Research progress in immunotherapy resistance of tumor<b>-</b>associated macrophages in gastric cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIU Tao ¹ , YU Chunyan ¹ , LI Tongtong ¹ , HUANG Yichu ¹ ,  JIANG Lei ^1,2

1. The First Clinical Medical College of Lanzhou University, Lanzhou 730000, P. R. China;
2. The Sixth Ward of General Surgery, the First Hospital of Lanzhou University, Lanzhou 730000, P. R. China;

Corresponding author：

JIANG Lei, Email: jiangyjsggyx@163.com

Keywords：

tumor-associated macrophage; gastric cancer; immunotherapy; resistance; tumor microenvironment

DOI：

10.7507/1007-9424.202407006

Video：

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Objective To summarize the research progress of tumor-associated macrophages (TAM) in immunotherapy and drug resistance of gastric cancer, and provide new ideas for the treatment of gastric cancer. Method The literatures about tumor-associated macrophages in immunotherapy and drug resistance of gastric cancer at home and abroad in recent years were searched and reviewed. Results The incidence and mortality of gastric cancer in China were significantly higher than those in other countries. Surgical treatment remained the primary approach for gastric cancer, and targeted therapy combined with immunotherapy had become the standard first-line treatment for advanced gastric cancer. TAM were a large population of immune cells present in the tumor immune microenvironment and had emerged as novel therapeutic targets and prognostic indicators in individualized treatment strategies. As the relationship between TAM and malignant tumors was further elucidated, TAM was expected to become a key target for the development of novel cancer therapeutics. However, some patients developed resistance during treatment. Recent preclinical and clinical studies had demonstrated that targeting TAM had yielded promising results in gastric cancer treatment. Conclusions The mechanism of TAM and the key factors driving the phenotypic changes of TAM in the microenvironment of gastric cancer remain to be further study. How to inhibit the tumor promoting effect of TAM will provide new clues for the future treatment of gastric cancer.

Citation： LIU Tao, YU Chunyan, LI Tongtong, HUANG Yichu, JIANG Lei. Research progress in immunotherapy resistance of tumor-associated macrophages in gastric cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2024, 31(12): 1528-1533. doi: 10.7507/1007-9424.202407006 Copy

1.	Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263. doi: 10.3322/caac.21834.
2.	闫超, 陕飞, 李子禹. 2020年全球胃癌负担分析: 聚焦中国流行现状. 中国肿瘤, 2023, 32(3): 161-170.
3.	Thrift AP, Wenker TN, El-Serag HB. Global burden of gastric cancer: epidemiological trends, risk factors, screening and prevention. Nat Rev Clin Oncol, 2023, 20(5): 338-349.
4.	Wagner AD, Syn NL, Moehler M, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev, 2017, 8(8): CD004064. doi:10.1002/14651858. CD004064. pub4. doi: 10.1002/14651858.CD004064.pub4.
5.	Guan WL, He Y, Xu RH. Gastric cancer treatment: recent progress and future perspectives. J Hematol Oncol, 2023, 16(1): 57. doi: 10.1186/s13045-023-01451-3.
6.	Liu K, Yuan S, Wang C, et al. Resistance to immune checkpoint inhibitors in gastric cancer. Front Pharmacol, 2023, 14: 1285343. doi: 10.3389/fphar.2023.1285343.
7.	Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol, 2010, 11(10): 889-896.
8.	赵骏杰, 秦净, 束平. 肿瘤相关巨噬细胞是胃癌重要的促进因素. 中国普外基础与临床杂志, 2013, 20(11): 1315-1319.
9.	Yunna C, Mengru H, Lei W, et al. Macrophage M1/M2 polarization. Eur J Pharmacol, 2020, 877: 173090. doi: 10.1016/j.ejphar.2020.173090.
10.	Mantovani A, Sica A, Sozzani S, et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol, 2004, 25(12): 677-686.
11.	Yang Q, Guo N, Zhou Y, et al. The role of tumor-associated macrophages (TAMs) in tumor progression and relevant advance in targeted therapy. Acta Pharm Sin B, 2020, 10(11): 2156-2170.
12.	Oya Y, Hayakawa Y, Koike K. Tumor microenvironment in gastric cancers. Cancer Sci, 2020, 111(8): 2696-2707.
13.	Li Y, Wang Z, Gao P, et al. CircRHBDD1 promotes immune escape via IGF2BP2/PD-L1 signaling and acts as a nanotherapeutic target in gastric cancer. J Transl Med, 2024, 22(1): 704. doi: 10.1186/s12967-024-05498-9.
14.	Zhang Z, Zhang W, Liu X, et al. T lymphocyte-related immune response and immunotherapy in gastric cancer (Review). Oncol Lett, 2024, 28(5): 537. doi: 10.3892/ol.2024.14670.
15.	Negura I, Pavel-Tanasa M, Danciu M. Regulatory T cells in gastric cancer: Key controllers from pathogenesis to therapy. Cancer Treat Rev, 2023, 120: 102629. doi: 10.1016/j.ctrv.2023.102629.
16.	Li S, Cong X, Gao H, et al. Tumor-associated neutrophils induce EMT by IL-17a to promote migration and invasion in gastric cancer cells. J Exp Clin Cancer Res, 2019, 38(1): 6. doi: 10.1186/s13046-018-1003-0.
17.	Zhu L, Huang Y, Li H, et al. Helicobacter pylori promotes gastric cancer progression through the tumor microenvironment. Appl Microbiol Biotechnol, 2022, 106(12): 4375-4385.
18.	Costa NL, Valadares MC, Souza PPC, et al. Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma. Oral Oncol, 2013, 49(3): 216-223.
19.	Chen W. TGF-β regulation of T cells. Annu Rev Immunol, 2023, 41: 483-512.
20.	Zhu L, Fu X, Chen X, et al. M2 macrophages induce EMT through the TGF-β/Smad2 signaling pathway. Cell Biol Int, 2017, 41(9): 960-968.
21.	Chen SM, McMiller T, Sankaran P, et al. The COX-2 pathway as a mediator of resistance to anti-PD-1 therapy. J Immunother Cancer, 2021, 9(Suppl 2): A312-A312. doi:10.1136/jitc-2021- SITC2021.288. doi: 10.1136/jitc-2021-SITC2021.288.
22.	Mulati K, Hamanishi J, Matsumura N, et al. VISTA expressed in tumour cells regulates T cell function. Br J Cancer, 2019, 120(1): 115-127.
23.	Lv K, Sun M, Fang H, et al. Targeting myeloid checkpoint Siglec-10 reactivates antitumor immunity and improves anti-programmed cell death 1 efficacy in gastric cancer. J Immunother Cancer, 2023, 11(11): e007669. doi: 10.1136/jitc-2023-007669.
24.	Du Y, Lin Y, Gan L, et al. Potential crosstalk between SPP1 + TAMs and CD8 + exhausted T cells promotes an immunosuppressive environment in gastric metastatic cancer. J Transl Med, 2024, 22(1): 158. doi: 10.1186/s12967-023-04688-1.
25.	Li M O, Wolf N, Raulet D H, et al. Innate immune cells in the tumor microenvironment. Cancer Cell, 2021, 39(6): 725-729.
26.	Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med, 2004, 10(9): 942-949.
27.	Yu S, Li Q, Yu Y, et al. Activated HIF1α of tumor cells promotes chemoresistance development via recruiting GDF15-producing tumor-associated macrophages in gastric cancer. Cancer Immunol Immunother, 2020, 69(10): 1973-1987.
28.	Osinsky S, Bubnovskaya L, Ganusevich I, et al. Hypoxia, tumour-associated macrophages, microvessel density, VEGF and matrix metalloproteinases in human gastric cancer: interaction and impact on survival. Clin Transl Oncol, 2011, 13(2): 133-138.
29.	Park JY, Sung JY, Lee J, et al. Polarized CD163⁺ tumor-associated macrophages are associated with increased angiogenesis and CXCL12 expression in gastric cancer. Clin Res Hepatol Gastroenterol, 2016, 40(3): 357-365.
30.	Mao D, Zhou Z, Chen H, et al. Pleckstrin-2 promotes tumour immune escape from NK cells by activating the MT1-MMP-MICA signalling axis in gastric cancer. Cancer Lett, 2023, 572: 216351. doi: 10.1016/j.canlet.2023.216351.
31.	Li Z, Suo B, Long G, et al. Exosomal miRNA-16-5p derived from M1 macrophages enhances T Cell-dependent immune response by regulating PD-L1 in gastric cancer. Front Cell Dev Biol, 2020, 8: 572689. doi: 10.3389/fcell.2020.572689.
32.	Cassetta L, Pollard J W. A timeline of tumour-associated macrophage biology. Nat Rev Cancer, 2023, 23(4): 238-257.
33.	Li C, Deng C, Wang S, et al. A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization. Redox Biol, 2024, 70: 103059. doi: 10.1016/j.redox.2024.103059.
34.	He X, Wang B, Deng W, et al. Impaired bisecting GlcNAc reprogrammed M1 polarization of macrophage. Cell Commun Signal, 2024, 22(1): 73. doi: 10.1186/s12964-023-01432-6.
35.	Zhang W, Xu W, Xiong S. Blockade of Notch1 signaling alleviates murine lupus via blunting macrophage activation and M2b polarization. J Immunol, 2010, 184(11): 6465-6478.
36.	Lu J, Cao Q, Zheng D, et al. Discrete functions of M2a and M2c macrophage subsets determine their relative efficacy in treating chronic kidney disease. Kidney Int, 2013, 84(4): 745-755.
37.	Wang S, Wang J, Chen Z, et al. Targeting M2-like tumor-associated macrophages is a potential therapeutic approach to overcome antitumor drug resistance. NPJ Precis Oncol, 2024, 8(1): 31. doi: 10.1038/s41698-024-00522-z.
38.	Deng C, Huo M, Chu H, et al. Exosome circATP8A1 induces macrophage M2 polarization by regulating the miR-1-3p/STAT6 axis to promote gastric cancer progression. Mol Cancer, 2024, 23(1): 49. doi: 10.1186/s12943-024-01966-4.
39.	Li C, Chen Z, Gao J, et al. MIR4435-2HG in exosomes promotes gastric carcinogenesis by inducing M2 polarization in macrophages. Front Oncol, 2022, 12: 1017745. doi: 10.3389/fonc.2022.1017745.
40.	Gao LF, Li W, Liu YG, et al. Inhibition of MIR4435-2HG on invasion, migration, and EMT of gastric carcinoma cells by mediating MiR-138-5p/Sox4 axis. Front Oncol, 2021, 11: 661288. doi: 10.3389/fonc.2021.661288.
41.	Kennedy LC, Bickford LR, Lewinski NA, et al. A new era for cancer treatment: gold-nanoparticle-mediated thermal therapies. Small, 2011, 7(2): 169-183.
42.	Li C, Wang L, Li Z, et al. Repolarizing tumor-associated macrophages and inducing immunogenic cell death: A targeted liposomal strategy to boost cancer immunotherapy. Int J Pharm, 2024, 651: 123729. doi: 10.1016/j.ijpharm.2023.123729.
43.	Chen Y, Gong L, Cao Y, et al. Reprogramming tumor-associated macrophages by a dually targeted milk exosome system as a potent monotherapy for cancer. J Control Release, 2024, 366: 395-409.
44.	Zhang W, Liu L, Su H, et al. Chimeric antigen receptor macrophage therapy for breast tumours mediated by targeting the tumour extracellular matrix. Br J Cancer, 2019, 121(10): 837-845.
45.	Snyder CM, Gill SI. Good CARMA: Turning bad tumor-resident myeloid cells good with chimeric antigen receptor macrophages. Immunol Rev, 2023, 320(1): 236-249.
46.	Kluger HM, Tawbi H, Feltquate D, et al. Society for Immunotherapy of Cancer (SITC) checkpoint inhibitor resistance definitions: efforts to harmonize terminology and accelerate immuno-oncology drug development. J Immunother Cancer, 2023, 11(7): e007309. doi: 10.1136/jitc-2023-007309.
47.	Klichinsky M, Ruella M, Shestova O, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol, 2020, 38(8): 947-953.
48.	Han Y, Sun B, Cai H, et al. Simultaneously target of normal and stem cells-like gastric cancer cells via cisplatin and anti-CD133 CAR-T combination therapy. Cancer Immunol Immunother, 2021, 70(10): 2795-2803.

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263. doi: 10.3322/caac.21834.
2. 闫超, 陕飞, 李子禹. 2020年全球胃癌负担分析: 聚焦中国流行现状. 中国肿瘤, 2023, 32(3): 161-170.
3. Thrift AP, Wenker TN, El-Serag HB. Global burden of gastric cancer: epidemiological trends, risk factors, screening and prevention. Nat Rev Clin Oncol, 2023, 20(5): 338-349.
4. Wagner AD, Syn NL, Moehler M, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev, 2017, 8(8): CD004064. doi:10.1002/14651858. CD004064. pub4. doi: 10.1002/14651858.CD004064.pub4.
5. Guan WL, He Y, Xu RH. Gastric cancer treatment: recent progress and future perspectives. J Hematol Oncol, 2023, 16(1): 57. doi: 10.1186/s13045-023-01451-3.
6. Liu K, Yuan S, Wang C, et al. Resistance to immune checkpoint inhibitors in gastric cancer. Front Pharmacol, 2023, 14: 1285343. doi: 10.3389/fphar.2023.1285343.
7. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol, 2010, 11(10): 889-896.
8. 赵骏杰, 秦净, 束平. 肿瘤相关巨噬细胞是胃癌重要的促进因素. 中国普外基础与临床杂志, 2013, 20(11): 1315-1319.
9. Yunna C, Mengru H, Lei W, et al. Macrophage M1/M2 polarization. Eur J Pharmacol, 2020, 877: 173090. doi: 10.1016/j.ejphar.2020.173090.
10. Mantovani A, Sica A, Sozzani S, et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol, 2004, 25(12): 677-686.
11. Yang Q, Guo N, Zhou Y, et al. The role of tumor-associated macrophages (TAMs) in tumor progression and relevant advance in targeted therapy. Acta Pharm Sin B, 2020, 10(11): 2156-2170.
12. Oya Y, Hayakawa Y, Koike K. Tumor microenvironment in gastric cancers. Cancer Sci, 2020, 111(8): 2696-2707.
13. Li Y, Wang Z, Gao P, et al. CircRHBDD1 promotes immune escape via IGF2BP2/PD-L1 signaling and acts as a nanotherapeutic target in gastric cancer. J Transl Med, 2024, 22(1): 704. doi: 10.1186/s12967-024-05498-9.
14. Zhang Z, Zhang W, Liu X, et al. T lymphocyte-related immune response and immunotherapy in gastric cancer (Review). Oncol Lett, 2024, 28(5): 537. doi: 10.3892/ol.2024.14670.
15. Negura I, Pavel-Tanasa M, Danciu M. Regulatory T cells in gastric cancer: Key controllers from pathogenesis to therapy. Cancer Treat Rev, 2023, 120: 102629. doi: 10.1016/j.ctrv.2023.102629.
16. Li S, Cong X, Gao H, et al. Tumor-associated neutrophils induce EMT by IL-17a to promote migration and invasion in gastric cancer cells. J Exp Clin Cancer Res, 2019, 38(1): 6. doi: 10.1186/s13046-018-1003-0.
17. Zhu L, Huang Y, Li H, et al. Helicobacter pylori promotes gastric cancer progression through the tumor microenvironment. Appl Microbiol Biotechnol, 2022, 106(12): 4375-4385.
18. Costa NL, Valadares MC, Souza PPC, et al. Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma. Oral Oncol, 2013, 49(3): 216-223.
19. Chen W. TGF-β regulation of T cells. Annu Rev Immunol, 2023, 41: 483-512.
20. Zhu L, Fu X, Chen X, et al. M2 macrophages induce EMT through the TGF-β/Smad2 signaling pathway. Cell Biol Int, 2017, 41(9): 960-968.
21. Chen SM, McMiller T, Sankaran P, et al. The COX-2 pathway as a mediator of resistance to anti-PD-1 therapy. J Immunother Cancer, 2021, 9(Suppl 2): A312-A312. doi:10.1136/jitc-2021- SITC2021.288. doi: 10.1136/jitc-2021-SITC2021.288.
22. Mulati K, Hamanishi J, Matsumura N, et al. VISTA expressed in tumour cells regulates T cell function. Br J Cancer, 2019, 120(1): 115-127.
23. Lv K, Sun M, Fang H, et al. Targeting myeloid checkpoint Siglec-10 reactivates antitumor immunity and improves anti-programmed cell death 1 efficacy in gastric cancer. J Immunother Cancer, 2023, 11(11): e007669. doi: 10.1136/jitc-2023-007669.
24. Du Y, Lin Y, Gan L, et al. Potential crosstalk between SPP1 + TAMs and CD8 + exhausted T cells promotes an immunosuppressive environment in gastric metastatic cancer. J Transl Med, 2024, 22(1): 158. doi: 10.1186/s12967-023-04688-1.
25. Li M O, Wolf N, Raulet D H, et al. Innate immune cells in the tumor microenvironment. Cancer Cell, 2021, 39(6): 725-729.
26. Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med, 2004, 10(9): 942-949.
27. Yu S, Li Q, Yu Y, et al. Activated HIF1α of tumor cells promotes chemoresistance development via recruiting GDF15-producing tumor-associated macrophages in gastric cancer. Cancer Immunol Immunother, 2020, 69(10): 1973-1987.
28. Osinsky S, Bubnovskaya L, Ganusevich I, et al. Hypoxia, tumour-associated macrophages, microvessel density, VEGF and matrix metalloproteinases in human gastric cancer: interaction and impact on survival. Clin Transl Oncol, 2011, 13(2): 133-138.
29. Park JY, Sung JY, Lee J, et al. Polarized CD163⁺ tumor-associated macrophages are associated with increased angiogenesis and CXCL12 expression in gastric cancer. Clin Res Hepatol Gastroenterol, 2016, 40(3): 357-365.
30. Mao D, Zhou Z, Chen H, et al. Pleckstrin-2 promotes tumour immune escape from NK cells by activating the MT1-MMP-MICA signalling axis in gastric cancer. Cancer Lett, 2023, 572: 216351. doi: 10.1016/j.canlet.2023.216351.
31. Li Z, Suo B, Long G, et al. Exosomal miRNA-16-5p derived from M1 macrophages enhances T Cell-dependent immune response by regulating PD-L1 in gastric cancer. Front Cell Dev Biol, 2020, 8: 572689. doi: 10.3389/fcell.2020.572689.
32. Cassetta L, Pollard J W. A timeline of tumour-associated macrophage biology. Nat Rev Cancer, 2023, 23(4): 238-257.
33. Li C, Deng C, Wang S, et al. A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization. Redox Biol, 2024, 70: 103059. doi: 10.1016/j.redox.2024.103059.
34. He X, Wang B, Deng W, et al. Impaired bisecting GlcNAc reprogrammed M1 polarization of macrophage. Cell Commun Signal, 2024, 22(1): 73. doi: 10.1186/s12964-023-01432-6.
35. Zhang W, Xu W, Xiong S. Blockade of Notch1 signaling alleviates murine lupus via blunting macrophage activation and M2b polarization. J Immunol, 2010, 184(11): 6465-6478.
36. Lu J, Cao Q, Zheng D, et al. Discrete functions of M2a and M2c macrophage subsets determine their relative efficacy in treating chronic kidney disease. Kidney Int, 2013, 84(4): 745-755.
37. Wang S, Wang J, Chen Z, et al. Targeting M2-like tumor-associated macrophages is a potential therapeutic approach to overcome antitumor drug resistance. NPJ Precis Oncol, 2024, 8(1): 31. doi: 10.1038/s41698-024-00522-z.
38. Deng C, Huo M, Chu H, et al. Exosome circATP8A1 induces macrophage M2 polarization by regulating the miR-1-3p/STAT6 axis to promote gastric cancer progression. Mol Cancer, 2024, 23(1): 49. doi: 10.1186/s12943-024-01966-4.
39. Li C, Chen Z, Gao J, et al. MIR4435-2HG in exosomes promotes gastric carcinogenesis by inducing M2 polarization in macrophages. Front Oncol, 2022, 12: 1017745. doi: 10.3389/fonc.2022.1017745.
40. Gao LF, Li W, Liu YG, et al. Inhibition of MIR4435-2HG on invasion, migration, and EMT of gastric carcinoma cells by mediating MiR-138-5p/Sox4 axis. Front Oncol, 2021, 11: 661288. doi: 10.3389/fonc.2021.661288.
41. Kennedy LC, Bickford LR, Lewinski NA, et al. A new era for cancer treatment: gold-nanoparticle-mediated thermal therapies. Small, 2011, 7(2): 169-183.
42. Li C, Wang L, Li Z, et al. Repolarizing tumor-associated macrophages and inducing immunogenic cell death: A targeted liposomal strategy to boost cancer immunotherapy. Int J Pharm, 2024, 651: 123729. doi: 10.1016/j.ijpharm.2023.123729.
43. Chen Y, Gong L, Cao Y, et al. Reprogramming tumor-associated macrophages by a dually targeted milk exosome system as a potent monotherapy for cancer. J Control Release, 2024, 366: 395-409.
44. Zhang W, Liu L, Su H, et al. Chimeric antigen receptor macrophage therapy for breast tumours mediated by targeting the tumour extracellular matrix. Br J Cancer, 2019, 121(10): 837-845.
45. Snyder CM, Gill SI. Good CARMA: Turning bad tumor-resident myeloid cells good with chimeric antigen receptor macrophages. Immunol Rev, 2023, 320(1): 236-249.
46. Kluger HM, Tawbi H, Feltquate D, et al. Society for Immunotherapy of Cancer (SITC) checkpoint inhibitor resistance definitions: efforts to harmonize terminology and accelerate immuno-oncology drug development. J Immunother Cancer, 2023, 11(7): e007309. doi: 10.1136/jitc-2023-007309.
47. Klichinsky M, Ruella M, Shestova O, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol, 2020, 38(8): 947-953.
48. Han Y, Sun B, Cai H, et al. Simultaneously target of normal and stem cells-like gastric cancer cells via cisplatin and anti-CD133 CAR-T combination therapy. Cancer Immunol Immunother, 2021, 70(10): 2795-2803.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research progress in immunotherapy resistance of tumor-associated macrophages in gastric cancer

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