A biomarker for predicting the efficacy of tumor immunotherapy and its application

Abstract

The present invention discloses a biomarker for predicting the efficacy of tumor immunotherapy and its application, which relates to the field of biomedicine technology. The biomarker is secretory frizzled-related protein 2 of tumor-associated fibroblasts. The present invention systematically reveals the function of secretory frizzled-related protein 2 of tumor-associated fibroblasts in the tumor microenvironment from multiple dimensions such as cell subpopulations themselves, interactions with the microenvironment, and spatial distribution characteristics, and confirms that secretory frizzled-related protein 2 of tumor-associated fibroblasts can be used as a biological marker to effectively predict the efficacy of tumor immunotherapy. This has important clinical value and significance for the early evaluation of the efficacy of immunotherapy in clinical tumor patients and the formulation of individualized treatment plans, and ultimately improving the survival rate of tumor patients.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and in particular to a biomarker for predicting the efficacy of tumor immunotherapy and its application. Background Art

[0002] The tumor extracellular matrix microenvironment plays an important role in the biological processes of tumor occurrence, development, and invasion, among which tumor-associated fibroblasts (CAFs) are one of the most important components of the matrix microenvironment. CAFs are more active and proliferate faster than ordinary fibroblasts. They can secrete a variety of cytokines, promote tumor angiogenesis, induce epithelial-mesenchymal transition in tumor cells, and break the homeostasis between tissue cells, thereby making the microenvironment more conducive to tumor cell growth. It has been found that CAFs play an important role in assisting tumor cells to escape immune system, promoting tumor cell proliferation, invasion and metastasis, and promoting tumor drug resistance.

[0003] Tumor immunotherapy is a treatment method that controls and kills tumor cells by mobilizing the body's immune system and enhancing anti-tumor immunity. In recent years, it has become one of the important treatments for a variety of tumors, such as lung cancer, breast cancer, and gastric cancer. More and more cancer patients benefit from immunotherapy. Currently, the most commonly used immunotherapy drugs are mainly immune checkpoint inhibitors such as PD-1 and PD-L1 antibodies. Many literatures have reported that CAFs can affect the efficacy of immunotherapy. Studies have shown that CAFs inhibit acquired immunity, especially through various mechanisms to inhibit cytotoxicity (i.e., CD8 + ) T cell function, direct interactions between CAFs and CD8 T cells also contribute to CAFs-mediated immunosuppression. The density and composition of the tumor extracellular matrix are mainly determined by CAFs activity, so CAFs can affect the penetration of T cells into the tumor core, thereby affecting anti-tumor immunity. In a series of cancers, it has been found that high CAFs content is associated with a weakened response to anti-CTLA-4, anti-PD-1 and anti-PD-L1 treatment. Therefore, targeting CAFs may be a promising strategy to overcome immunotherapy resistance.

[0004] Secreted frizzled-related protein 2 (SFRP2) is a new angiogenic factor secreted by tumor cells, endothelial cells and activated T cells. So far, the mechanism of action of CAFs with high SFRP2 expression in tumor growth and its effect on the efficacy of immunotherapy are still unclear. Therefore, exploring the biological function of CAFs with high SFRP2 expression in tumor progression and using it as a biomarker for early prediction of the efficacy of tumor immunotherapy can provide a scientific basis for the optimal treatment decision of tumors in clinical practice, which is of great clinical significance. Summary of the invention

[0005] The purpose of the present invention is to provide a biomarker for predicting the efficacy of tumor immunotherapy and its application, so as to solve the problems existing in the above-mentioned prior art. The biomarker can effectively predict the efficacy of tumor immunotherapy, which has important clinical value and significance for the early evaluation of the efficacy of immunotherapy in clinical tumor patients and the formulation of individualized treatment plans, and ultimately improves the survival rate of tumor patients.

[0006] To achieve the above object, the present invention provides the following solutions:

[0007] The present invention provides a biomarker for predicting the efficacy of tumor immunotherapy, wherein the biomarker is secretory frizzled-related protein 2 of tumor-associated fibroblasts.

[0008] Furthermore, the expression level of the secreted frizzled-related protein 2 in the tumor-associated fibroblasts is increased, indicating that the efficacy of tumor immunotherapy for tumor patients is poor.

[0009] The present invention also provides the use of a reagent for detecting the expression amount of secretory frizzled-related protein 2 of tumor-associated fibroblasts in the preparation of a product for predicting the efficacy of tumor immunotherapy.

[0010] Furthermore, the tumor is lung cancer, kidney cancer, gastric cancer or metastatic urothelial carcinoma.

[0011] Furthermore, the lung cancer is non-small cell lung cancer.

[0012] Furthermore, the product is a kit or a reagent.

[0013] The present invention also provides a product for predicting the efficacy of tumor immunotherapy, including a reagent for detecting the expression level of secretory frizzled-related protein 2 in tumor-associated fibroblasts.

[0014] Furthermore, the tumor is lung cancer, kidney cancer, gastric cancer or metastatic urothelial carcinoma.

[0015] Furthermore, the lung cancer is non-small cell lung cancer.

[0016] Furthermore, the product is a kit or a reagent.

[0017] The present invention discloses the following technical effects:

[0018] The present invention uses a variety of technologies such as multicolor immunofluorescence technology, bioinformatics functional analysis, cell communication analysis, spatial transcriptome analysis, etc. to systematically reveal the function of the expression level of secretory frizzled-related protein 2 of tumor-associated fibroblasts in the tumor microenvironment from multiple dimensions such as cell subpopulations themselves, interactions with the microenvironment, and spatial distribution characteristics, laying a solid theoretical foundation for the tumor treatment model targeting tumor-associated fibroblasts that highly express SFRP2.

[0019] The present invention confirms that the secretory frizzled-related protein 2 of tumor-associated fibroblasts can be used as a biological marker to effectively predict the efficacy of tumor immunotherapy, which has important clinical value and significance for the early evaluation of the efficacy of immunotherapy in clinical tumor patients and the formulation of individualized treatment plans, and ultimately improving the survival rate of tumor patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0021] Figure 1 The results of verifying the existence of CAF cell populations with high expression of SFRP2 on human lung cancer tissue chips; wherein A is a thumbnail of tissue spots on the chip, B is a schematic diagram of the staining results of CD31 used to characterize blood vessels, C is a schematic diagram of the staining results of SFRP2, and D is a schematic diagram of the staining results of αSMA used to characterize tumor-associated fibroblasts;

[0022] Figure 2 The expression of SFRP2 in different cell subpopulations divided by sequencing data sets of lung adenocarcinoma (AC) and non-small cell lung cancer (DF); wherein A is the result of cell subpopulation division of tumor fibroblast data of lung cancer single-cell sequencing data set (GSE131907); B is the distribution display result of SFRP2 expression level in cell subpopulation A on a two-dimensional plane; C is the quantitative evaluation result of SFRP2 expression level in cell subpopulation A; D is the result of cell subpopulation division of tumor fibroblast data of lung cancer single-cell sequencing data set (GSE127465); E is the distribution display result of SFRP2 expression level in cell subpopulation D on a two-dimensional plane; F is the quantitative evaluation result of SFRP2 expression level in cell subpopulation D;

[0023] Figure 3 Functional enrichment diagram of SFRP2 high expression group compared with SFRP2 low expression group in lung adenocarcinoma (A) and non-small cell lung cancer (B);

[0024] Figure 4Figure 2 is the interaction relationship between CAFs with high and low SFRP2 expression and various cells in lung adenocarcinoma (AC) and non-small cell lung cancer (DF); A is the result of dividing the cell subpopulations of lung cancer single-cell sequencing dataset (GSE131907) according to markers; BC is SFRP2 - CAF and SFRP2 + Schematic diagram of the interaction between CAF cell population and other cell populations; D is the result of dividing the cell subpopulations based on the single-cell sequencing dataset of lung cancer (GSE127465) according to the markers; EF are SFRP2 - CAF and SFRP2 + Schematic diagram of the interaction between CAF cell populations and other cell populations;

[0025] Figure 5 Schematic diagram of SFRP2 expression and distribution of fibroblasts, macrophages and blood vessels in spatial transcriptome sequencing data of human lung cancer;

[0026] Figure 6 Schematic diagram of SFRP2 expression and distribution of fibroblasts, macrophages, and CD8 T cells in four samples of human renal cancer cohort;

[0027] Figure 7 Figure 3. SFRP2 expression level and CD8 in TCGA lung adenocarcinoma (A) and breast cancer (B) datasets. + Correlation plot of T cell infiltration;

[0028] Figure 8 This is a graph of progression-free survival for high and low expression groups of biomarkers of tumor-associated fibroblasts that highly express SFRP2 in the lung cancer immunotherapy cohort;

[0029] Fig. 9 The clinical cohort results of Example 3; A and B are the comparison results of SFRP2 expression levels of tumor-associated fibroblasts in patients with different treatment response groups in the metastatic urothelial carcinoma cohort and gastric cancer cohort, respectively; C and D are the progression-free survival diagrams of patients with renal cancer and lung cancer, respectively. DETAILED DESCRIPTION

[0030] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0031] It should be understood that the terms described in the present invention are only for describing a particular embodiment and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. The intermediate value in any stated value or stated range, and each smaller range between any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0032] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0033] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to those skilled in the art. The present invention description and examples are exemplary only.

[0034] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0035] Terminology Note:

[0036] In the present invention, SFRP2 refers to secreted frizzled-related protein 2;

[0037] FBLN1 refers to senescence-critical protein 1;

[0038] DCN refers to core proteoglycan;

[0039] MMP2 refers to matrix metalloproteinase 2;

[0040] WIF1 refers to WNT inhibitory factor 1;

[0041] PI16 refers to peptidase inhibitor 16;

[0042] WISP2 refers to WNT1-induced signaling pathway protein 2;

[0043] CXCL14 refers to chemokine ligand 14;

[0044] COL1A1 refers to type I collagen α1;

[0045] MFAP4 refers to microfibril-associated protein 4;

[0046] C1R refers to complement component 1r;

[0047] CTHRC1 refers to collagen triple helix repeat-containing protein 1;

[0048] COL6A2 refers to type VI human collagen;

[0049] COL1A2 refers to type I collagen α2;

[0050] COL6A1 refers to type VI collagen α1;

[0051] CTSK refers to cathepsin K;

[0052] CFD refers to complement factor D;

[0053] NBL1 refers to neuroblastoma tumor suppressor protein 1;

[0054] CFH refers to complement factor H;

[0055] SERPINF1 refers to pigment epithelium-derived factor;

[0056] IGFBP4 refers to human insulin-like growth factor binding protein 4;

[0057] FBLN2 refers to senescence-critical protein 2;

[0058] SOD3 refers to extracellular superoxide dismutase;

[0059] CLU refers to clusterin;

[0060] C1S refers to complement component 1s;

[0061] LUM refers to basement membrane polysaccharide;

[0062] FHL1 refers to four plus one-half LIM domain protein 1;

[0063] PLAC9 refers to placenta-specific protein 9;

[0064] PPAP2B stands for phosphatidic acid phosphatase 2B

[0065] TIMP1 refers to tissue inhibitor of metalloproteinase 1;

[0066] S100A6 refers to S100 calcium-binding protein A6;

[0067] CD9 refers to the transmembrane protein CD9;

[0068] GSN refers to gelsolin;

[0069] PDGFRL refers to platelet-derived growth factor receptor-like protein;

[0070] SERPING1 refers to serine protease inhibitor G1;

[0071] CYBRD1 refers to tenascin-like protein 1;

[0072] ANGPTL5 refers to angiopoietin-like protein 5;

[0073] THBS2 refers to thrombospondin 2;

[0074] DPT refers to dermal pontin;

[0075] SLIT3 refers to Slit homologous protein 3;

[0076] CD99 refers to the transmembrane protein CD99;

[0077] CPE refers to carboxypeptidase E;

[0078] COL3A1 refers to type III collagen α1;

[0079] MGP refers to matrix Gla protein;

[0080] OSR2 refers to tooth development-related protein OSR2;

[0081] COMP refers to cartilage oligomeric matrix protein;

[0082] FSTL1 refers to follistatin-like protein 1;

[0083] PCOLCE2 refers to procollagen C-terminal protease enhancer 2;

[0084] MFAP5 refers to microfibril-associated protein 5;

[0085] PTGDS refers to the gene prostaglandin D synthase.

[0086] Example 1

[0087] The following experiments were performed to investigate the function of tumor-associated fibroblasts based on high expression of secreted frizzled-related protein 2 (SFRP2) in the tumor microenvironment:

[0088] S1. Based on multiplex immunofluorescence technology, the presence of tumor-associated fibroblasts with high expression of SFRP2 was pathologically detected in the clinical cohort.

[0089] Multiple immunofluorescence techniques include: using the BioNu Panoramic Multi-target Immunofluorescence Staining Kit to detect CD31, α-SMA, and SFRP2 indicators on human lung cancer tissue chips, labeling endothelial cells with CD31 (recombinant Anti-CD31 antibody, ab182981) to evaluate tumor angiogenesis; labeling CAFs with the CAFs biomarker α-SMA (recombinant Anti-alpha smoothmuscle Actin, ab32575). The above labeling method confirms the presence of tumor blood vessels and CAFs in human lung cancer tissue chips, and the distribution of the three is checked by labeling SFRP2 (Anti-SFRP2 antibody-C-terminal, ab137560). The results are as follows: Figure 1 As shown. The specific experimental method includes: baking the tissue sections in a 65℃ oven for 2h; dewaxing with xylene; hydrating with ethanol; soaking in citrate solution (or EDTA solution), high-pressure antigen repair; inactivating endogenous peroxidase with 3% hydrogen peroxide; blocking with blocking solution for 30min; incubating with primary antibody at 4℃ overnight; rinsing with PBST 3 times, adding secondary antibody, incubating at room temperature for 30min; dyeing with room temperature dye for 10min, rinsing with PBST 3 times; microwave elution of primary antibody and secondary antibody complex; starting from blocking with blocking solution, cyclic staining; after all detection indicators are stained, adding DAPI-containing sealing agent and covering with coverslip. The sections were scanned using a high-resolution panoramic pathology scanner.

[0090] The results showed that CD31-labeled tumor blood vessels were tightly surrounded by α-SMA-labeled CAFs, and the expression level of SFRP2 in the surrounding area of ​​these CAFs was high ( Figure 1 ), indicating that there are tumor-associated fibroblasts with high expression of SFRP2 around tumor blood vessels, that is, the existence of CAFs with high expression of SFRP2 was verified by pathological detection in clinical specimens.

[0091] S2. Based on bioinformatics analysis, it was found that tumor-associated fibroblasts with high expression of SFRP2 were highly enriched in pathways such as pro-angiogenesis and pro-collagen matrix formation.

[0092] First, we selected tumor fibroblast data from a lung cancer single-cell sequencing dataset (GSE131907) and divided the cells in the dataset into six cell subpopulations numbered 0-5 using the Uniform Manifold Approximation and Projection (UMAP) method ( Figure 2 Next, the expression level of SFRP2 in each CAF cell subset was displayed on a two-dimensional plane ( Figure 2 B) and quantitative evaluation ( Figure 2C). It can be found that SFRP2 is highly expressed in CAF subgroup 1 ( Figure 2 Similar analysis and verification were performed in another lung cancer single-cell sequencing dataset (GSE127465), and the results showed that SFRP2 was highly expressed in CAF subpopulations 0 and 2 in this dataset ( Figure 2 (in DF).

[0093] Finally, subgroup 1 in GSE131907 and subgroups 0 and 2 in GSE127465 were defined as the SFRP2 high-expression CAF group, and the rest were the SFRP2 low-expression CAF group. Then, the differentially expressed genes of tumor-associated fibroblasts with high and low SFRP2 expression were used for functional analysis through Metascape. The results showed that compared with the SFRP2 low-expression group, the SFRP2 high-expression group CAF cells in the two datasets were highly enriched in pathways such as angiogenesis, collagen matrix formation, high response to the IGF pathway, and cell death. Figure 3 (middle AB).

[0094] S3. Based on cell communication analysis, it was found that tumor-associated fibroblasts with high expression of SFRP2 significantly interacted with endothelial cells, M2 macrophages, CD8 T cells, etc.

[0095] This example further explores the interaction between tumor-associated fibroblasts and other cells, and the effect of SFRP2 expression on cell interaction. A single-cell sequencing dataset of lung cancer (GSE131907) was selected, and t-distributed random neighbor embedding (t-SNE) was used for dimensionality reduction and visualization. FindClusters was used for unsupervised clustering, and cells were divided into 19 groups according to markers ( Figure 4 Middle A): Alveolar macrophage, B cells, C1QC+macrophage, CD163 + Macrophages (CD163+macrophage), dendritic cells (DCs), endothelial cells, FCN1 + Macrophages (FCN1+macrophage), GZMB + PRF1 + T cells, IL7R + T cells, LTB + T cells, mast cells, microglial cells, NK cells, NKT cells, normal epithelial cells, SFRP2 -CAF, SFRP2 + CAF, TCF7 + T cells and tumor cells.

[0096] To evaluate the screened SFRP2 - CAF and SFRP2 + The potential for interaction between CAF cell populations and other cell populations was investigated using the newly developed CellChat platform (Jin et al., 2021) and implemented using the scRNA-seq Seurat object in R. The results showed that SFRP2 - Compared with CAF, SFRP2 + CAFs have extensive interactions with endothelial cells, M2 macrophages, and CD8 T cells ( Figure 4 BC). Similarly, in the GSE127465 dataset, it can be found that tumor-associated fibroblasts with high expression of SFRP2 have significant interactions with endothelial cells, M2 macrophages, CD8 T cells, etc. ( Figure 4 (in DF).

[0097] S4. Based on spatial transcriptome data analysis, we found that tumor-associated fibroblasts with high expression of SFRP2 can form a paravascular niche that is not conducive to CD8 T cell infiltration.

[0098] First, human lung cancer spatial transcriptome sequencing data (10x Genomics, https: / / support.10xgenomics.com) were selected for analysis; the marker score of each cell was calculated by the irGSEA package to characterize the specific cell type, including blood vessels ("PECAM1", "VWF", "RAMP2", "GNG11", "CLDN5" and "EPAS1"), pericytes ("RGS5", "PDGFRB" and "MCAM"), tumor-associated fibroblasts ("COL1A2", "COL1A1", "DCN", "LUM", "THY1", "ACTA2", "S100A4" and "PDPN"), CD8 T cells ("PDCD1", "LAG3", "HAVCR2", "GZMA" and "CCL5"), monocytes / macrophages ("CSF1R", "CD68", "CD14", "LYZ", "MARCO" and "AIF1"). Then, spatial transcription analysis was performed using the Seurat package to visualize the spatial information of the cell population ( Figure 5 The results showed that tumor-associated fibroblasts with high expression of SFRP2 were distributed around blood vessels, accompanied by infiltration of macrophages, and CD8 +The number of T cells is small. Next, the spatial transcriptome sequencing data of 4 samples in the human renal cancer cohort were selected for verification. According to the expression level of SFRP2, they were divided into a high expression group (SFRP2 low: GSM5924035, GSM5924040) and a low expression group (SFRP2high: GSM5924038, GSM5924030). It can be found that the results are basically consistent with the previous results. Compared with the SFRP2 low expression group, the CAFs in the SFRP2 high expression group were distributed around the blood vessels, accompanied by the infiltration of macrophages and CD8 + Decreased number of T cells ( Figure 6 ).

[0099] Finally, the present invention also selected the transcriptome data of lung adenocarcinoma and breast cancer from The Cancer Genome Atlas Program (TCGA). The present invention used log2 to logarithmically normalize the original matrix, and calculated the infiltration ratio of CD8 T cells in each transcriptome using Cistrome Data Browser (http: / / timer.cistrome.org / ), and then used Spearman correlation test to analyze the correlation between SFRP2 expression level and CD8 + The relationship between the degree of T cell infiltration.

[0100] The results showed that in the lung adenocarcinoma dataset, SFRP2 expression levels were significantly correlated with CD8 + The degree of T cell infiltration was negatively correlated, which was statistically significant (P<0.01, Figure 7 Similarly, in breast cancer datasets, it was found that SFRP2 expression levels were significantly correlated with CD8 + There was a significant negative correlation between the infiltration of T cells and Figure 7 (middle B).

[0101] Combined with the above conclusions, it is not difficult to infer that CAFs with high expression of SFRP2 will reshape the tumor microenvironment matrix, thereby forming a paravascular niche that is not conducive to CD8 T cell infiltration.

[0102] Example 2

[0103] This example explores the predictive effect of the biomarker score of tumor-associated fibroblasts with high expression of SFRP2 on the efficacy of tumor immunotherapy. The specific process is as follows:

[0104] First, the characteristic genes of CAFs with high expression of SFRP2 were determined by the FindMarker algorithm, including SFRP2, FBLN1, DCN, MMP2, WIF1, PI16, WISP2, CXCL14, COL1A1, MFAP4, C1R, CTHRC1, COL6A2, COL1A2, COL6A1, CTSK, CFD, NBL1, CFH, SERPINF1, IGFBP4, FBLN2, SOD3, CLU, C1S, LUM, FHL1, PLAC9, PPAP2B, TIMP1, S100A6, CD9, GSN, PDGFRL, SERPING1, CYBRD1, ANGPTL5, THBS2, DPT, SLIT3, CD99, CPE, COL3A1, MGP, OSR2, COMP, FSTL1, PCOLCE2, MFAP5 and PTGDS. Next, the gene scores of these markers were calculated using the GSVA algorithm. Finally, the present invention evaluated the clinical predictive value of the CAFs gene score with high expression of SFRP2 in predicting the efficacy of immunotherapy in the non-small cell lung cancer immunotherapy cohort (GSE126044, GSE135222). According to the median value of the gene score of the cohort, the present invention was divided into two groups: high expression (HIGH) and low expression (LOW). The results showed that the progression-free survival (PFS) of the CAF marker group with high expression of SFRP2 was significantly lower than that of the SFRP2 low expression group ( Figure 8 ).

[0105] This example demonstrates that the biomarker score of tumor-associated fibroblasts with high expression of SFRP2 can effectively predict the efficacy of tumor immunotherapy.

[0106] Example 3

[0107] In the immunotherapy patient cohort of Nanfang Hospital of Southern Medical University, the predictive role of the immunotherapy efficacy of the high-expression SFRP2 tumor-associated fibroblast biomarker score was validated:

[0108] process:

[0109] In the early stage of this invention, baseline tumor tissue specimens of patients treated with anti-PD-1 or anti-PD-L1 antibodies were collected and RNA sequencing was performed, and the patient's immunotherapy response and survival status were tracked through return visits and regular follow-up. Based on the RNA-seq data of baseline tumor tissue, the expression level of SFRP2 in tumor-associated fibroblasts of each patient was obtained.

[0110] The results showed that in metastatic urothelial carcinoma, patients with progressive disease (PD) or persistent disease (SD) had high expression of SFRP2 in tumor-associated fibroblasts, while patients with partial response (PR) or complete response (CR) had lower scores ( Fig. 9 In gastric cancer, SFRP2 expression in tumor-associated fibroblasts was high in patients who did not respond to immunotherapy, whereas it was lower in patients who responded to treatment ( Fig. 9 In the renal cancer cohort, patients whose tumor-associated fibroblasts expressed high levels of SFRP2 had significantly lower survival rates after immunotherapy than those with low expression levels ( Fig. 9 In the lung cancer cohort, patients with high SFRP2 expression in tumor-associated fibroblasts had significantly lower survival rates after immunotherapy than those with low expression ( Fig. 9 (middle D).

[0111] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. Use of a reagent for detecting the expression of secretory frizzled-related protein 2 in tumor-associated fibroblasts in the preparation of a product for predicting the efficacy of tumor immunotherapy, characterized in that: The expression level of secreted frizzled-related protein 2 in the tumor-associated fibroblasts is increased, indicating that the efficacy of tumor immunotherapy for tumor patients is poor; The tumor is lung cancer, kidney cancer or gastric cancer; The drug used in the tumor immunotherapy is an anti-PD-1 or anti-PD-L1 antibody.

2. The use according to claim 1, characterized in that: The lung cancer is non-small cell lung cancer.

3. The use according to claim 1, characterized in that: The product is a kit or a reagent.

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