In one even more preferred embodiment, the score is calculated according to the following formula: score = (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.183) + (SEQ ID NO: 12 (hsa-223-3p) x -0.043) + (SEQ ID NO: 16 (hsa-miR-199b-5p) x -0.003) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.102) + (SEQ ID NO: 2 (hsa-miR-let-7f-5p) x 0.123), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

[0162] It should be noted that the CT level of each miRNA having a SEQ ID NO as indicated above must be inserted into the above formula to finally calculate the score.

[0163] In one still even more preferred embodiment, the cut-off score is about 0.397 and wherein a score > about 0.397 indicates that the patient will not respond to immunotherapy, or a score < about 0.397 indicates that the patient will respond to immunotherapy.

[0164] In one another more preferred embodiment, the score is determined by summarizing the weighted levels of 16 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR- 143-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR-199b-5p).

[0165] In one another even more preferred embodiment, the score is calculated according to the following formula: score = (SEQ ID NO: 12 (hsa-miR-223-3p) x -0.632) + (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.620) + (SEQ ID NO: 4 (hsa-miR-148a-3p) x -0.297) + (SEQ ID NO: 7 (hsa-miR-125a-5p) x -0.231) + (SEQ ID NO: 14 (hsa-miR-145-5p) x -0.191) + (SEQ ID NO: 10 (hsa-miR-148b-3p) x -0.116) + (SEQ ID NO: 11 (hsa-miR-143-3p) x -0.0436) + (SEQ ID NO: 16 (hsa-miR-199b- 5p) x -0.0206) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.157] + (SEQ ID NO: 9 (hsa-miR-142- 5p) x 0.192) + (SEQ ID NO: 8 (hsa-miR-576-5p) x 0.196) + (SEQ ID NO: 6 (hsa-miR-451a) x 0.232) + (SEQ ID NO: 5 (hsa-miR-192-5p) x 0.296) + (SEQ ID NO: 3 (hsa-miR-155-5p) x 0.336) + (SEQ ID NO: 2 (hsa-let-7f-5p) x 0.353) + (SEQ ID NO: 1 (hsa-miR-342-3p) x 0.405), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

[0166] In one another still even more preferred embodiment, the cut-off score is about 4.365 and wherein a score > about 4.365 indicates that the patient will not respond to immunotherapy, or a score < about 4.365 indicates that the patient will respond to immunotherapy.

[0167] In one another more preferred embodiment, the score is determined by summarizing the weighted levels of 17 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR- 223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR-30e-3p).

[0168] In one another even more preferred embodiment, the score is calculated according to the following formula: score = (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.902) + (SEQ ID NO: 12 (hsa-miR-223-3p) x - 0.843) + (SEQ ID NO: 4 (hsa-miR-148a-3p) x -0.555) + (SEQ ID NO: 7 (hsa-miR-125a-5p) x - 0.367) + (SEQ ID NO: 10 (hsa-miR-148b-3p) x -0.354) + (SEQ ID NO: 14 (hsa-miR-145-5p) x - 0.255) + (SEQ ID NO: 17 (hsa-miR-93-3p) x -0.120) + (SEQ ID NO: 18 (hsa-miR-151a-3p) x 0.137) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.189) + (SEQ ID NO: 19 (hsa-miR-30e-3p) x 0.190) + (SEQ ID NO: 5 (hsa-miR-192-5p) x 0.299) + (SEQ ID NO: 9 (hsa-miR-142-5p) x 0.322) + (SEQ ID NO: 8 (hsa-miR-576-5p) x 0.335) + (SEQ ID NO: 6 (hsa-miR-451a) x 0.375) + (SEQ ID NO: 3 (hsa-miR-155-5p) x 0.465) + (SEQ ID NO: 2 (hsa-let-7f-5p) x -0.488) + (SEQ ID NO: 1 (hsa-miR-342-3p) x 0.623, wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

[0169] In one another still even more preferred embodiment, the cut-off score is about 6.093 and wherein a score > about 6.093 indicates that the patient will not respond to immunotherapy, or a score < about 6.093 indicates that the patient will respond to immunotherapy.

[0170] The patient whose blood sample is analysed in the method of the first aspect of the present invention has optionally a PD-L1 Tumor Proportion Score (TPS) of > 50%. Especially, the patient having a PD-L1 TPS of > 50% has no oncogene activating mutations. Such oncogene activating mutations may be EGFR mutations, BRAF V660e mutations, ALK translocations, and / or ROS-1 translocations.

[0171] It is preferred that the immunotherapy is accompanied with the administration of at least one immunotherapeutic agent such as an immune checkpoint inhibitor. It is more preferred that the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades. Specifically, the at least one immune checkpoint inhibitor is an inhibitor targeting PD- 1 / PD-L1 or the PD-1 / PD-L1 pathway. It is even more preferred that the at least one inhibitor targeting PD-1 / PD-L1 or the PD-1 / PD-L1 pathway is selected from the group consisting of pembrolizumab, nivolumab, cemiplima, durvalumab, and atezolizumab. For example, the (in vitro) method of predicting a response to lung cancer immunotherapy of a patient suffering from lung cancer comprises the step of: determining the level of at least one miRNA(e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 miRNA(s)) in a blood sample of a patient suffering from lung cancer, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR- 125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto, wherein the patient has a PD-L1 Tumor Proportion Score (TPS) of > 50%, and / or the immunotherapy is accompanied with the administration of at least one immune checkpoint inhibitor. Preferably, the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades. More preferably, the at least one inhibitor targeting PD-1 / PD-L1 is selected from the group consisting of pembrolizumab, nivolumab, cemiplima, durvalumab, and atezolizumab.

[0172] Specifically, the lung cancer is eligible for immunotherapy. More specifically, the lung cancer is sensitive to immune checkpoint inhibition / immune checkpoint therapy. Even more specifically, the immune checkpoint inhibition is accompanied with the administration of at least one immune checkpoint inhibitor. Still even more specifically, the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades. Alternatively, the lung cancer is a PD-L1 expressing cancer.

[0173] It is (alternatively or additionally) preferred that the lung cancer is non-small-cell lung carcinoma (NSCLC), preferably NSCLC of stage IV.

[0174] If it is revealed in the above method that the patient will respond to lung cancer immunotherapy, the patient can be assigned to lung cancer immunotherapy and subsequently treated with said lung cancer immunotherapy. If it is revealed in the above method that the patient will not respond to lung cancer immunotherapy, the patient can be assigned to another lung cancer therapy than lung cancer immunotherapy and subsequently treated with said another lung cancer therapy. This another lung cancer therapy is specifically immunochemotherapy. As mentioned above, the miRNA biomarkers of the present invention can be used as alternative biomarkers for the PD-L1 biomarker in immunotherapy. PD-L1 is a biomarker of response to immune-checkpoint inhibitors. The experimental data of the present invention show that the miRNA biomarkers of the present invention allow to predict a response of patients suffering from lung cancer to immunotherapy, e.g. with immune checkpoint inhibitors. The miRNA biomarkers of the present invention can also complement the PD-L1 biomarker. The mainstay of response prediction to immunotherapies in the PD-1 inhibitor class is the quantification of tumor PD-L1 expression. However, still only approximately 30% of patients will achieve a positive response. The combinatory use of the miRNA biomarkers of the present invention with the PD-L1 biomarker known in the prior art may improve / increase the value of 30%.

[0175] The level of the miRNA in the above method may be determined by sequencing such as next generation sequencing (e.g. ABI SOLID, Illumina Genome Analyzer, Roche 454 GS FL, BGISEQ), nucleic acid hybridization (e.g. microarray or beads), nucleic acid amplification (e.g. PCR, RT-PCR, qRT-PCR, or high-throughput RT-PCR), polymerase extension, mass spectrometry, flow cytometry (e.g. LUMINEX), or any combination thereof. Preferably, the level is determined by polymerase chain reaction (PCR), preferably quantitative PCR (qPCR). Specifically, the level of the miRNA is the expression level of said miRNA.

[0176] The present inventors found that the new miRNA markers also allow the provision of a survival prognosis to a patient suffering from lung cancer. Thus, in a second aspect, the present invention relates to a (an) (in vitro) method of providing a survival prognosis to a patient suffering from lung cancer (who is eligible to immunotherapy) comprising the step of: determining the level of at least one miRNA (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 miRNA(s)) in a blood sample of a patient suffering from lung cancer, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR- 125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

[0177] In one embodiment, at least one further miRNA (e.g. 1, 2, 3, 4, 5, or 6 miRNA(s)) having a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR- 150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto is determined in the above method.

[0178] Specifically, the level of at least one miRNA having

[0179] (i) a nucleotide sequence according to SEQ ID NO: 1 to SEQ ID NO: 19,

[0180] (ii) a nucleotide sequence that is a fragment of the nucleotide sequence according to (i), preferably, a nucleotide sequence that is a fragment which is between 1 and 12, more preferably between 1 and 8, and most preferably between 1 and 5 or 1 and 3, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, nucleotides shorter than the nucleotide sequence according to

[0181] (i), or

[0182] (iii) a nucleotide sequence that has at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity to the nucleotide sequence according to (i) or nucleotide sequence fragment according to (ii) is determined in a blood sample of a patient suffering from lung cancer.

[0183] Preferably, the at least one miRNA whose level is determined in a blood sample of a patient suffering from lung cancer

[0184] (i) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 13 (hsa-miR- 23a-3p), SEQ ID NO: 12 (hsa-223-3p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 2 (hsa-miR-let-7f-5p), a fragment thereof, and a sequence having at least 80%, more preferably at least 85%, even more preferably at least 90%, and still even more preferably at least 95% or 99%, e.g. 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto,

[0185] (ii) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR- 223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), a fragment thereof, and a sequence having at least 80%, more preferably at least 85%, even more preferably at least 90%, and still even more preferably at least 95% or 99%, e.g. 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto,

[0186] (iii) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR- 223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a- 3p), and SEQ ID NO: 5 (hsa-miR-192-5p), a fragment thereof, and a sequence having at least 80%, more preferably at least 85%, even more preferably at least 90%, and still even more preferably at least 95% or 99%, e.g. 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto,

[0187] (iv) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR- 342-3 p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa- miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR- 199b-5p), and / or

[0188] (v) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR- 342-3 p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa- miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR-30e-3p).

[0189] More preferably, the miRNAs whose levels are determined in a blood sample of a patient suffering from lung cancer

[0190] (i) have a nucleotide sequence according to SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO:

[0191] 12 (hsa-223-3p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 2 (hsa-miR-let-7f-5p),

[0192] (ii) have a nucleotide sequence according to SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO:

[0193] 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p),

[0194] (iii) have a nucleotide sequence according to SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p),

[0195] (iv) have a nucleotide sequence according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa- miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 12 (hsa- miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR-199b-5p), and / or

[0196] (v) have a nucleotide sequence according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa- miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa- miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR-30e-3p).

[0197] It should be noted that in cases where the levels of 2 or more miRNAs are determined, said miRNAs are designated as miRNA set or signature.

[0198] The level of the at least one miRNA is associated with or correlated to a survival prognosis.

[0199] In one preferred embodiment, the level of the at least one miRNA is compared to a reference level of said at least one miRNA. In this case, the (in vitro) method of providing a survival prognosis to a patient suffering from lung cancer (who is eligible to immunotherapy) comprises the steps of:

[0200] (i) determining the level of at least one miRNA (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 miRNA(s)) in a blood sample of a patient suffering from lung cancer, and

[0201] (ii) comparing the level of the at least one miRNA (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 miRNA(s)) to a reference level of said at least one miRNA, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155- 5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto.

[0202] The level of at least one further miRNA (e.g. 1, 2, 3, 4, 5, or 6 miRNA(s)) having a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto may also be determined.

[0203] In particular, the reference level is the level of the at least one miRNA determined empirically by measuring a number of reference blood samples from subjects suffering from lung cancer having a known poor survival prognosis (under immunotherapy). For example, the reference level is determined from at least 2, at least 10, at least 50, at least 100, at least 200, at least 300, at least 400, at least 500, at least 1000, at least 1500, at least 2000 at least 5000 reference samples from subjects suffering from lung cancer having a known poor survival prognosis (under immunotherapy).

[0204] In one more preferred embodiment, the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 17, a fragment thereof, and a sequence having at least 80% sequence identity thereto below the reference level indicates that the patient has / will have / is expected to have a good survival prognosis (under immunotherapy), or the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 15, SEQ ID NO: 18, SEQ ID NO: 19, a fragment thereof, and a sequence having at least 80% sequence identity thereto above the reference level indicates that the patient has / will have / is expected to have a good survival prognosis (under immunotherapy).

[0205] Additionally, or alternatively, the reference level is the level of the at least one miRNA determined empirically by measuring a number of reference blood samples from subjects suffering from lung cancer having a known good survival prognosis (under immunotherapy). For example, the reference level is determined from at least 2, at least 10, at least 50, at least 100, at least 200, at least 300, at least 400, at least 500, at least 1000, at least 1500, at least 2000 at least 5000 reference samples from subjects suffering from lung cancer having a known good survival prognosis (under immunotherapy).

[0206] In one more preferred embodiment, the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 17, a fragment thereof, and a sequence having at least 80% sequence identity thereto above the reference level indicates that the patient has / will have / is expected to have a poor survival prognosis (under immunotherapy), or the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 15, SEQ ID NO: 18, SEQ ID NO: 19, a fragment thereof, and a sequence having at least 80% sequence identity thereto below the reference level indicates that the patient has / will have / is expected to have a poor survival prognosis (under immunotherapy).

[0207] It is practicable to take one reference blood sample per subject for analysis. Said reference level may be an average reference level. It may be determined by measuring reference levels of subjects and calculating the “average” value (e.g. mean, median or modal value) thereof. It is preferred that the reference blood sample is from the same source (e.g. whole blood or blood fraction) than the blood sample of the patient. It is further preferred that the reference level is of a subject of the same gender (e.g. female or male) and / or of a similar age / phase of life (e.g. adults or elderly) than the patient to be tested.

[0208] Preferably, the level of the at least one miRNA is at least 0.6-fold or 0.7-fold, more preferably at least 0.8-fold or 0.9-fold, even more preferably at least 1.2-fold, 1.5-fold, or 2.0-fold, and still even more preferably at least 3.0-fold or 4.0-fold below / above the reference level. For example, the level of the at least one miRNA is at least 0.6-fold, at least 0.7-fold, at least 0.8-fold, at least 0.9- fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, at least 3.0-fold, at least 3.1-fold, at least 3.2- fold, at least 3.3-fold, at least 3.4-fold, at least 3.5-fold, at least 3.6-fold, at least 3.7-fold, at least 3.8-fold, at least 3.9-fold, or at least 4.0-fold below / above the reference level.

[0209] In one (alternative or additional) preferred embodiment, the method further comprises the step of determining a score by summarizing the weighted levels of at least two miRNAs, e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 miRNAs.

[0210] Particularly, the score is compared to a cut-off score which allows to classify the patient has having a good survival prognosis or poor survival prognosis (under immunotherapy).

[0211] In this case, the (in vitro) method of providing a survival prognosis to a patient suffering from lung cancer who is eligible to immunotherapy comprises the steps of:

[0212] (i) determining the levels of at least two miRNAs (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 miRNA(s)) in a blood sample of a patient suffering from lung cancer,

[0213] (ii) determining a score by summarizing the weighted levels of the at least two miRNAs (e.g.

[0214] 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 miRNAs), and (iii) comparing the score to a cut-off score which allows to classify the patient as having a good survival prognosis or poor survival prognosis, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155- 5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto.

[0215] The level of at least one further miRNA (e.g. 1, 2, 3, 4, 5, or 6 miRNA(s)) having a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto may also be determined.

[0216] More particularly, the good survival prognosis is associated with a high chance / probability of surviving a certain time period / time, or the poor survival prognosis is associated with a low chance / probability of surviving a certain time period / time.

[0217] Even more particularly, the patient having a good survival prognosis has a chance / probability of greater than 50%, preferably of greater than 60%, more preferably of greater than 70%, even more preferably of greater than 80%, still even more preferably of greater than 90%, or most preferably of greater than 95% to survive a certain time period, or the patient having a poor survival prognosis has a chance / probability of equal to or lower than 50%, preferably lower 40%, more preferably of lower than 30%, even more preferably of lower than 20%, still even more preferably of lower than 10%, and most preferably of lower than 5 % to survive a certain time period.

[0218] Still even more specifically, the certain time period is a time period of (at least / at most) 3 months, 6 months, 9 months, 12 months (1 year), 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years. For example, the patient having a good survival prognosis has a chance / probability of greater than 50%, preferably of greater than 60%, more preferably of greater than 70%, even more preferably of greater than 80%, still even more preferably of greater than 90%, or most preferably of greater than 95% to survive a time period of (at least) 3 months, 6 months, 9 months, 12 months (1 year), 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years, or the patient having a low survival prognosis has a chance / probability of equal to or lower than 50%, preferably lower 40%, more preferably of lower than 30%, even more preferably of lower than 20%, still even more preferably of lower than 10%, and most preferably of lower than 5 % to survive a time period of (at most) 3 months, 6 months, 9 months, 12 months (1 year), 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years.

[0219] The survival prognosis may also be defined as the predicted survival at 2- or 5-years follow-up. For example, a patient having a good survival prognosis will still be alive at a 2- or 5-years followup, while a patient having a poor survival prognosis will not be alive at a 2- or 5-years follow up anymore.

[0220] As mentioned above, the method may further comprise the step of determining a score by summarizing the weighted levels of at least two miRNAs, e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 miRNAs.

[0221] Particularly, the score is compared to a cut-off score which allows to classify the patient has having a good survival prognosis or poor survival prognosis.

[0222] More particularly, the score above the cut-off score indicates that the patient has a poor survival prognosis, or the score below or equal to the cut-off score indicates that the patient has a good survival prognosis. In one more preferred embodiment, the score is determined by summarizing the weighted levels of 5 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 12 (hsa-223-3p), SEQ ID NO: 16 (hsa-miR-199b- 5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 2 (hsa-miR-let-7f-5p).

[0223] In one even more preferred embodiment, the score is calculated according to the following formula: score = (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.183) + (SEQ ID NO: 12 (hsa-223-3p) x -0.043) + (SEQ ID NO: 16 (hsa-miR-199b-5p) x -0.003) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.102) + (SEQ ID NO: 2 (hsa-miR-let-7f-5p) x 0.123), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

[0224] It should be noted that the CT level of each miRNA having a SEQ ID NO as indicated above must be inserted into the above formula to finally calculate the score. In one still even more preferred embodiment, the cut-off score is about 0.397 and wherein a score > about 0.397 indicates that the patient has a poor survival prognosis, or a score < about 0.397 indicates that the patient has a good survival prognosis.

[0225] In one another more preferred embodiment, the score is determined by summarizing the weighted levels of 16 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a- 3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa- miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR- 150-5p), and SEQ ID NO: 16 (hsa-miR-199b-5p).

[0226] In one another even more preferred embodiment, the score is calculated according to the following formula: score = (SEQ ID NO: 12 (hsa-miR-223-3p) x -0.632) + (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.620) + (SEQ ID NO: 4 (hsa-miR-148a-3p) x -0.297) + (SEQ ID NO: 7 (hsa-miR-125a-5p) x -0.231) + (SEQ ID NO: 14 (hsa-miR-145-5p) x -0.191) + (SEQ ID NO: 10 (hsa-miR-148b-3p) x -0.116) + (SEQ ID NO: 11 (hsa-miR-143-3p) x -0.0436) + (SEQ ID NO: 16 (hsa-miR-199b- 5p) x -0.0206) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.157] + (SEQ ID NO: 9 (hsa-miR-142- 5p) x 0.192) + (SEQ ID NO: 8 (hsa-miR-576-5p) x 0.196) + (SEQ ID NO: 6 (hsa-miR-451a) x 0.232) + (SEQ ID NO: 5 (hsa-miR-192-5p) x 0.296) + (SEQ ID NO: 3 (hsa-miR-155-5p) x 0.336) + (SEQ ID NO: 2 (hsa-let-7f-5p) x 0.353) + (SEQ ID NO: 1 (hsa-miR-342-3p) x 0.405), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

[0227] In one still even more preferred embodiment, the cut-off score is about 4.365 and wherein a score > about 4.365 indicates that the patient has a poor survival prognosis, or a score < about 4.365 indicates that the patient has a good survival prognosis.

[0228] In one another more preferred embodiment, the score is determined by summarizing the weighted levels of 17 miRNAs having a nucleotide selected from the group consisting of / according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa- miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150- 5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR-30e-3p). In one another even more preferred embodiment, the score is calculated according to the following formula: score = (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.902) + (SEQ ID NO: 12 (hsa-miR-223-3p) x - 0.843) + (SEQ ID NO: 4 (hsa-miR-148a-3p) x -0.555) + (SEQ ID NO: 7 (hsa-miR-125a-5p) x - 0.367) + (SEQ ID NO: 10 (hsa-miR-148b-3p) x -0.354) + (SEQ ID NO: 14 (hsa-miR-145-5p) x - 0.255) + (SEQ ID NO: 17 (hsa-miR-93-3p) x -0.120) + (SEQ ID NO: 18 (hsa-miR-151a-3p) x 0.137) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.189) + (SEQ ID NO: 19 (hsa-miR-30e-3p) x 0.190) + (SEQ ID NO: 5 (hsa-miR-192-5p) x 0.299) + (SEQ ID NO: 9 (hsa-miR-142-5p) x 0.322) + (SEQ ID NO: 8 (hsa-miR-576-5p) x 0.335) + (SEQ ID NO: 6 (hsa-miR-451a) x 0.375) + (SEQ ID NO: 3 (hsa-miR-155-5p) x 0.465) + (SEQ ID NO: 2 (hsa-let-7f-5p) x -0.488) + (SEQ ID NO: 1 (hsa-miR-342-3p) x 0.623), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

[0229] In one still even more preferred embodiment, the cut-off score is about 6.093 and wherein a score > about 6.093 indicates that the patient has a poor survival prognosis, or a score < about 6.093 indicates that the patient has a good survival prognosis.

[0230] The patient whose blood sample is analysed in the method of the second aspect of the present invention has optionally a PD-L1 Tumor Proportion Score (TPS) of > 50%. Especially, the patient having a PD-L1 TPS of > 50% has no oncogene activating mutations. Such oncogene activating mutations may be EGFR mutations, BRAF V660e mutations, ALK translocations, and / or ROS-1 translocations.

[0231] The patient may be a patient to whom lung cancer immunotherapy will be, is, or has been administered. Preferably, the patient is a treatment naive lung cancer patient. If it is revealed that the patient has a good survival prognosis under immunotherapy, the patient can be assigned to lung cancer immunotherapy and subsequently treated with said lung cancer immunotherapy. If it is revealed that the patient has a poor survival prognosis under immunotherapy, the patient can be assigned to another lung cancer therapy than lung cancer immunotherapy and subsequently treated with said another lung cancer therapy. This another lung cancer therapy is specifically immunochemotherapy .

[0232] It is preferred that the immunotherapy is accompanied with the administration of at least one immunotherapeutic agent such as an immune checkpoint inhibitor. It is more preferred that the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades. Specifically, the at least one immune checkpoint inhibitor is an inhibitor targeting PD- 1 / PD-L1 or the PD-1 / PD-L1 pathway. It is even more preferred that the at least one inhibitor targeting PD-1 / PD-L1 or the PD-1 / PD-L1 pathway is selected from the group consisting of pembrolizumab, nivolumab, cemiplima, durvalumab, and atezolizumab.

[0233] For example, the (in vitro) method of providing a survival prognosis to a patient suffering from lung cancer under immunotherapy comprises the step of: determining the level of at least one miRNA(e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 miRNA(s)) in a blood sample of a patient suffering from lung cancer, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR- 125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto, wherein the patient has a PD-L1 Tumor Proportion Score (TPS) of > 50%, and / or the immunotherapy is accompanied with the administration of at least one immune checkpoint inhibitor. Preferably, the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades. More preferably, the at least one inhibitor targeting PD-1 / PD-L1 is selected from the group consisting of pembrolizumab, nivolumab, cemiplima, durvalumab, and atezolizumab.

[0234] Specifically, the lung cancer is eligible for immunotherapy. More specifically, the lung cancer is sensitive to immune checkpoint inhibition / immune checkpoint therapy. Even more specifically, the immune checkpoint inhibition is accompanied with the administration of at least one immune checkpoint inhibitor. Still even more specifically, the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades. Alternatively, the lung cancer is a PD-L1 expressing cancer.

[0235] It is (alternatively or additionally) preferred that the lung cancer is non-small-cell lung carcinoma (NSCLC), preferably NSCLC of stage IV.

[0236] The level of the miRNA in the above method may be determined by sequencing such as next generation sequencing (e.g. ABI SOLID, Illumina Genome Analyzer, Roche 454 GS FL, BGISEQ), nucleic acid hybridization (e.g. microarray or beads), nucleic acid amplification (e.g. PCR, RT-PCR, qRT-PCR, or high-throughput RT-PCR), polymerase extension, mass spectrometry, flow cytometry (e.g. LUMINEX), or any combination thereof. Preferably, the level is determined by polymerase chain reaction (PCR), preferably quantitative PCR (qPCR). Specifically, the level of the miRNA is the expression level of said miRNA.

[0237] As to the other preferred embodiments, it is referred to the first aspect of the present invention.

[0238] In a third aspect, the present invention relates to a method of determining whether to treat a patient suffering from lung cancer with immunotherapy comprising the steps of:

[0239] (i) carrying out the method of the first aspect, thereby identifying the patient as patient who will respond to lung cancer immunotherapy, or carrying out the method of the second aspect, thereby identifying the patient as patient having a good survival prognosis under immunotherapy, and

[0240] (ii) assigning the patient to (said) lung cancer immunotherapy.

[0241] Preferably, the immunotherapy is accompanied with the administration of at least one immunotherapeutic agent such as an immune checkpoint inhibitor. More preferably, the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades. Even more preferably, the at least one immune checkpoint inhibitor targeting PD-1 / PD-L1 is selected from the group consisting of pembrolizumab, nivolumab, cemiplima, durvalumab, and atezolizumab.

[0242] In this respect, it should be noted that a patient who is identified as lung cancer immunotherapy non-responder is assigned to lung cancer immunochemotherapy, or a patient who is identified as having a poor survival prognosis under immunotherapy is assigned to lung cancer immunochemotherapy.

[0243] Immunochemotherapy is a combination of immunotherapy and chemotherapy.

[0244] While immunotherapy is accompanied with the administration of at least one immunotherapeutic agent such as an immune checkpoint inhibitor, chemotherapy is accompanied with the administration of at least one chemotherapeutic agent.

[0245] Preferably, the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades, and / or the at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, folinic acid, a folate antagonist, a mitotic inhibitor, an anthracycline, a topoisomerase inhibitor, an antibody, a signal transduction inhibitor, an inhibitor of angiogenesis, and an inhibitor of histone deacetylase, and a platinum doublet. More preferably, the at least one immune checkpoint inhibitor targeting PD-1 / PD-L1 is selected from the group consisting of pembrolizumab, nivolumab, cemiplima, durvalumab, and atezolizumab, and / or the at least one chemotherapeutic agent is selected from the group consisting of Cisplatin (CDDP), Carboplatin (CBDCA), and Nedaplatin (CDGP).

[0246] In a further aspect, the present invention relates to a method of treating a patient suffering from lung cancer with immunotherapy comprising the steps of:

[0247] (i) carrying out the method of the first aspect, thereby identifying the patient as patient who will respond to lung cancer immunotherapy, or carrying out the method of the second aspect, thereby identifying the patient as patient having a good survival prognosis under immunotherapy, and

[0248] (ii) treating the patient with lung cancer immunotherapy.

[0249] Preferably, the immunotherapy is accompanied with the administration of at least one immunotherapeutic agent such as an immune checkpoint inhibitor. More preferably, the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades. Even more preferably, the at least one immune checkpoint inhibitor targeting PD-1 / PD-L1 is selected from the group consisting of pembrolizumab, nivolumab, cemiplima, durvalumab, and atezolizumab.

[0250] In this respect, it should be noted that a patient who is identified as lung cancer immunotherapy non-responder is treated with lung cancer immunochemotherapy, or a patient who is identified as having a poor survival prognosis under immunotherapy is treated with lung cancer immunochemotherapy.

[0251] Immunochemotherapy is a combination of immunotherapy and chemotherapy.

[0252] While immunotherapy is accompanied with the administration of at least one immunotherapeutic agent such as an immune checkpoint inhibitor, chemotherapy is accompanied with the administration of at least one chemotherapeutic agent.

[0253] Preferably, the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades, and / or the at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, folinic acid, a folate antagonist, a mitotic inhibitor, an anthracycline, a topoisomerase inhibitor, an antibody, a signal transduction inhibitor, an inhibitor of angiogenesis, and an inhibitor of histone deacetylase, and a platinum doublet.

[0254] More preferably, the at least one immune checkpoint inhibitor targeting PD-1 / PD-L1 is selected from the group consisting of pembrolizumab, nivolumab, cemiplima, durvalumab, and atezolizumab, and / or the at least one chemotherapeutic agent is selected from the group consisting of Cisplatin (CDDP), Carboplatin (CBDCA), and Nedaplatin (CDGP).

[0255] Immunotherapy is revolutionizing the standard of care for numerous cancers. However, an important current limitation is the lack of reliable efficacy biomarkers. In advanced stage NSCLC (stage IV) expressing high levels of PD-L1 (PD-L1 Tumor Proportion Score (TPS) > 50%), for example, immunotherapy alone or immunotherapy in combination with chemotherapy are recommended as treatment options in major international guidelines. Nevertheless, there remains uncertainty as to the ideal therapeutic choice in individual patients. The present inventors have identified new miRNAs which allow to select a patient suffering from lung cancer to benefit from immunochemotherapy or immunotherapy. Alongside the remarkable advantages, immunochemotherapy can be associated with characteristic (and sometimes severe) side effects. For this reason, it is required to administer immunochemotherapy only to those patients in which the benefits are predicted to outweigh the risks. In turn, other lung cancer patients are already benefiting from immunotherapy.

[0256] Thus, in a fourth aspect, the present invention relates to a (an) (in vitro) method of selecting a patient suffering from lung cancer to (likely) benefit from immunotherapy or immunochemotherapy comprising the step of: determining the level of at least one miRNA (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 miRNA(s)) in a blood sample of a patient suffering from lung cancer, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR- 342-3 p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa- miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 14 (hsa- miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

[0257] Specifically, the level of at least one miRNA having

[0258] (i) a nucleotide sequence according to SEQ ID NO: 1 to SEQ ID NO: 19, (ii) a nucleotide sequence that is a fragment of the nucleotide sequence according to (i), preferably, a nucleotide sequence that is a fragment which is between 1 and 12, more preferably between 1 and 8, and most preferably between 1 and 5 or 1 and 3, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, nucleotides shorter than the nucleotide sequence according to

[0259] (i), or

[0260] (iii) a nucleotide sequence that has at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity to the nucleotide sequence according to (i) or nucleotide sequence fragment according to (ii) is determined in a blood sample of a patient suffering from lung cancer.

[0261] Preferably, the at least one miRNA whose level is determined in a blood sample of a patient suffering from lung cancer

[0262] (i) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 13 (hsa-miR- 23a-3p), SEQ ID NO: 12 (hsa-223-3p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 2 (hsa-miR-let-7f-5p), a fragment thereof, and a sequence having at least 80%, more preferably at least 85%, even more preferably at least 90%, and still even more preferably at least 95% or 99%, e.g. 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto,

[0263] (ii) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR- 223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), a fragment thereof, and a sequence having at least 80%, more preferably at least 85%, even more preferably at least 90%, and still even more preferably at least 95% or 99%, e.g. 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto,

[0264] (iii) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR- 223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a- 3p), and SEQ ID NO: 5 (hsa-miR-192-5p), a fragment thereof, and a sequence having at least 80%, more preferably at least 85%, even more preferably at least 90%, and still even more preferably at least 95% or 99%, e.g. 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto,

[0265] (iv) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR- 342-3 p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa- miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR- 199b-5p), and / or

[0266] (v) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR- 342-3 p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa- miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR-30e-3p).

[0267] More preferably, the miRNAs whose levels are determined in a blood sample of a patient suffering from lung cancer

[0268] (i) have a nucleotide sequence according to SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO:

[0269] 12 (hsa-223-3p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 2 (hsa-miR-let-7f-5p),

[0270] (ii) have a nucleotide sequence according to SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO:

[0271] 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p),

[0272] (iii) have a nucleotide sequence according to SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p),

[0273] (iv) have a nucleotide sequence according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa- miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 12 (hsa- miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR-199b-5p), and / or

[0274] (v) have a nucleotide sequence according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa- miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa- miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR-30e-3p).

[0275] It should be noted that in cases where the levels of 2 or more miRNAs are determined, said miRNAs are designated as miRNA set or signature.

[0276] In one preferred embodiment, the method comprises the step of determining a score by summarizing the weighted levels of at least two miRNAs (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 miRNAs).

[0277] Particularly, the score is compared to a cut-off score which allows to determine whether the patient will benefit from lung cancer immunotherapy or whether the patient will benefit from lung cancer immunochemotherapy. In this case, the (in vitro) method of selecting a patient suffering from lung cancer to benefit from immunotherapy or immunochemotherapy comprises the steps of:

[0278] (i) determining the levels of at least two miRNAs (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 miRNAs) in a blood sample of a patient suffering from lung cancer,

[0279] (ii) determining a score by summarizing the weighted levels of the at least two miRNAs (e.g.

[0280] 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 miRNAs), and

[0281] (iii) comparing the score to a cut-off score which allows to determine whether the patient will (likely) benefit from lung cancer immunotherapy or whether the patient will (likely) benefit from lung cancer immunochemotherapy, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR- 342-3 p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa- miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 14 (hsa- miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

[0282] More particularly, the score above the cut-off score indicates that the patient will not benefit from immunotherapy alone and will require immunotherapy in combination with chemotherapy, or the score below or equal to the cut-off score indicates that the patient will benefit from either immunotherapy with or without chemotherapy.

[0283] In other words, the score above the cut-off score indicates that the patient will benefit from immunochemotherapy, or the score below or equal to the cut-off score indicates that the patient will benefit from immunochemotherapy or immunotherapy.

[0284] In one more preferred embodiment, the score is determined by summarizing the weighted levels of 5 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 12 (hsa-223-3p), SEQ ID NO: 16 (hsa-miR-199b- 5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 2 (hsa-miR-let-7f-5p).

[0285] In one even more preferred embodiment, the score is calculated according to the following formula: score = (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.183) + (SEQ ID NO: 12 (hsa-223-3p) x -0.043) + (SEQ ID NO: 16 (hsa-miR-199b-5p) x -0.003) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.102) + (SEQ ID NO: 2 (hsa-miR-let-7f-5p) x 0.123), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

[0286] It should be noted that the CT level of each miRNA having a SEQ ID NO as indicated above must be inserted into the above formula to finally calculate the score.

[0287] In one still even more preferred embodiment, the cut-off score is about 0.397 and a score > about 0.397 indicates that the patient will not benefit from immunotherapy alone and will require immunotherapy in combination with chemotherapy, or a score < about 0.397 indicates that the patient will benefit from either immunotherapy with or without chemotherapy.

[0288] In one another more preferred embodiment, the score is determined by summarizing the weighted levels of 16 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR- 143-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR-199b-5p).

[0289] In one another even more preferred embodiment the score is calculated according to the following formula: score = (SEQ ID NO: 12 (hsa-miR-223-3p) x -0.632) + (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.620) + (SEQ ID NO: 4 (hsa-miR-148a-3p) x -0.297) + (SEQ ID NO: 7 (hsa-miR-125a-5p) x -0.231) + (SEQ ID NO: 14 (hsa-miR-145-5p) x -0.191) + (SEQ ID NO: 10 (hsa-miR-148b-3p) x -0.116) + (SEQ ID NO: 11 (hsa-miR-143-3p) x -0.0436) + (SEQ ID NO: 16 (hsa-miR-199b- 5p) x -0.0206) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.157] + (SEQ ID NO: 9 (hsa-miR-142- 5p) x 0.192) + (SEQ ID NO: 8 (hsa-miR-576-5p) x 0.196) + (SEQ ID NO: 6 (hsa-miR-451a) x 0.232) + (SEQ ID NO: 5 (hsa-miR-192-5p) x 0.296) + (SEQ ID NO: 3 (hsa-miR-155-5p) x 0.336) + (SEQ ID NO: 2 (hsa-let-7f-5p) x 0.353) + (SEQ ID NO: 1 (hsa-miR-342-3p) x 0.405), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

[0290] In one another still even more preferred embodiment, the cut-off score is about 4.365 and a score > about 4.365 indicates that the patient will not benefit from immunotherapy alone and will require immunotherapy in combination with chemotherapy, or a score < about 4.365 indicates that the patient will benefit from either immunotherapy with or without chemotherapy.

[0291] In one another more preferred embodiment, the score is determined by summarizing the weighted levels of 17 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR- 223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR-30e-3p).

[0292] In one another even more preferred embodiment the score is calculated according to the following formula: score = (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.902) + (SEQ ID NO: 12 (hsa-miR-223-3p) x - 0.843) + (SEQ ID NO: 4 (hsa-miR-148a-3p) x -0.555) + (SEQ ID NO: 7 (hsa-miR-125a-5p) x - 0.367) + (SEQ ID NO: 10 (hsa-miR-148b-3p) x -0.354) + (SEQ ID NO: 14 (hsa-miR-145-5p) x - 0.255) + (SEQ ID NO: 17 (hsa-miR-93-3p) x -0.120) + (SEQ ID NO: 18 (hsa-miR-151a-3p) x 0.137) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.189) + (SEQ ID NO: 19 (hsa-miR-30e-3p) x 0.190) + (SEQ ID NO: 5 (hsa-miR-192-5p) x 0.299) + (SEQ ID NO: 9 (hsa-miR-142-5p) x 0.322) + (SEQ ID NO: 8 (hsa-miR-576-5p) x 0.335) + (SEQ ID NO: 6 (hsa-miR-451a) x 0.375) + (SEQ ID NO: 3 (hsa-miR-155-5p) x 0.465) + (SEQ ID NO: 2 (hsa-let-7f-5p) x -0.488) + (SEQ ID NO: 1 (hsa-miR-342-3p) x 0.623), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

[0293] In one another still even more preferred embodiment, the cut-off score is about 6.093 and a score > about 6.093 indicates that the patient will not benefit from immunotherapy alone and will require immunotherapy in combination with chemotherapy, or a score < about 6.093 indicates that the patient will benefit from either immunotherapy with or without chemotherapy.

[0294] While immunotherapy is accompanied with the administration of at least one immunotherapeutic agent such as an immune checkpoint inhibitor, chemotherapy is accompanied with the administration of at least one chemotherapeutic agent.

[0295] Preferably, the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades, and / or the at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, folinic acid, a folate antagonist, a mitotic inhibitor, an anthracycline, a topoisomerase inhibitor, an antibody, a signal transduction inhibitor, an inhibitor of angiogenesis, and an inhibitor of histone deacetylase, and a platinum doublet.

[0296] More preferably, the at least one immune checkpoint inhibitor targeting PD-1 / PD-L1 is selected from the group consisting of pembrolizumab, nivolumab, cemiplima, durvalumab, and atezolizumab, and / or the at least one chemotherapeutic agent is selected from the group consisting of Cisplatin (CDDP), Carboplatin (CBDCA), and Nedaplatin (CDGP).

[0297] The patient whose blood sample is analysed in the method of the fourth aspect of the present invention has optionally a PD-L1 Tumor Proportion Score (TPS) of > 50%. Especially, the patient having a PD-L1 TPS of > 50% has no oncogene activating mutations. Such oncogene activating mutations may be EGFR mutations, BRAF V660e mutations, ALK translocations, and / or ROS-1 translocations.

[0298] Specifically, the lung cancer is eligible for immunotherapy or immunochemotherapy. More specifically, the lung cancer is sensitive to immune checkpoint inhibition / immune checkpoint therapy or therapy using chemotherapeutic agents. Even more specifically, the immune checkpoint inhibition is accompanied with the administration of at least one immune checkpoint inhibitor. Still even more specifically, the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades. Alternatively, the lung cancer is a PD-L1 expressing cancer.

[0299] It is (alternatively or additionally) preferred that the lung cancer is non-small-cell lung carcinoma (NSCLC), preferably NSCLC of stage IV.

[0300] The level of the miRNA in the above method may be determined by sequencing such as next generation sequencing (e.g. ABI SOLID, Illumina Genome Analyzer, Roche 454 GS FL, BGISEQ), nucleic acid hybridization (e.g. microarray or beads), nucleic acid amplification (e.g. PCR, RT-PCR, qRT-PCR, or high-throughput RT-PCR), polymerase extension, mass spectrometry, flow cytometry (e.g. LUMINEX), or any combination thereof. Preferably, the level is determined by polymerase chain reaction (PCR), preferably quantitative PCR (qPCR). Specifically, the level of the miRNA is the expression level of said miRNA.

[0301] In a fifth aspect, the present invention relates to a method of determining whether to treat a patient suffering from lung cancer with immunochemotherapy or immunotherapy comprising the steps of:

[0302] (i) carrying out the method of the fourth aspect, thereby identifying the patient as patient who will (likely) benefit from immunochemotherapy or immunotherapy, and

[0303] (ii) assigning the patient to said therapy.

[0304] This aspect can alternatively be worded as a method of determining whether to treat a patient suffering from lung cancer with immunotherapy with or without chemotherapy comprising the steps of:

[0305] (i) carrying out the method of the fourth aspect, thereby identifying the patient as patient who will (likely) benefit from immunotherapy or will require the addition of chemotherapy, and

[0306] (ii) assigning the patient to said therapy.

[0307] The immunotherapy encompasses the administration of at least one immunotherapeutic agent such as an immune checkpoint inhibitor and the immunochemotherapy encompasses the administration of at least one immunotherapeutic agent such as an immune checkpoint inhibitor and at least one chemotherapeutic agent.

[0308] Preferably, the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades, and / or the at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, folinic acid, a folate antagonist, a mitotic inhibitor, an anthracycline, a topoisomerase inhibitor, an antibody, a signal transduction inhibitor, an inhibitor of angiogenesis, and an inhibitor of histone deacetylase, and a platinum doublet.

[0309] More preferably, the at least one immune checkpoint inhibitor targeting PD-1 / PD-L1 is selected from the group consisting of pembrolizumab, nivolumab, cemiplima, durvalumab, and atezolizumab, and / or the at least one chemotherapeutic agent is selected from the group consisting of Cisplatin (CDDP), Carboplatin (CBDCA), and Nedaplatin (CDGP).

[0310] In a sixth aspect, the present invention relates to a method of treating a patient suffering from lung cancer with immunochemotherapy or immunotherapy comprising the steps of: (i) carrying out the method of the fourth aspect, thereby identifying the patient as patient who will (likely) benefit from immunochemotherapy or immunotherapy, and

[0311] (ii) treating the patient with said therapy.

[0312] This aspect can alternatively be worded as a method of treating a patient suffering from lung cancer with immunotherapy with or without chemotherapy comprising the steps of:

[0313] (i) carrying out the method of any one of claims 49 to 63, thereby identifying the patient as patient who will benefit from immunotherapy or will require the addition of chemotherapy, and

[0314] (ii) treating the patient with said therapy.

[0315] The immunotherapy encompasses the treatment of the patient with at least one immunotherapeutic agent such as an immune checkpoint inhibitor and the immunochemotherapy encompasses the treatment of the patient with at least one immunotherapeutic agent such as an immune checkpoint inhibitor and at least one chemotherapeutic agent.

[0316] Preferably, the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades, and / or the at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, folinic acid, a folate antagonist, a mitotic inhibitor, an anthracycline, a topoisomerase inhibitor, an antibody, a signal transduction inhibitor, an inhibitor of angiogenesis, and an inhibitor of histone deacetylase, and a platinum doublet.

[0317] More preferably, the at least one immune checkpoint inhibitor targeting PD-1 / PD-L1 is selected from the group consisting of pembrolizumab, nivolumab, cemiplima, durvalumab, and atezolizumab, and / or the at least one chemotherapeutic agent is selected from the group consisting of Cisplatin (CDDP), Carboplatin (CBDCA), and Nedaplatin (CDGP).

[0318] In a seventh aspect, the present invention relates to the (in vitro) use of at least one miRNA (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 miRNA(s)) or at least one polynucleotide allowing the detection of said at least one miRNA for predicting a response to lung cancer immunotherapy of a patient suffering from lung cancer, for providing a survival prognosis to a patient suffering from lung cancer who is eligible to immunotherapy, or for determining whether to treat a patient suffering from lung cancer with immunotherapy, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155- 5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80%%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto.

[0319] In one embodiment, at least one further miRNA (e.g. 1, 2, 3, 4, 5, or 6 miRNA(s)) having a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR- 150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto is used.

[0320] Specifically, the at least one miRNA has

[0321] (i) a nucleotide sequence according to SEQ ID NO: 1 to SEQ ID NO: 19,

[0322] (ii) a nucleotide sequence that is a fragment of the nucleotide sequence according to (i), preferably, a nucleotide sequence that is a fragment which is between 1 and 12, more preferably between 1 and 8, and most preferably between 1 and 5 or 1 and 3, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, nucleotides shorter than the nucleotide sequence according to (i), or

[0323] (iii) a nucleotide sequence that has at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity to the nucleotide sequence according to (i) or nucleotide sequence fragment according to (ii).

[0324] In an eighth aspect, the present invention relates to the (in vitro) use of at least one miRNA (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 miRNA(s)) or at least one polynucleotide allowing the detection of said at least one miRNA for selecting a patient suffering from lung cancer to benefit from immunotherapy or immunochemotherapy, or for determining whether to treat a patient suffering from lung cancer with immunochemotherapy or immunotherapy, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR- 342-3 p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa- miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 14 (hsa- miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto.

[0325] Specifically, the at least one miRNA has

[0326] (i) a nucleotide sequence according to SEQ ID NO: 1 to SEQ ID NO: 19,

[0327] (ii) a nucleotide sequence that is a fragment of the nucleotide sequence according to (i), preferably, a nucleotide sequence that is a fragment which is between 1 and 12, more preferably between 1 and 8, and most preferably between 1 and 5 or 1 and 3, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, nucleotides shorter than the nucleotide sequence according to

[0328] (i), or

[0329] (iii) a nucleotide sequence that has at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity to the nucleotide sequence according to (i) or nucleotide sequence fragment according to (ii).

[0330] Preferably, the at least one miRNA used in the seventh or eighth aspect

[0331] (i) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 13 (hsa-miR- 23a-3p), SEQ ID NO: 12 (hsa-223-3p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 2 (hsa-miR-let-7f-5p), a fragment thereof, and a sequence having at least 80%, more preferably at least 85%, even more preferably at least 90%, and still even more preferably at least 95% or 99%, e.g. 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto,

[0332] (ii) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR- 223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), a fragment thereof, and a sequence having at least 80%, more preferably at least 85%, even more preferably at least 90%, and still even more preferably at least 95% or 99%, e.g. 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto,

[0333] (iii) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR- 223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a- 3p), and SEQ ID NO: 5 (hsa-miR-192-5p), a fragment thereof, and a sequence having at least 80%, more preferably at least 85%, even more preferably at least 90%, and still even more preferably at least 95% or 99%, e.g. 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto,

[0334] (iv) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR- 342-3 p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa- miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR- 199b-5p), and / or

[0335] (v) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR- 342-3 p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa- miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR-30e-3p).

[0336] More preferably, the miRNAs used in the seventh or eighth aspect

[0337] (i) have a nucleotide sequence according to SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO:

[0338] 12 (hsa-223-3p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 2 (hsa-miR-let-7f-5p),

[0339] (ii) have a nucleotide sequence according to SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO:

[0340] 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p),

[0341] (iii) have a nucleotide sequence according to SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p),

[0342] (iv) have a nucleotide sequence according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa- miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 12 (hsa- miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR-199b-5p), and / or

[0343] (v) have a nucleotide sequence according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa- miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa- miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR-30e-3p).

[0344] Regarding the eighth or seventh aspect, the immunotherapy encompasses the treatment of the patient with at least one immunotherapeutic agent such as an immune checkpoint inhibitor and the immunochemotherapy encompasses the treatment of the patient with at least one immunotherapeutic agent such as an immune checkpoint inhibitor and at least one chemotherapeutic agent.

[0345] Preferably, the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades, and / or the at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, folinic acid, a folate antagonist, a mitotic inhibitor, an anthracycline, a topoisomerase inhibitor, an antibody, a signal transduction inhibitor, an inhibitor of angiogenesis, and an inhibitor of histone deacetylase, and a platinum doublet.

[0346] More preferably, the at least one immune checkpoint inhibitor targeting PD-1 / PD-L1 is selected from the group consisting of pembrolizumab, nivolumab, cemiplima, durvalumab, and atezolizumab, and / or the at least one chemotherapeutic agent is selected from the group consisting of Cisplatin (CDDP), Carboplatin (CBDCA), and Nedaplatin (CDGP).

[0347] Specifically, the lung cancer is non-small-cell lung carcinoma (NSCLC), preferably NSCLC of stage IV.

[0348] As to other preferred embodiments, it is referred to the first to sixth aspect of the present invention.

[0349] The polynucleotide may be a primer (e.g. a primer probe) or a polynucleotide probe. The primer (e.g. a primer probe) or a polynucleotide probe allows the detection of the miRNA via polymerase chain reaction (PCR), preferably quantitative PCR (qPCR). The determination is carried out in a blood sample obtained from the patient.

[0350] In a ninth aspect, the present invention relates to (the (in vitro) use of) a kit for predicting a response to lung cancer immunotherapy of a patient suffering from lung cancer, for providing a survival prognosis to a patient suffering from lung cancer who is eligible to immunotherapy, or for determining whether to treat a patient suffering from lung cancer with immunotherapy, wherein said kit comprises: means for determining the level of at least one miRNA (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 miRNA(s)) having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142- 5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto.

[0351] In one embodiment, the kit comprises means for determining the level of at least one further miRNA (e.g. 1, 2, 3, 4, 5, or 6 miRNA(s)), wherein said at least one further miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150- 5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto.

[0352] The kit may further comprise instructions on how to carry out the methods of the first to third aspect. The kit may also be useful for conducting the methods of the first to third aspect.

[0353] In a tenth aspect, the present invention relates to (the (in vitro) use of) a kit for selecting a patient suffering from lung cancer to benefit from immunotherapy or immunochemotherapy, or for determining whether to treat a patient suffering from lung cancer with immunochemotherapy or immunotherapy, wherein said kit comprises: means for determining the level of at least one miRNA (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 miRNA(s)) having a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR- 142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), SEQ ID NO: 19 (hsa-miR-30e- 3p), a fragment thereof, and a sequence having at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto.

[0354] The kit may further comprise instructions on how to carry out the methods of the fourth to sixth aspect. The kit may also be useful for conducting the methods of the fourth to sixth aspect.

[0355] Specifically, the kit of the ninth or tenth aspect comprises means for determining the level of at least one miRNA having

[0356] (i) a nucleotide sequence according to SEQ ID NO: 1 to SEQ ID NO: 19,

[0357] (ii) a nucleotide sequence that is a fragment of the nucleotide sequence according to (i), preferably, a nucleotide sequence that is a fragment which is between 1 and 12, more preferably between 1 and 8, and most preferably between 1 and 5 or 1 and 3, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, nucleotides shorter than the nucleotide sequence according to (i), or

[0358] (iii) a nucleotide sequence that has at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% or 99%, e.g. at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity to the nucleotide sequence according to (i) or nucleotide sequence fragment according to (ii).

[0359] Preferably, the at least one miRNA referred to in the ninth or tenth aspect

[0360] (i) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 13 (hsa-miR- 23a-3p), SEQ ID NO: 12 (hsa-223-3p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 2 (hsa-miR-let-7f-5p), a fragment thereof, and a sequence having at least 80%, more preferably at least 85%, even more preferably at least 90%, and still even more preferably at least 95% or 99%, e.g. 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto,

[0361] (ii) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR- 223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), a fragment thereof, and a sequence having at least 80%, more preferably at least 85%, even more preferably at least 90%, and still even more preferably at least 95% or 99%, e.g. 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto, and / or (iii) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR- 223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a- 3p), and SEQ ID NO: 5 (hsa-miR-192-5p), a fragment thereof, and a sequence having at least 80%, more preferably at least 85%, even more preferably at least 90%, and still even more preferably at least 95% or 99%, e.g. 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%, sequence identity thereto,

[0362] (iv) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR- 342-3 p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa- miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR- 199b-5p), and / or

[0363] (v) has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR- 342-3 p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa- miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR-30e-3p).

[0364] More preferably, the miRNAs referred to in the ninth or tenth aspect

[0365] (i) have a nucleotide sequence according to SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO:

[0366] 12 (hsa-223-3p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 2 (hsa-miR-let-7f-5p),

[0367] (ii) have a nucleotide sequence according to SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO:

[0368] 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p),

[0369] (iii) have a nucleotide sequence according to SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), and / or (iv) have a nucleotide sequence according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa- miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 12 (hsa- miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR-199b-5p), and / or

[0370] (v) have a nucleotide sequence according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa- miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa- miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR-30e-3p).

[0371] Regarding the ninth or tenth aspect, the immunotherapy encompasses the treatment of the patient with at least one immunotherapeutic agent such as an immune checkpoint inhibitor and the immunochemotherapy encompasses the treatment of the patient with at least one immunotherapeutic agent such as an immune checkpoint inhibitor and at least one chemotherapeutic agent.

[0372] Preferably, the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades, and / or the at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, folinic acid, a folate antagonist, a mitotic inhibitor, an anthracycline, a topoisomerase inhibitor, an antibody, a signal transduction inhibitor, an inhibitor of angiogenesis, and an inhibitor of histone deacetylase, and a platinum doublet.

[0373] More preferably, the at least one immune checkpoint inhibitor targeting PD-1 / PD-L1 is selected from the group consisting of pembrolizumab, nivolumab, cemiplima, durvalumab, and atezolizumab, and / or the at least one chemotherapeutic agent is selected from the group consisting of Cisplatin (CDDP), Carboplatin (CBDCA), and Nedaplatin (CDGP).

[0374] Specifically, the lung cancer is non-small-cell lung carcinoma (NSCLC), preferably NSCLC of stage IV. As to other preferred embodiments, it is referred to the first to eighths aspect of the present invention.

[0375] In one preferred embodiment, the kit of the ninth or tenth aspect comprises means for carrying out next generation sequencing (NGS), at least one polynucleotide (probe) for detecting the at least one miRNA, at least one primer (e.g. a primer pair) for binding the at least one miRNA, and / or at least one antibody capable of binding a hybrid of said at least one polynucleotide (probe) and said at least one miRNA.

[0376] Said means allow to determine the level of the at least one miRNA in a blood sample of a patient suffering from lung cancer and, thus, to predict a response to lung cancer therapy of the patient suffering from lung cancer, to provide a survival prognosis to the patient suffering from lung cancer, or to determine whether to treat the patient suffering from lung cancer.

[0377] The at least one polynucleotide (probe) may be part of a microarray / biochip or may be attached to beads of a beads-based multiplex system. The at least one polynucleotide (primer, primer pair) may be part of a RT-PCR system, a PCR-system, or a next generation sequencing system.

[0378] Said means may further comprise a microarray, an RT-PCT system, a PCR-system, a flow cytometer, a Luminex system, and / or a next generation sequencing system.

[0379] The at least one miRNA is detected / determined in a blood sample of the patient suffering from lung cancer.

[0380] Specifically, the kit of the ninth or tenth aspect comprises means for determining the level of PD-L1, in particular in a biological sample, such as a tissue sample, from a patient suffering from cancer. Said means can encompass a polynucleotide (probe), a primer (e.g. a primer pair), and / or an antibody being PD-L1 specific. Thus, in a preferred embodiment, the kit can comprise both, specific means such as polynucleotides for determining the level of the miRNAs identified by the present inventions (preferred combinations are disclosed above) and means for determining the level of PD-L1.

[0381] The kit may further comprise

[0382] (a container, and / or a data carrier.

[0383] The data carrier may be a non-electronical data carrier, e.g. a graphical data carrier such as an information leaflet, an information sheet, a bar code or an access code, or an electronical data carrier such as a floppy disk, a compact disk (CD), a digital versatile disk (DVD), a microchip or another semiconductor-based electronical data carrier. The access code may allow the access to a database, e.g. an internet database, a centralized, or a decentralized database. The access code may also allow access to an application software that causes a computer to perform tasks for computer users or a mobile app which is a software designed to run on smartphones and other mobile devices.

[0384] Said data carrier may further comprise the at least one reference, e.g. the reference level of the level of the at least one miRNA determined herein or the cut-off score. In case that the data carrier comprises an access-code which allows the access to a database, said at least one reference, e.g. said reference level or cut-off score may be deposited in this database.

[0385] The data carrier may also comprise information or instructions on how to carry out the methods as described herein.

[0386] The kit may also comprise materials desirable from a commercial and user standpoint including a buffer(s), a reagent(s) and / or a diluent(s) for determining the level mentioned above.

[0387] As to the first to tenth aspect, the patient suffering from lung cancer is preferably a mammal, particularly a human. As to the first to tenth aspect, the blood sample is preferably whole blood or a blood fraction. More preferably, the blood fraction is selected from the group consisting of a blood cell fraction, plasma, and serum. The blood cell fraction may comprise erythrocytes, leukocytes, and / or thrombocytes. Even more preferably, the blood cell fraction is a fraction of leukocytes, or the blood cell fraction is a mixture of erythrocytes, leukocytes, and thrombocytes.

[0388] Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope of invention. Although the invention has been described in connection with specific preferred embodiments, the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the art in the relevant fields are intended to be covered by the present invention.

[0389] BRIEF DESCRIPTION OF THE FIGURES

[0390] The following Figures are merely illustrative of the present invention and should not be construed to limit the scope of the invention as indicated by the appended claims in any way.

[0391] Figure 1: Overall survival of 121 immunotherapy treated advanced stage NSCLC patients stratified by the 16-miRNA signature. Patients with a low-risk score survive for significantly longer (log rank test pval = 1.066e-08).

[0392] Figure 2: Overall survival of 121 immunotherapy treated advanced stage NSCLC patients stratified by the 5-miRNA signature. Patients with a low-risk score survive for significantly longer (log rank test pval = 0.000154). Figure 3: Overall survival of 121 immunotherapy treated advanced stage NSCLC patients stratified by the 17-miRisk signature. Patients with a low-risk score survive for significantly longer (log-rank test, p = 8e-8).

[0393] EXAMPLES

[0394] The examples given below are for illustrative purposes only and do not limit the invention described above in any way.

[0395] EXAMPLE 1:

[0396] Previously, an NGS based signature predictive of immunotherapy efficacy in advanced stage NSLC (with PD-L1 TPS > 50%) was discovered (Rajakumar et al, 2022a, 2022b). Further translational development of such a test would benefit from its transfer to a qPCR platform for kittability, easese of decentralised testing and cost.

[0397] Here, a large internal lung cancer screening cohort (1699 patients) with paired small RNAseq data and clinical blood counts was leveraged to perform independent feature selection. The patients were derived from the following studies:

[0398] • Grosshansdorf (DRKS00018784 ): 872 patients

[0399] • Essen (DRKS00020137): 729 patients

[0400] • Konstanz (DRKS00013647): 58 patients

[0401] • miRSort-2 (DRKS00022300 ): 40 patients

[0402] All participants donated whole blood in PAXgene RNA collection tubes, which underwent processing, RNA extraction and RNA sequencing in a previously described study (Early Detection of Lung Cancer Using Small RNAs, Sikosek, Tobias et al., Journal of Thoracic Oncology, Volume 18, Issue 11, 1504 - 1523).

[0403] The aim of the feature selection was to identify miRNAs that are:

[0404] • highly expressed miRNAs,

[0405] • miRNAs expressed in the cellular fraction of blood, as assessed by a small RNA blood expression atlas (Jehn et al, 2024), and / or

[0406] • important miRNA features in ML models trained to predict systemic inflammation (NLR). This was achieved bioinformatically by training machine learning models and using LI regularisation as a means to ensure sparse models and achieve feature selection. Three models were trained to obtain a candidate list of features:

[0407] 1. LI regularised linear regression model to predict NLR

[0408] 2. LI regularised linear regression model to predict NLR with grid search to optimise regularisation penalty

[0409] 3. LI regularised logistic regression model to predict binarized NLR

[0410] Three separate feature shortlists were generated (Table 1) which were manually curated to identify a final candidate list of 20 miRNAs (Table 2) for further development.

[0411] A qPCR plate layout containing probes against the 20 selected miRNAs (Table 2) was designed and RNA extracted from whole blood PAXgene samples. 121 advanced stage NSCLC patients with high PD-L1 expression (PD-L1 TPS > 50%) were analysed, from studies approved by the Heidelberg University (S-296 / 2016, S-089 / 2019) and Grosshansdorf hospital ethics committee (AZ 12-238).

[0412] Quantification of miRNA using LNA RT-qPCR on Quantstudio

[0413] REFERENCES:

[0414] • miRCURY® LNA® miRNA PCR Handbook For highly sensitive, real-time RT-PCR detection of miRNAs (HB-2431-002, 2019, QIAGEN)

[0415] • miRCURY® LNA® miRNA PCR Exosomes, Serum / Plasma and Other Biofluid Samples Handbook (HB-2439-002, 2019, QIAGEN)

[0416] • QuantStudio 6 and 7 Flex Real-Time PCR Systems Maintenance and Administration Guide (4489821, 2013, Life Technologies Corporation)

[0417] Kits and plates used for qPCR: a) miRCURY LNA rt Kit b) miRCURY LNA S YBR Green PCR Kit (4000rxn) c) miRCURY LNA miRNA Custom PCR Panels a) miRCURY LNA rt Kit

[0418] • Thaw samples on ice / in the fridge

[0419] • Pipet calculated volume of water and sample (vortex before pipetting) on ice to obtain a concentration of 25 ng / pl • Prepare the RT MM with 10% excess according to the protocol (see table below). Increase / decrease volume of RT approach if necessary.

[0420] • Note: If using the UniSP6 Vial for the first-time centrifuge Vial down, add 80 pl water and let it resolve for 20-30 min. Aliquot the rest in adequate volumes

[0421] Reaction Buffer 2

[0422] Uni Sp6 Spike In 0.5

[0423] 1 Ox miRCURY RT Enzyme Mix 1

[0424] RNA Template (25 ng / pl) 6.5

[0425] Total Volume 10

[0426] • Seal the Plate with a thermostable foil, vortex, centrifuge and put reactions into the thermocycler with the following protocol: • If RT reactions are not used the same day, store them at -20 °C b) miRCURY LNA SYBR Green PCR Kit

[0427] • Thaw cDNA on ice / fridge if it is not used the same day of preparation

[0428] • Prepare qPCR MM with 15% excess according to the table below

[0429] Volumes per sample:

[0430] Assay No.: 384 miRCURY qPCR [ l]

[0431] 2x miRCURY SYBR Green

[0432] Master Mix 5

[0433] ROX Reference Dye 0. lx 0.05 cDNA template undil. 0.05

[0434] RNase-free water 4.95

[0435] Total volume 10.05 c) miRCURY LNA miRNA Custom PCR Panels • Open the package of the pre-spotted qPCR Plate, seal it to some extent with foil and centrifuge it down (Imin, 1250g)

[0436] • Pipet the 10 pl of the corresponding mastermix per well

[0437] • seal plate with an optical foil, vortex the plate until the pink spots are no longer visible, incubate 5 min at RT, and centrifuge plate again (30s, 1250g).

[0438] • Open ‘QuantStudio™ Real-Time PCR Software’ and select: o Which instrument type are you using to run the experiment? QuantStudio 6 Flex System o Which block are you using to run the experiment? Either 384-Well (for miRISK v2) or Fast 96-Well (0. ImL) o What type of experiment do you want to set up? Comparative CT (AACT) o Which reagents do you want to use to detect the target sequence? Green reagents o What properties do you want for the instrument run? Standard and tick “Include Melt Curve”

[0439] • In Run Method, indicate 10 pl in "Reaction Volume per Well" and the following program:

[0440] • Data of qPCR can be either exported automatically or manual as ‘ .xls’ data after the run. If you export data automatically take care of the export file location. In the XLS file following information must be included: Sample Setup, Amplification and Results.

[0441] 10-fold cross validation was used to optimise the alpha parameter of an LI regularised Cox proportional hazards model using the scikitsurv python package scikit-survival (version 0.15.1, (Pblsterl, S. (2020) scikit-survival: A Library for Time-to-Event Analysis Built on Top of scikit- learn. Journal of Machine Learning Research 21, 1-6), before a final model was trained on the entire dataset using the previously determined optimal value for alpha. This final model included 16 miRNA features with non-zero coefficients (Table 3) and stratified advanced stage NSCLC patients with high PD-L1 expression into low and high-risk groups with significantly different survival outcomes (see Figure 1, logrank test p-val = 1.066e-08), when using a median risk score threshold (4.365).

[0442] To explore a more condensed model that uses fewer features, a regularisation alpha of 0.1 was set and the model retrained. This resulted in a 5 miRNA feature model (Table 4) that again stratified advanced stage NSCLC patients with high PD-L1 expression into low and high-risk groups with significantly different survival outcomes (see Figure 2, logrank test p-val = 0.000154), when using a median risk score threshold (0.397).

[0443] This signature has utility as a complementary diagnostic to identify those low-risk patients who may benefit from treatment with PD-(L)1 inhibitor immunotherapy alone as opposed to the high- risk patients who may require immunotherapy with additional chemotherapy.

[0444] Table 1 Table 2

[0445] Table 3

[0446] Thus, the following signatures have been tested:

[0447] A signature of 5 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 12 (hsa-223-3p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 2 (hsa-miR-let-7f-5p).

[0448] Its score is calculated according to the following formula: score = (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.183) + (SEQ ID NO: 12 (hsa-223-3p) x -0.043) + (SEQ ID NO: 16 (hsa-miR-199b-5p) x -0.003) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.102) + (SEQ ID NO: 2 (hsa-miR-let-7f-5p) x 0.123), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

[0449] Its cut-off score is about 0.397, wherein a score > about 0.397 indicates that the patient will not respond to immunotherapy, or a score < about 0.397 indicates that the patient will respond to immunotherapy.

[0450] A signature of 16 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR- 143-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR-199b-5p).

[0451] Its score is calculated according to the following formula: score = (SEQ ID NO: 12 (hsa-miR-223-3p) x -0.632) + (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.620) + (SEQ ID NO: 4 (hsa-miR-148a-3p) x -0.297) + (SEQ ID NO: 7 (hsa-miR-125a-5p) x -0.231) + (SEQ ID NO: 14 (hsa-miR-145-5p) x -0.191) + (SEQ ID NO: 10 (hsa-miR-148b-3p) x -0.116) + (SEQ ID NO: 11 (hsa-miR-143-3p) x -0.0436) + (SEQ ID NO: 16 (hsa-miR-199b- 5p) x -0.0206) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.157] + (SEQ ID NO: 9 (hsa-miR-142- 5p) x 0.192) + (SEQ ID NO: 8 (hsa-miR-576-5p) x 0.196) + (SEQ ID NO: 6 (hsa-miR-451a) x 0.232) + (SEQ ID NO: 5 (hsa-miR-192-5p) x 0.296) + (SEQ ID NO: 3 (hsa-miR-155-5p) x 0.336) + (SEQ ID NO: 2 (hsa-let-7f-5p) x 0.353) + (SEQ ID NO: 1 (hsa-miR-342-3p) x 0.405), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

[0452] Its cut-off score is about 4.365, wherein a score > about 4.365 indicates that the patient will not respond to immunotherapy, or a score < about 4.365 indicates that the patient will respond to immunotherapy.

[0453] In the same way, the above cut-off score allows to determine, whether the patient has a poor or whether the patient has a good survival prognosis.

[0454] In addition, the above cut-off score allows to determine that the patient will not benefit from immunotherapy alone and will require immunotherapy in combination with chemotherapy, or that the patient will benefit from either immunotherapy with or without chemotherapy.

[0455] EXAMPLE 2:

[0456] An alternative model / score was generated by repeating the same COX model as described in Example 1, but this time excluding miRNAs having a nucleotide sequence according to SEQ ID NO: 11 (hsa-miR-143-3p) and SEQ ID NO: 16 (hsa-miR-199b-5p). In addition, the miRNAs having a nucleotide sequence according to SEQ ID NO: 17 to SEQ ID NO: 19 were used.

[0457] This resulted in a 17 miRNA feature model (Table 5) that again stratified advanced stage NSCLC patients with high PD-L1 expression into low and high-risk groups with significantly different survival outcomes (see Figure 3, logrank test = 8e-08), when using a median risk score threshold (6.093).

[0458] Table 5:

[0459]

[0460] Thus, the following signature has been tested:

[0461] A signature of 17 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR- 223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR-30e-3p).

[0462] Its score is calculated according to the following formula: score = (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.902) + (SEQ ID NO: 12 (hsa-miR-223-3p) x - 0.843) + (SEQ ID NO: 4 (hsa-miR-148a-3p) x -0.555) + (SEQ ID NO: 7 (hsa-miR-125a-5p) x - 0.367) + (SEQ ID NO: 10 (hsa-miR-148b-3p) x -0.354) + (SEQ ID NO: 14 (hsa-miR-145-5p) x - 0.255) + (SEQ ID NO: 17 (hsa-miR-93-3p) x -0.120) + (SEQ ID NO: 18 (hsa-miR-151a-3p) x 0.137) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.189) + (SEQ ID NO: 19 (hsa-miR-30e-3p) x 0.190) + (SEQ ID NO: 5 (hsa-miR-192-5p) x 0.299) + (SEQ ID NO: 9 (hsa-miR-142-5p) x 0.322) + (SEQ ID NO: 8 (hsa-miR-576-5p) x 0.335) + (SEQ ID NO: 6 (hsa-miR-451a) x 0.375) + (SEQ ID NO: 3 (hsa-miR-155-5p) x 0.465) + (SEQ ID NO: 2 (hsa-let-7f-5p) x -0.488) + (SEQ ID NO: 1 (hsa-miR-342-3p) x 0.623), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

[0463] Its cut-off score is about 6.093, wherein a score > about 6.093 indicates that the patient will not respond to immunotherapy, or a score < about 6.093 indicates that the patient will respond to immunotherapy. In the same way, the above cut-off score allows to determine, whether the patient has a poor or whether the patient has a good survival prognosis.

[0464] In addition, the above cut-off score allows to determine that the patient will not benefit from immunotherapy alone and will require immunotherapy in combination with chemotherapy, or that the patient will benefit from either immunotherapy with or without chemotherapy.

[0465] REFERENCES

[0466] Jehn J, Trudzinski F, Horos R, Schenz J, Uhle F, Weigand MA, Frank M, Kahraman M, Heuvelman M, Sikosek T, et al (2024) miR-Blood - a small RNA atlas of human blood components. Sci Data 11 : 164

[0467] Rajakumar T, Horos R, Jehn J, Schenz J, Muley T, Pelea O, Hofmann S, Kittner P, Kahraman M, Heuvelman M, et al (2022a) A blood-based miRNA signature with prognostic value for overall survival in advanced stage non-small cell lung cancer treated with immunotherapy. Npj Precis Oncol 6: 19

[0468] Rajakumar T, Horos R, Kittner P, Kahraman M, Sikosek T, Hinkfoth F, Tikk K, Mercaldo N, Stenzinger A, Rabe KF, et al (2022b) Brief Report: A blood-based miRNA complementary diagnostic predicts immunotherapy efficacy in advanced stage NSCLC with PD-L1 TPS >50%. Jto Clin Res Reports 3 : 100369

Claims

CLAIMS1. A method of predicting a response to lung cancer immunotherapy of a patient suffering from lung cancer comprising the step of: determining the level of at least one miRNA in a blood sample of a patient suffering from lung cancer, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa- miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR- 148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

2. The method of claim 1, wherein the level of at least one further miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa- miR-150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto is determined.

3. The method of claims 1 or 2, wherein the level of the at least one miRNA is compared to a reference level of said at least one miRNA.

4. The method of claim 3, wherein the reference level is the level of the at least one miRNA determined empirically by measuring a number of reference blood samples from subjects suffering from lung cancer who are non-responders to lung cancer immunotherapy.

5. The method of claim 4, wherein the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 17, a fragment thereof, and a sequence having at least 80% sequence identity thereto below the reference level indicates that the patient will respond to lung cancer immunotherapy, orthe level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 15, SEQ ID NO: 18, SEQ ID NO: 19, a fragment thereof, and a sequence having at least 80% sequence identity thereto above the reference level indicates that the patient will respond to lung cancer immunotherapy.

6. The method of any one of claims 3 to 5, wherein the reference level is the level of the at least one miRNA determined empirically by measuring a number of reference blood samples from subjects suffering from lung cancer who are responders to lung cancer immunotherapy.

7. The method of claim 6, wherein the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 17, a fragment thereof, and a sequence having at least 80% sequence identity thereto above the reference level indicates that the patient will not respond to lung cancer immunotherapy, or the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 15, SEQ ID NO: 18, SEQ ID NO: 19, a fragment thereof, and a sequence having at least 80% sequence identity thereto below the reference level indicates that the patient will not respond to lung cancer immunotherapy.

8. The method of any one of claims 1 to 7, wherein the method further comprises the step of determining a score by summarizing the weighted levels of at least two miRNAs.

9. The method of claim 8, wherein the score is compared to a cut-off score which allows to determine whether the patient will respond to lung cancer immunotherapy or will not respond to lung cancer immunotherapy.

10. The method of claim 9, wherein the score above the cut-off score indicates that the patient will not respond to lung cancer immunotherapy, or the score below or equal to the cut-off score indicates that the patient will respond to lung cancer immunotherapy.

11. The method of any one of claims 8 to 10, wherein the score is determined by summarizing the weighted levels of 5 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 12 (hsa-223- 3p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 2 (hsa-miR-let-7f-5p).

12. The method of claim 11, wherein the score is calculated according to the following formula: score = (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.183) + (SEQ ID NO: 12 (hsa-223-3p) x - 0.043) + (SEQ ID NO: 16 (hsa-miR-199b-5p) x -0.003) + (SEQ ID NO: 15 (hsa-miR-150- 5p) x 0.102) + (SEQ ID NO: 2 (hsa-miR-let-7f-5p) x 0.123), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

13. The method of claim 12, wherein the cut-off score is about 0.397 and wherein a score > about 0.397 indicates that the patient will not respond to immunotherapy, or a score < about 0.397 indicates that the patient will respond to immunotherapy.

14. The method of any one of claims 8 to 10, wherein the score is determined by summarizing the weighted levels of 16 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f- 5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a- 5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 12 (hsa-miR-223- 3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR-199b-5p).

15. The method of claim 14, wherein the score is calculated according to the following formula: score = (SEQ ID NO: 12 (hsa-miR-223-3p) x -0.632) + (SEQ ID NO: 13 (hsa-miR-23a- 3p) x -0.620) + (SEQ ID NO: 4 (hsa-miR-148a-3p) x -0.297) + (SEQ ID NO: 7 (hsa-miR- 125a-5p) x -0.231) + (SEQ ID NO: 14 (hsa-miR-145-5p) x -0.191) + (SEQ ID NO: 10 (hsa-miR-148b-3p) x -0.116) + (SEQ ID NO: 11 (hsa-miR-143-3p) x -0.0436) + (SEQ ID NO: 16 (hsa-miR-199b-5p) x -0.0206) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.157]+ (SEQ ID NO: 9 (hsa-miR-142-5p) x 0.192) + (SEQ ID NO: 8 (hsa-miR-576-5p) x 0.196) + (SEQ ID NO: 6 (hsa-miR-451a) x 0.232) + (SEQ ID NO: 5 (hsa-miR-192-5p) x 0.296) + (SEQ ID NO: 3 (hsa-miR-155-5p) x 0.336) + (SEQ ID NO: 2 (hsa-let-7f-5p) x 0.353) + (SEQ ID NO: 1 (hsa-miR-342-3p) x 0.405), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

16. The method of claim 15, wherein the cut-off score is about 4.365 and wherein a score > about 4.365 indicates that the patient will not respond to immunotherapy, or a score < about 4.365 indicates that the patient will respond to immunotherapy.

17. The method of any one of claims 8 to 10, wherein the score is determined by summarizing the weighted levels of 17 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f- 5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a- 5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a- 3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO:17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR- 30e-3p).

18. The method of claim 17, wherein the score is calculated according to the following formula: score = (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.902) + (SEQ ID NO: 12 (hsa-miR-223- 3p) x -0.843) + (SEQ ID NO: 4 (hsa-miR-148a-3p) x -0.555) + (SEQ ID NO: 7 (hsa-miR- 125a-5p) x -0.367) + (SEQ ID NO: 10 (hsa-miR-148b-3p) x -0.354) + (SEQ ID NO: 14 (hsa-miR-145-5p) x -0.255) + (SEQ ID NO: 17 (hsa-miR-93-3p) x -0.120) + (SEQ ID NO:18 (hsa-miR-151a-3p) x 0.137) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.189) + (SEQ ID NO: 19 (hsa-miR-30e-3p) x 0.190) + (SEQ ID NO: 5 (hsa-miR-192-5p) x 0.299) + (SEQ ID NO: 9 (hsa-miR-142-5p) x 0.322) + (SEQ ID NO: 8 (hsa-miR-576-5p) x 0.335) + (SEQ ID NO: 6 (hsa-miR-451a) x 0.375) + (SEQ ID NO: 3 (hsa-miR-155-5p) x 0.465) + (SEQ ID NO: 2 (hsa-let-7f-5p) x -0.488) + (SEQ ID NO: 1 (hsa-miR-342-3p) x 0.623), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

19. The method of claim 18, wherein the cut-off score is about 6.093 and whereina score > about 6.093 indicates that the patient will not respond to immunotherapy, or a score < about 6.093 indicates that the patient will respond to immunotherapy.

20. The method of any one of claims 1 to 19, wherein the immunotherapy is accompanied with the administration of at least one immune checkpoint inhibitor.

21. The method of claim 20, wherein the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades.

22. The method of any one of claims 1 to 21, wherein the lung cancer is non-small-cell lung carcinoma (NSCLC), preferably NSCLC of stage IV.

23. The method of any one of claims 1 to 22, wherein the level is determined by polymerase chain reaction (PCR), preferably quantitative PCR (qPCR).

24. A method of providing a survival prognosis to a patient suffering from lung cancer who is eligible to immunotherapy comprising the step of: determining the level of at least one miRNA in a blood sample of a patient suffering from lung cancer, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa- miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR- 148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

25. The method of claim 24, wherein the level of at least one further miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223- 3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 19 (hsa-miR-30e- 3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto is determined.

26. The method of claims 24 or 25, wherein the level of the at least one miRNA is compared to a reference level of said at least one miRNA.

27. The method of claim 26, wherein the reference level is the level of the at least one miRNA determined empirically by measuring a number of reference blood samples from subjects suffering from lung cancer having a known poor survival prognosis.

28. The method of claim 27, wherein the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 17, a fragment thereof, and a sequence having at least 80% sequence identity thereto below the reference level indicates that the patient has a good survival prognosis, or the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 15, SEQ ID NO: 18, SEQ ID NO: 19, a fragment thereof, and a sequence having at least 80% sequence identity thereto above the reference level indicates that the patient has a good survival prognosis.

29. The method of any one of claims 26 to 28, wherein the reference level is the level of the at least one miRNA determined empirically by measuring a number of reference blood samples from subjects suffering from lung cancer having a known good survival prognosis.

30. The method of claim 29, wherein the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 17, a fragment thereof, and a sequence having at least 80% sequence identity thereto above the reference level indicates that the patient has a poor survival prognosis, or the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 15, SEQ ID NO: 18, SEQ ID NO: 19, a fragment thereof, and a sequence having at least 80% sequence identity thereto below the reference level indicates that the patient has a poor survival prognosis.

31. The method of any one of claims 24 to 30, wherein the method further comprises the step of determining a score by summarizing the weighted levels of at least two miRNAs.

32. The method of claim 31, wherein the score is compared to a cut-off score which allows to classify the patient has having a good or poor survival prognosis.

33. The method of any one of claims 27 to 32, wherein the good survival prognosis is associated with a high chance / probability of surviving a certain time period, or the poor survival prognosis is associated with a low chance / probability of surviving a certain time period.

34. The method of claim 33, wherein the patient having a good survival prognosis has a chance / probability of greater than 50%, preferably of greater than 60%, more preferably of greater than 70%, even more preferably of greater than 80%, still even more preferably of greater than 90%, or most preferably of greater than 95% to survive a certain time period.

35. The method of claim 33, wherein the patient having a poor prognosis has a chance / probability of equal to or lower than 50%, preferably lower 40%, more preferably of lower than 30%, even more preferably of lower than 20%, still even more preferably of lower than 10%, and most preferably of lower than 5 % to survive a certain time period.

36. The method of any one of claims 33 to 35, wherein the certain time period is a time period of 3 months, 6 months, 9 months, 12 months (1 year), 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years.

37. The method of any one of claims 31 to 36, wherein the score above the cut-off score indicates that the patient has a poor survival prognosis, or the score below or equal to the cut-off score indicates that the patient has a good survival prognosis.

38. The method of any one of claims 31 to 37, wherein the score is determined by summarizing the weighted levels of 5 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 12 (hsa-223-3p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 2 (hsa-miR-let-7f-5p).

39. The method of claim 38, wherein the score is calculated according to the following formula: score = (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.183) + (SEQ ID NO: 12 (hsa-223-3p) x - 0.043) + (SEQ ID NO: 16 (hsa-miR-199b-5p) x -0.003) + (SEQ ID NO: 15 (hsa-miR-150- 5p) x 0.102) + (SEQ ID NO: 2 (hsa-miR-let-7f-5p) x 0.123), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

40. The method of claim 39, wherein the cut-off score is about 0.397 and wherein a score > about 0.397 indicates that the patient has a poor survival prognosis, or a score < about 0.397 indicates that the patient has a good survival prognosis.

41. The method of any one of claims 31 to 37, wherein the score is determined by summarizing the weighted levels of 16 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f- 5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a- 5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 12 (hsa-miR-223- 3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR-199b-5p).

42. The method of claim 41, wherein the score is calculated according to the following formula: score = (SEQ ID NO: 12 (hsa-miR-223-3p) x -0.632) + (SEQ ID NO: 13 (hsa-miR-23a- 3p) x -0.620) + (SEQ ID NO: 4 (hsa-miR-148a-3p) x -0.297) + (SEQ ID NO: 7 (hsa-miR- 125a-5p) x -0.231) + (SEQ ID NO: 14 (hsa-miR-145-5p) x -0.191) + (SEQ ID NO: 10 (hsa-miR-148b-3p) x -0.116) + (SEQ ID NO: 11 (hsa-miR-143-3p) x -0.0436) + (SEQ ID NO: 16 (hsa-miR-199b-5p) x -0.0206) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.157] + (SEQ ID NO: 9 (hsa-miR-142-5p) x 0.192) + (SEQ ID NO: 8 (hsa-miR-576-5p) x 0.196) + (SEQ ID NO: 6 (hsa-miR-451a) x 0.232) + (SEQ ID NO: 5 (hsa-miR-192-5p) x 0.296) + (SEQ ID NO: 3 (hsa-miR-155-5p) x 0.336) + (SEQ ID NO: 2 (hsa-let-7f-5p) x 0.353) + (SEQ ID NO: 1 (hsa-miR-342-3p) x 0.405),wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

43. The method of claim 42, wherein the cut-off score is about 4.365 and wherein a score > about 4.365 indicates that the patient has a poor survival prognosis, or a score < about 4.365 indicates that the patient has a good survival prognosis.

44. The method of any one of claims 31 to 37, wherein the score is determined by summarizing the weighted levels of 17 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f- 5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a- 5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a- 3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO:17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR- 30e-3p).

45. The method of claim 44, wherein the score is calculated according to the following formula: score = (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.902) + (SEQ ID NO: 12 (hsa-miR-223- 3p) x -0.843) + (SEQ ID NO: 4 (hsa-miR-148a-3p) x -0.555) + (SEQ ID NO: 7 (hsa-miR- 125a-5p) x -0.367) + (SEQ ID NO: 10 (hsa-miR-148b-3p) x -0.354) + (SEQ ID NO: 14 (hsa-miR-145-5p) x -0.255) + (SEQ ID NO: 17 (hsa-miR-93-3p) x -0.120) + (SEQ ID NO:18 (hsa-miR-151a-3p) x 0.137) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.189) + (SEQ ID NO: 19 (hsa-miR-30e-3p) x 0.190) + (SEQ ID NO: 5 (hsa-miR-192-5p) x 0.299) + (SEQ ID NO: 9 (hsa-miR-142-5p) x 0.322) + (SEQ ID NO: 8 (hsa-miR-576-5p) x 0.335) + (SEQ ID NO: 6 (hsa-miR-451a) x 0.375) + (SEQ ID NO: 3 (hsa-miR-155-5p) x 0.465) + (SEQ ID NO: 2 (hsa-let-7f-5p) x -0.488) + (SEQ ID NO: 1 (hsa-miR-342-3p) x 0.623), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

46. The method of claim 45, wherein the cut-off score is about 6.093 and wherein a score > about 6.093 indicates that the patient has a poor survival prognosis, or a score < about 6.093 indicates that the patient has a good survival prognosis.

47. The method of any one of claims 24 to 46, wherein the patient is a patient to whom a lung cancer immunotherapy will be, is, or has been administered.

48. The method of any one of claims 24 to 47, wherein the immunotherapy is accompanied with the administration of at least one immune checkpoint inhibitor.

49. The method of claim 48, wherein the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades.

50. The method of any one of claims 24 to 49, wherein the lung cancer is non-small-cell lung carcinoma (NSCLC), preferably NSCLC of stage IV.

51. The method of any one of claims 24 to 50, wherein the level is determined by polymerase chain reaction (PCR), preferably quantitative PCR (qPCR).

52. A method of determining whether to treat a patient suffering from lung cancer with immunotherapy comprising the steps of:(i) carrying out the method of any one of claims 1 to 23, thereby identifying the patient as patient who will respond to lung cancer immunotherapy, or carrying out the method of any one of claims 24 to 51, thereby identifying the patient as patient having a good survival prognosis under immunotherapy, and(ii) assigning the patient to (said) lung cancer immunotherapy.

53. The method of claim 52, wherein the immunotherapy is accompanied with the administration of at least one immune checkpoint inhibitor.

54. The method of claim 53, wherein the at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades.

55. A method of selecting a patient suffering from lung cancer to benefit from immunotherapy or immunochemotherapy comprising the step of: determining the level of at least one miRNA in a blood sample of a patient suffering from lung cancer,wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155- 5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576- 5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150- 5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

56. The method of claim 55, wherein the at least one miRNA has a nucleotide sequence selected from(i) the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa- miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), a fragment thereof, and a sequence having at least 80% sequence identity thereto, and / or(ii) the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa- miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), a fragment thereof, and a sequence having at least 80% sequence identity thereto,(iii) the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let- 7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR- 142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR-199b-5p), and / or(iv) the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let- 7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR- 142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR-223-3p),SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa- miR-151a-3p), and SEQ ID NO: 19 (hsa-miR-30e-3p).

57. The method of claims 55 or 56, wherein the method further comprises the step of determining a score by summarizing the weighted levels of at least two miRNAs.

58. The method of claim 57, wherein the score is compared to a cut-off score which allows to determine whether the patient will benefit from lung cancer immunotherapy or whether the patient will benefit from lung cancer immunochemotherapy.

59. The method of claim 58, wherein the score above the cut-off score indicates that the patient will not benefit from immunotherapy alone and will require immunotherapy in combination with chemotherapy, or the score below or equal to the cut-off score indicates that the patient will benefit from either immunotherapy with or without chemotherapy.

60. The method of any one of claims 57 to 59, wherein the score is determined by summarizing the weighted levels of 5 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 12 (hsa-223- 3p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 2 (hsa-miR-let-7f-5p).

61. The method of claim 60, wherein the score is calculated according to the following formula: score = (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.183) + (SEQ ID NO: 12 (hsa-223-3p) x - 0.043) + (SEQ ID NO: 16 (hsa-miR-199b-5p) x -0.003) + (SEQ ID NO: 15 (hsa-miR-150- 5p) x 0.102) + (SEQ ID NO: 2 (hsa-miR-let-7f-5p) x 0.123), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

62. The method of claim 61, wherein the cut-off score is about 0.397 and wherein a score > about 0.397 indicates that the patient will not benefit from immunotherapy alone and will require immunotherapy in combination with chemotherapy, ora score < about 0.397 indicates that the patient will benefit from either immunotherapy with or without chemotherapy.

63. The method of any one of claims 57 to 59, wherein the score is determined by summarizing the weighted levels of 16 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f- 5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a- 5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 12 (hsa-miR-223- 3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), and SEQ ID NO: 16 (hsa-miR-199b-5p).

64. The method of claim 63, wherein the score is calculated according to the following formula: score = (SEQ ID NO: 12 (hsa-miR-223-3p) x -0.632) + (SEQ ID NO: 13 (hsa-miR-23a- 3p) x -0.620) + (SEQ ID NO: 4 (hsa-miR-148a-3p) x -0.297) + (SEQ ID NO: 7 (hsa-miR- 125a-5p) x -0.231) + (SEQ ID NO: 14 (hsa-miR-145-5p) x -0.191) + (SEQ ID NO: 10 (hsa-miR-148b-3p) x -0.116) + (SEQ ID NO: 11 (hsa-miR-143-3p) x -0.0436) + (SEQ ID NO: 16 (hsa-miR-199b-5p) x -0.0206) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.157] + (SEQ ID NO: 9 (hsa-miR-142-5p) x 0.192) + (SEQ ID NO: 8 (hsa-miR-576-5p) x 0.196) + (SEQ ID NO: 6 (hsa-miR-451a) x 0.232) + (SEQ ID NO: 5 (hsa-miR-192-5p) x 0.296) + (SEQ ID NO: 3 (hsa-miR-155-5p) x 0.336) + (SEQ ID NO: 2 (hsa-let-7f-5p) x 0.353) + (SEQ ID NO: 1 (hsa-miR-342-3p) x 0.405), wherein the miRNA level corresponds to its CT level as assessed by qPCR.

65. The method of claim 64, wherein the cut-off score is about 4.365 and wherein a score > about 4.365 indicates that the patient will not benefit from immunotherapy alone and will require immunotherapy in combination with chemotherapy, or a score < about 4.365 indicates that the patient will benefit from either immunotherapy with or without chemotherapy.

66. The method of any one of claims 57 to 59, wherein the score is determined by summarizing the weighted levels of 17 miRNAs having a nucleotide sequence selected from the group consisting of / according to SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a- 5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a- 3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO:17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), and SEQ ID NO: 19 (hsa-miR- 30e-3p).

67. The method of claim 66, wherein the score is calculated according to the following formula: score = (SEQ ID NO: 13 (hsa-miR-23a-3p) x -0.902) + (SEQ ID NO: 12 (hsa-miR-223- 3p) x -0.843) + (SEQ ID NO: 4 (hsa-miR-148a-3p) x -0.555) + (SEQ ID NO: 7 (hsa-miR- 125a-5p) x -0.367) + (SEQ ID NO: 10 (hsa-miR-148b-3p) x -0.354) + (SEQ ID NO: 14 (hsa-miR-145-5p) x -0.255) + (SEQ ID NO: 17 (hsa-miR-93-3p) x -0.120) + (SEQ ID NO:18 (hsa-miR-151a-3p) x 0.137) + (SEQ ID NO: 15 (hsa-miR-150-5p) x 0.189) + (SEQ ID NO: 19 (hsa-miR-30e-3p) x 0.190) + (SEQ ID NO: 5 (hsa-miR-192-5p) x 0.299) + (SEQ ID NO: 9 (hsa-miR-142-5p) x 0.322) + (SEQ ID NO: 8 (hsa-miR-576-5p) x 0.335) + (SEQ ID NO: 6 (hsa-miR-451a) x 0.375) + (SEQ ID NO: 3 (hsa-miR-155-5p) x 0.465) + (SEQ ID NO: 2 (hsa-let-7f-5p) x -0.488) + (SEQ ID NO: 1 (hsa-miR-342-3p) x 0.623), wherein the miRNA level corresponds to its respective CT level as assessed by qPCR.

68. The method of claim 67, wherein the cut-off score is about 6.093 and wherein a score > about 6.093 indicates that the patient will not benefit from immunotherapy alone and will require immunotherapy in combination with chemotherapy, or a score < about 6.093 indicates that the patient will benefit from either immunotherapy with or without chemotherapy.

69. The method of any one of claims 55 to 68, wherein the immunotherapy is accompanied with the administration of at least one immune checkpoint inhibitor, or the immunochemotherapy is accompanied with the administration of at least one immune checkpoint inhibitor and with the administration of at least one chemotherapeutic agent.

70. The method of claim 69, whereinthe at least one immune checkpoint inhibitor is selected from the group consisting of an inhibitor targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIGIT, CD73 and intrinsic checkpoint blockades, and / or the at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, folinic acid, a folate antagonist, a mitotic inhibitor, an anthracycline, a topoisomerase inhibitor, an antibody, a signal transduction inhibitor, an inhibitor of angiogenesis, and an inhibitor of histone deacetylase.

71. The method of any one of claims 55 to 70, wherein the lung cancer is non-small-cell lung carcinoma (NSCLC), preferably NSCLC of stage IV.

72. The method of any one of claims 55 to 71, wherein the level is determined by polymerase chain reaction (PCR), preferably quantitative PCR (qPCR).

73. A method of determining whether to treat a patient suffering from lung cancer with immunochemotherapy or immunotherapy comprising the steps of:(i) carrying out the method of any one of claims 55 to 72, thereby identifying the patient as patient who will benefit from immunochemotherapy or immunotherapy, and(ii) assigning the patient to said therapy.

74. A method of treating a patient suffering from lung cancer with immunochemotherapy or immunotherapy comprising the steps of:(i) carrying out the method of any one of claims 55 to 72, thereby identifying the patient as patient who will benefit from immunochemotherapy or immunotherapy, and(ii) treating the patient with said therapy.

75. Use of at least one miRNA or at least one polynucleotide allowing the detection of said at least one miRNA for predicting a response to lung cancer immunotherapy of a patient suffering from lung cancer, for providing a survival prognosis to a patient suffering from lung cancer who is eligible to immunotherapy, or for determining whether to treat a patient suffering from lung cancer with immunotherapy, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ IDNO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR- 192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b- 3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

76. The use of claim 75, wherein at least one further miRNA or at least one polynucleotide allowing the detection of said at least one further miRNA is used, wherein said at least one further miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR- 145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

77. Use of at least one miRNA or at least one polynucleotide allowing the detection of said at least one miRNA for selecting a patient suffering from lung cancer to benefit from immunotherapy or immunochemotherapy, or for determining whether to treat a patient suffering from lung cancer with immunochemotherapy or immunotherapy, wherein the at least one miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155- 5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576- 5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150- 5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 17 (hsa-miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

78. A kit for predicting a response to lung cancer immunotherapy of a patient suffering from lung cancer, for providing a survival prognosis to a patient suffering from lung cancer who is eligible to immunotherapy, or for determining whether to treat a patient suffering from lung cancer with immunotherapy, wherein said kit comprises:means for determining the level of at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa-miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa- miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR-148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 17 (hsa- miR-93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

79. The kit of claim 78, wherein the kit comprises means for determining the level of at least one further miRNA, wherein said at least one further miRNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

80. The kit of claims 78 or 79, wherein said kit further comprises instructions on how to carry out the methods according to any one of claims 1 to 54.

81. The kit of any one of claims 78 to 80, wherein the kit is useful for conducting the methods according to any one of claims 1 to 54.

82. A kit for selecting a patient suffering from lung cancer to benefit from immunotherapy or immunochemotherapy, or for determining whether to treat a patient suffering from lung cancer with immunochemotherapy or immunotherapy, wherein said kit comprises: means for determining the level of at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 (hsa-miR-223-3p), SEQ ID NO: 13 (hsa-miR-23a-3p), SEQ ID NO: 1 (hsa-miR-342-3p), SEQ ID NO: 2 (hsa-let-7f-5p), SEQ ID NO: 3 (hsa-miR-155-5p), SEQ ID NO: 4 (hsa-miR-148a-3p), and SEQ ID NO: 5 (hsa- miR-192-5p), SEQ ID NO: 6 (hsa-miR-451a), SEQ ID NO: 7 (hsa-miR-125a-5p), SEQ ID NO: 8 (hsa-miR-576-5p), SEQ ID NO: 9 (hsa-miR-142-5p), SEQ ID NO: 10 (hsa-miR- 148b-3p), SEQ ID NO: 11 (hsa-miR-143-3p), SEQ ID NO: 14 (hsa-miR-145-5p), SEQ ID NO: 15 (hsa-miR-150-5p), SEQ ID NO: 16 (hsa-miR-199b-5p), SEQ ID NO: 17 (hsa-miR- 93-3p), SEQ ID NO: 18 (hsa-miR-151a-3p), SEQ ID NO: 19 (hsa-miR-30e-3p), a fragment thereof, and a sequence having at least 80% sequence identity thereto.

83. The kit of claim 82, wherein said kit further comprises instructions on how to carry out the methods according to any one of claims 55 to 74.

84. The kit of any one of claims 82 or 83, wherein the kit is useful for conducting the methods according to any one of claims 55 to 74.

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