Application of IL4I1 as a drug target in enhancing the efficacy of anti-pd-1 antibody in the treatment of lung adenocarcinoma

Abstract

The application discloses application of IL4I1 as a drug target in enhancing the curative effect of anti-PD-1 antibody treatment on lung adenocarcinoma. The application first finds that the expression amount of IL4I1 in tumor tissues of lung adenocarcinoma patients is significantly higher than that in normal tissues, and is significantly negatively correlated with the survival period of the patients; experimental verification obtains that knocking down IL4I1 can block the nuclear entry of AHR and significantly inhibit the expression of downstream target genes of AHR; animal model verification obtains that knocking down IL4I1 can remodel the activated immune microenvironment by blocking the AHR pathway to inhibit the progression of lung adenocarcinoma; verification obtains that knocking down IL4I1 can significantly enhance the treatment effect of anti-PD-1 antibody on lung adenocarcinoma mice, proving that IL4I1 is an important target for enhancing the anti-PD-1 antibody treatment of lung adenocarcinoma, and developing small molecule drugs targeting IL4I1 is an important strategy for sensitizing the immunotherapy of lung adenocarcinoma. The application provides a new target and strategy for the combined immunotherapy of lung adenocarcinoma, and has important application value.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of biological medicine, and particularly relates to application of IL4I1 as a drug target in enhancing the curative effect of anti-PD-1 antibody treatment on lung adenocarcinoma. BACKGROUND

[0002] Lung cancer is a malignant tumor that seriously threatens human life and health, and its mortality ranks first among malignant tumors. Lung adenocarcinoma is the most common pathological type of lung cancer. Immune checkpoint inhibitor therapy represented by anti-PD-1 antibody is the most promising new method for anti-tumor treatment. At present, nivolumab and other anti-PD-1 antibodies have been approved for inclusion in the first-line treatment regimen for patients with advanced lung adenocarcinoma. However, the clinical efficacy of anti-PD-1 antibody is not good, and the overall treatment response rate in lung adenocarcinoma patients is only about 20%. Therefore, in-depth analysis of the mechanism of poor efficacy of anti-PD-1 antibody in lung adenocarcinoma and identification of new combination therapy targets are the frontiers that need to be solved in current lung adenocarcinoma immunotherapy.

[0003] The efficacy of anti-PD-1 antibody is closely related to the tumor immune microenvironment. The dysfunction of immune cells such as CD8 + T cells, NK cells, and the infiltration of regulatory T cells (Tregs), M2 macrophages and other suppressive immune cells can affect the efficacy of anti-PD-1 antibody through various mechanisms. Therefore, remodeling the activated immune microenvironment of lung adenocarcinoma, especially increasing the proportion and activity of CD8 + T cells in the tumor, is an important strategy to improve the efficacy of anti-PD-1 antibody.

[0004] Previous studies have found that the tryptophan (Trp) / aryl hydrocarbon receptor (AHR) pathway is an important pathway that promotes the formation of tumor suppressive immune microenvironment. Trp in tumor cells is in a high metabolic state, and the metabolites produced by its decomposition are endogenous ligands of AHR. After AHR pathway is activated, it can regulate the expression of various metabolic enzymes and immunosuppressive cytokines in the nucleus, thereby widely promoting the formation of tumor suppressive microenvironment. Therefore, treatment targeting the Trp / AHR metabolic immune pathway is a research hotspot in current tumor immunotherapy. Previous studies believe that IDO1 (indoleamine 2,3-dioxygenase 1) is a key enzyme substance that catalyzes the decomposition of Trp, so various inhibitors targeting IDO1 have been developed for combination therapy with immune checkpoint inhibitors. However, almost all clinical trials have ended in failure, indicating that IDO1 is not a key catalytic enzyme in the Trp / AHR pathway.

[0005] IL4I1 (Interleukin 4 induced 1) belongs to the L-amino-acid oxidase (LAAO) family of flavin adenine dinucleotide (FAD)-binding enzymes, which can catalyze the decomposition of phenylalanine to produce phenylpyruvic acid. Previous studies have shown that IL4I1 can promote central nervous system remyelination by inhibiting the proliferation and activation of T cells, and it can also regulate the function of CD8 + T cells, Treg cells, macrophages and B cells, and other immune cells, thereby promoting the progression of ovarian cancer and leukemia. In addition, an article published in Cell magazine in 2020 showed that IL4I1 is the key enzyme of Trp metabolism compared with IDO1, and IL4I1 can activate the AHR pathway by catalyzing the decomposition of Trp to promote the immune escape of glioma. Previous studies have shown that IL4I1 can promote the progression of glioma, ovarian cancer, lymphoma, melanoma, but its role in lung adenocarcinoma is not clear.

[0006] At present, the regulatory effect of IL4I1 on the immune microenvironment in lung adenocarcinoma, the regulatory effect on the Trp / AHR signaling pathway, and whether it can be used as a drug target to enhance the efficacy of anti-PD-1 antibody therapy are not clear. SUMMARY

[0007] Therefore, the present application aims to overcome the defects in the prior art and proposes the application of IL4I1 as a drug target in enhancing the efficacy of anti-PD-1 antibody in treating lung adenocarcinoma.

[0008] To achieve the above-mentioned purpose, the technical solution of the present application is as follows:

[0009] IL4I1 as a drug target in the development, screening or preparation of drugs for preventing and / or treating lung adenocarcinoma.

[0010] Preferably, the drug inhibits or reduces the expression and / or activity of IL4I1.

[0011] Preferably, the drug has one or more of the following effects:

[0012] 1) blocking the nuclear entry of AHR in lung adenocarcinoma cells to inhibit the growth of lung adenocarcinoma;

[0013] 2) inhibiting the expression of AHR downstream target genes in lung adenocarcinoma cells to inhibit the growth of lung adenocarcinoma;

[0014] 3) inhibiting the activity of AHR pathway in lung adenocarcinoma cells to inhibit the growth of lung adenocarcinoma;

[0015] 4) modulating the tumor immune microenvironment of lung adenocarcinoma to achieve the effect of inhibiting the growth of lung adenocarcinoma;

[0016] 5) enhancing the killing activity of CD8 + T cells on lung adenocarcinoma;

[0017] 6) the effect of sensitizing lung adenocarcinoma to anti-PD-1 antibody treatment.

[0018] A combination drug for preventing and / or treating lung adenocarcinoma, the combination drug comprising a drug inhibiting or reducing the expression and / or activity of IL4I1 and an anti-PD-1 antibody.

[0019] Preferably, the combination drug enhances the efficacy of anti-PD-1 antibody treatment for lung adenocarcinoma by inhibiting or reducing the expression and / or activity of IL4I1.

[0020] Preferably, the combination drug has one or more of the following effects:

[0021] 1) blocking the nuclear entry of AHR in lung adenocarcinoma cells to achieve the effect of inhibiting the growth of lung adenocarcinoma;

[0022] 2) inhibiting the expression of AHR downstream target genes in lung adenocarcinoma cells to achieve the effect of inhibiting the growth of lung adenocarcinoma;

[0023] 3) inhibiting the activity of the AHR pathway in lung adenocarcinoma cells to achieve the effect of inhibiting the growth of lung adenocarcinoma;

[0024] 4) modulating the tumor immune microenvironment of lung adenocarcinoma to achieve the effect of inhibiting the growth of lung adenocarcinoma;

[0025] 5) enhancing the killing activity of CD8 + T cells on lung adenocarcinoma;

[0026] 6) the effect of sensitizing lung adenocarcinoma to anti-PD-1 antibody treatment.

[0027] Compared with the prior art, the present application has the following advantages:

[0028] (1) The present application first found that the expression level of IL4I1 in lung adenocarcinoma patients was significantly higher than that in the paired adjacent tissues, and the expression level of IL4I1 was negatively correlated with the overall survival and progression-free survival of lung adenocarcinoma patients, indicating that IL4I1 is an important oncogene in lung adenocarcinoma.

[0029] (2) The present application also found that knocking down IL4I1 can significantly block the nuclear entry of AHR in lung adenocarcinoma cells and inhibit the expression of its downstream target genes, indicating that IL4I1 can be used as a drug target to block the activation of the AHR pathway.

[0030] (3) In the orthotopic lung adenocarcinoma mouse model, knockdown of IL4I1 can significantly inhibit the growth of mouse tumors and prolong the survival of mice, suggesting that IL4I1 is an important target for the treatment of lung adenocarcinoma.

[0031] (4) In the orthotopic lung adenocarcinoma mouse model, knockdown of IL4I1 can remodel the activated tumor immune microenvironment, and the proportion of CD8 + T cells in the microenvironment is significantly increased and the killing function is significantly enhanced, and the proportion of M1 type macrophages is also significantly up-regulated, and the proportion of regulatory T cells (Treg) and M2 type macrophages is significantly decreased. Therefore, IL4I1 is an important drug target for remodeling the tumor immune microenvironment to inhibit the progression of lung adenocarcinoma.

[0032] (5) In the orthotopic lung adenocarcinoma mouse model, compared with the control group, the efficacy of anti-PD-1 antibody in the IL4I1 knockdown group was significantly enhanced, and the tumor was almost completely inhibited, and the survival of the mice was significantly prolonged, and the proportion of CD8 + T cells in the spleen of the mice was significantly increased, indicating that IL4I1 is an important new drug target for enhancing the efficacy of anti-PD-1 antibody in lung adenocarcinoma. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 Expression analysis of IL4I1 in lung adenocarcinoma patients. A. Differences in IL4I1 mRNA levels in lung adenocarcinoma orthotopic tumors and normal tissues; B-C. Differences in IL4I1 protein levels in lung adenocarcinoma orthotopic tumors and normal tissues and statistical analysis of gray values; D-E. Immunohistochemical staining of IL4I1 in lung adenocarcinoma orthotopic tumors and normal tissues and statistical analysis of H scores; F. Analysis of differences in IL4I1 mRNA levels in lung adenocarcinoma orthotopic tumors and normal tissues using TCGA database; G. Analysis of differences in IL4I1 protein levels in lung adenocarcinoma orthotopic tumors and normal tissues using CPTAC database; H. Analysis of differences in IL4I1 protein levels in lung adenocarcinoma tumors of different grades using CPTAC database; I-J. Analysis of the correlation between IL4I1 and the overall survival and progression-free survival of patients using TCGA lung adenocarcinoma database. NT, normal tissue; LUAD, lung adenocarcinoma.

[0034] Figure 2To knock down the inhibitory effect of IL4I1 on the AHR pathway. A. Detection of the knockdown efficiency of IL4I1 protein level in LLC cells; B. Detection of the knockdown efficiency of IL4I1 mRNA level in LLC cells; C. Effect of knockdown of IL4I1 on total AHR expression in LLC cells; D. Effect of knockdown of IL4I1 on AHR expression in the cytoplasm and nucleus of LLC cells and statistical analysis of gray value; E. Effect of knockdown of IL4I1 on the localization of AHR in LLC cells and statistical analysis of fluorescence quantification; F. Effect of knockdown of IL4I1 on the expression of AHR downstream target genes in LLC cells.

[0035] Figure 3 To knock down the inhibitory effect of IL4I1 on lung adenocarcinoma in mice. A. Small animal live imaging to detect the effect of knockdown of IL4I1 on the growth of lung adenocarcinoma in mice; B. Effect of knockdown of IL4I1 on the survival of mice.

[0036] Figure 4 To knock down the regulatory effect of IL4I1 on the immune microenvironment of lung adenocarcinoma. A-B. Flow cytometry analysis of the effect of knockdown of IL4I1 on the proportion of T cells and their subtypes in the tumor; C-E. Flow cytometry analysis of the effect of knockdown of IL4I1 on the proportion of Treg cells (C), macrophages and their subtypes (D), and NK cells (E) in the tumor; F. Immunohistochemical staining to detect the effect of knockdown of IL4I1 on the infiltration of CD8 + T cells in the tumor and statistical analysis; G. Immunohistochemical staining to detect the effect of knockdown of IL4I1 on the infiltration of GZMB + T cells in the tumor and statistical analysis.

[0037] Figure 5 To knock down the effect of IL4I1 on the efficacy of anti-PD-1 antibody in lung adenocarcinoma in mice. A. Small animal live imaging to detect the growth of lung adenocarcinoma in four groups of mice; B. Statistical analysis of fluorescence quantification of small animal live imaging; C. Statistics of the survival of four groups of mice; D-E. Flow cytometry analysis of the proportion of CD3 + T cells and CD8 + T cells in the spleen of four groups of mice. DETAILED DESCRIPTION

[0038] Unless otherwise defined, the technical terms used in the following examples have the same meanings as generally understood by those skilled in the art to which the present invention pertains. The experimental reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods, unless otherwise specified, are all conventional methods.

[0039] The present invention will be described in detail below with reference to the examples.

[0040] Example 1 The expression of IL4I1 in tumor tissues of lung adenocarcinoma patients was significantly higher than that in normal tissues, and was significantly negatively correlated with the survival of patients.

[0041] The specific steps are as follows: lung adenocarcinoma patient specimens were collected from the Department of Thoracic Surgery of Tianjin Medical University General Hospital, including in situ tumor tissues and paired adjacent tissues. A part of the tissue specimens was placed in 1 mL Trizol solution for tissue disruption, and subsequent RNA and protein extraction, and the expression of IL4I1 mRNA level and protein level was detected by qRT-PCR and western blot, respectively. Another part of the tissue was placed in 4% paraformaldehyde solution, and paraffin sections were prepared by fixation, dehydration, embedding, sectioning, etc. for IL4I1 immunohistochemical staining. In addition, the TCGA lung adenocarcinoma database was analyzed to compare the difference in IL4I1 expression between in situ tumor and normal tissue, and to analyze its correlation with patient prognosis.

[0042] The results are shown in Figure 1 : The mRNA and protein levels of IL4I1 in lung adenocarcinoma patients in situ tumor tissues were significantly higher than those in normal tissues Figure 1 A-C). Immunohistochemical staining showed that the staining of IL4I1 in tumor tissues was significantly enhanced, and the H-score of the immunohistochemical results showed a significant statistical difference Figure 1 D-E). Analysis of TCGA and CPTAC databases also found that the mRNA and protein levels of IL4I1 in lung adenocarcinoma patients in situ tumor tissues were significantly increased, and the protein level of IL4I1 increased with the increase of tumor grade Figure 1 F-H). In addition, the expression of IL4I1 was significantly negatively correlated with the overall survival and progression-free survival of patients Figure 1 I-J). Therefore, IL4I1 is an important oncogene in lung adenocarcinoma patients.

[0043] Example 2 Knockdown of IL4I1 significantly inhibits the activation of AHR pathway.

[0044] The specific steps are as follows: the shIL4I1-1 (AAAAG CAAGA AAGCC ATGAATAAGT TTGGA TCCAA ACTTA TTCAT GGCTT TCTTG C) and shIL4I1-2 (AAAAG CCCAT CGCGCCTCAT ATTCT TTGGA TCCAA AGAAT ATGAG GCGCG ATGGG C) targeting mouse IL4I1 expression and the control shRNA plasmid (AAAAGCAGTT ATCTG GAAGA TCAGG TTGGA TCAAC CTGAT CTTCC AGATA ACTGC) are connected to the lentiviral vector pLV-H1-EF1a-puro. The successfully constructed plasmid is co-transfected into 293T cells with a packaging plasmid to obtain lentivirus expressing shIL4I1-1, shIL4I1-2 and shCtrl. The lentivirus is used to infect the Luciferase-expressing mouse lung adenocarcinoma cell line LLC, and 2 ug / mL puromycin is used for screening. After the screening is completed, the total protein and RNA of the cells are extracted for detection of IL4I1 protein level and mRNA level.

[0045] After the knockdown efficiency of IL4I1 is determined, the total protein of the control group (shCtrl) and the LLC cells with IL4I1 knocked down (shIL4I1-1, shIL4I1-2) is collected, and the expression level of total AHR in the cells is detected. The cell precipitate of the control group (shCtrl) and the LLC with IL4I1 knocked down (shIL4I1-1, shIL4I1-2) is collected, CER I solution is added, vortexed for 15 s, and then placed on ice for 10 min. CER II solution is added, vortexed for 5 s, and then placed on ice for 1 min. After centrifugation, the supernatant is collected to obtain cytoplasmic protein; after washing the precipitate, NER solution is added, and ultrasonic lysis is performed for 1 min. After centrifugation, the supernatant is collected to obtain nuclear protein. Western Blot is used to detect the expression of AHR in cytoplasmic protein and nuclear protein, and Image J software is used for gray scale analysis of the bands.

[0046] The control group (shCtrl) and the LLC cells with IL4I1 knocked down (shIL4I1-2) are subjected to cell climbing, and after the cells adhere, the cells are fixed and blocked with 4% paraformaldehyde solution. AHR antibody and IL4I1 antibody are added for staining, and incubated at 4°C overnight. Fluorescent secondary antibody is incubated at room temperature for 1 h, and then the cells are washed and the nuclei are stained with DAPI. After dehydration and mounting, the localization of AHR is detected by confocal microscopy.

[0047] RNA extraction, reverse transcription and qRT-PCR were performed on LLC cells with control (shCtrl) and knockdown of IL4I1 (shIL4I1-1, shIL4I1-2) to detect the expression of AHR downstream target genes (Il6, Il10, Il22, Il1b, Arg1, Serpinb2, Tiparp, Mmp13, Cyp1b1) in cells.

[0048] Results are shown in Figure 2 Western blot and qRT-PCR detection confirmed that LLC cells with knockdown of IL4I1 (shIL4I1-1, shIL4I1-2) were successfully constructed Figure 2 A-B). The total AHR expression in cells was slightly reduced after knockdown of IL4I1 Figure 2 C). Both nuclear and cytoplasmic separation and immunofluorescence detection found that knockdown of IL4I1 could significantly inhibit the nuclear entry of AHR Figure 2 D-E). In addition, the expression of AHR downstream target genes was also significantly decreased Figure 2 F). Therefore, it is proved that knockdown of IL4I1 in lung adenocarcinoma can significantly inhibit the activity of AHR pathway, and IL4I1 is an important target for inhibiting the activation of AHR pathway in lung adenocarcinoma.

[0049] Example 3 Knockdown of IL4I1 significantly inhibits the progression of lung adenocarcinoma in mice.

[0050] The specific steps are as follows: resuspend the control group (shCtrl) and LLC-Luciferase cells with knockdown of IL4I1 (shIL4I1-2), and mix with an equal volume of Matrigel glue on ice. C57BL / 6 mice, the right chest is disinfected with iodophor, the needle is inserted into the right 4-5 intercostal space of the mouse sternum, the depth of the needle is about 5mm, 1×10 6 cells are injected into each mouse, and the injection site is pressed with a cotton ball after injection, which completes the establishment of the lung adenocarcinoma orthotopic tumor model (6 mice in each group). After 18 days of tumor implantation, the size of the tumor is detected by small animal live imaging. Similarly, the lung adenocarcinoma mouse model is constructed by the above-mentioned method, and 8 mice in each group are observed for the survival period of the mice.

[0051] Results are shown in Figure 3 The fluorescence signal of the lung orthotopic tumor of the mice in the IL4I1 knockdown group was significantly lower than that of the control group mice. In addition, the observation of the survival period of the mice found that knockdown of IL4I1 can significantly prolong the survival period of the mice Figure 3 B). Therefore, this part of the study shows that IL4I1 is an important target for inhibiting the progression of lung adenocarcinoma.

[0052] Example 4 Knockdown of IL4I1 promotes the formation of activated immune microenvironment of lung adenocarcinoma.

[0053] The specific steps are as follows: LLC-Luciferase cells expressing shCtrl and shIL4I1-2 are used to construct a mouse lung orthotopic tumor model. 18 days after tumor inoculation, the tumor tissue is removed from the mouse, a part of the tissue is ground and added with trypsin and collagenase for digestion. After treatment with red blood cell lysate and washing, a single cell suspension is filtered with a 40 μm nylon filter and transferred into a flow tube, and a flow cytometry antibody is added, and incubated in the dark for 30 min. If intracellular factor staining is required, the cells are fixed with flow cytometry fixing solution, then resuspended with membrane breaking solution, incubated in the dark for 15 min, and then the corresponding flow cytometry antibody is added and incubated for 30 min. After washing, the proportion of various immune cells is analyzed by flow cytometry, and the cells and staining scheme are shown in Table 1:

[0054] Table 1 Flow cytometry staining scheme

[0055]

[0056] Another part of the tumor tissue is placed in a 4% paraformaldehyde solution, and paraffin sections are prepared by fixation, dehydration, embedding, sectioning, etc. for CD8 and GZMB immunohistochemical staining.

[0057] The results are shown below: Figure 4 After knocking down IL4I1, the proportion of CD8 + T cells in the mouse tumor is significantly increased, and the proportion of T cells expressing GZMB killing type cytokines is also significantly increased, indicating that knocking down IL4I1 can increase the infiltration of CD8 + T cells in the tumor and enhance their killing function Figure 4 A-B). In addition, after knocking down IL4I1, the proportion of Treg cells decreases, the proportion of total macrophages does not change significantly, the proportion of M1 type macrophages increases, the proportion of M2 type macrophages decreases, and the proportion of NK cells does not change significantly Figure 4 C-E). The results of immunohistochemistry also show that the staining of CD8 and GZMB in tumor tissue with knocked down IL4I1 is significantly stronger than that of the control group Figure 4 F-G). This part of the study shows that knocking down IL4I1 can reshape the activated tumor immune microenvironment, especially the activity of CD8 + T cells, suggesting that IL4I1 is an important target for regulating the tumor immune microenvironment.

[0058] Example 5 Knocking down IL4I1 significantly enhances the therapeutic effect of anti-PD-1 antibody on lung adenocarcinoma mice.

[0059] The specific steps are as follows: LLC-Luciferase cell models expressing shCtrl and shIL4I1-2 are constructed, and 10 mice are included in each group. On the 5th day after tumor inoculation, the mice in the shCtrl group and the shIL4I1-2 group are divided into two groups (5 mice in each group), and 10 mg / kg of anti-IgG-2a or anti-PD-1 antibody (CD279) is injected intraperitoneally once a week. On the 21st day after tumor inoculation, the size of the tumor is detected by small animal live imaging. Similarly, a lung adenocarcinoma mouse model is constructed by the above method, and 7 mice are included in each group. The survival period of the mice is observed.

[0060] The spleen of the mouse in the above model is taken out 21 days after tumor inoculation, ground into a single cell suspension, treated with red blood cell lysis solution, washed, filtered into a single cell suspension with a nylon filter, transferred to a flow tube, washed, and then stained with CD45-APC, CD3-FITC, and CD8-PE / CY7 flow cytometry antibodies. The sample is incubated in the dark for 30 min. After washing, the sample is analyzed by flow cytometry.

[0061] The results are shown in Figure 5 Knocking down IL4I1 can significantly enhance the therapeutic effect of anti-PD-1 antibody, and the tumor of the mouse is almost completely inhibited, and the survival period is significantly prolonged Figure 5 A-C) After knocking down IL4I1 and anti-PD-1 antibody treatment, no orthotopic tumor foci are visible, so CD8 + T cells in the spleen are detected. The results show that the proportion of CD8 + T cells in the spleen of the mouse treated by knocking down IL4I1 and adding anti-PD-1 antibody is significantly increased Figure 5 D-E) Therefore, IL4I1 is an important drug target for sensitizing lung adenocarcinoma anti-PD-1 antibody treatment.

[0062] The above only describes preferred embodiments of the present application, and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. Use of a medicine for inhibiting or reducing the expression and / or activity of IL4I1 in combination with an anti-PD-1 antibody in the preparation of a drug for preventing and / or treating lung adenocarcinoma; The medicine for inhibiting or reducing the expression and / or activity of IL4I1 contains any one of the following shRNAs: AAAAG CAAGA AAGCC ATGAA TAAGT TTGGA TCCAA ACTTA TTCAT GGCTT TCTTG C; AAAAG CCCAT CGCGC CTCAT ATTCT TTGGA TCCAA AGAAT ATGAG GCGCG ATGGG C.

2. Use according to claim 1, characterized in that: The medicine sensitizes the efficacy of anti-PD-1 antibody on lung adenocarcinoma by inhibiting or reducing the expression and / or activity of IL4I1.

3. Use according to claim 1, characterized in that: The medicine plays one or more of the following roles: 1) blocking the nuclear entry of AHR in lung adenocarcinoma cells to inhibit the growth of lung adenocarcinoma; 2) inhibiting the expression of AHR downstream target genes in lung adenocarcinoma cells to inhibit the growth of lung adenocarcinoma; 3) inhibiting the activity of AHR pathway in lung adenocarcinoma cells to inhibit the growth of lung adenocarcinoma; 4) regulating the immune microenvironment of lung adenocarcinoma to inhibit the growth of lung adenocarcinoma; 5) enhance CD8 + T cell killing activity against lung adenocarcinoma; 6) sensitizing the efficacy of anti-PD-1 antibody on lung adenocarcinoma.

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