Research progress of tumor-associated macrophages in colorectal cancer_West China Medical Journal

Authors：

ZHANG Xinfeng ¹ , ZHANG Xiaoli ¹ , WANG Yajing ² , LUO Huayou ¹ , WANG Yuhan ¹ ,  TIAN Yan ¹

1. Department of Gastrointestinal and Hernia Surgery, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P. R. China;
2. Department of General Surgery, Third Medical Center, PLA General Hospital, Beijing 100000, P. R. China;

Corresponding author：

TIAN Yan, Email: 905790434@qq.com

Keywords：

Tumor-associated macrophages; colorectal cancer; gut microbiota; reprogramming; tumor prognosis

DOI：

10.7507/1002-0179.202108230

Video：

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Abstract Full text Figures/Tables Video References Cited by

There is a bidirectional association between tumor-associated macrophage (TAM) and colorectal cancer. Small molecular substances metabolized by colorectal cancer affect the reprogramming of TAM, and TAM in turn regulates the biological behavior of colorectal cancer cells by secreting small molecular substances, and promotes the progression of colorectal cancer. In addition, gut microbiota metabolites are closely related to TAM reprogramming, and intestinal flora imbalance leads to gut barrier damage, favoring bacterial translocation and causing chronic tumorigenic inflammation. Studying the reprogramming mechanism affecting TAM and its relationship with the occurrence and development of colorectal cancer may provide new ideas for the study of immunotherapy in patients with colorectal cancer. This article reviews the research progress of TAM in patients with colorectal cancer, aims to provide a reference for clinical research.

Citation： ZHANG Xinfeng, ZHANG Xiaoli, WANG Yajing, LUO Huayou, WANG Yuhan, TIAN Yan. Research progress of tumor-associated macrophages in colorectal cancer. West China Medical Journal, 2022, 37(9): 1414-1418. doi: 10.7507/1002-0179.202108230 Copy

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3.	Hsu PC, Jablons DM, Yang CT, et al. Epidermal growth factor receptor (EGFR) pathway, yes-associated protein (YAP) and the regulation of programmed death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC). Int J Mol Sci, 2019, 20(15): 3821.
4.	De Souza ALPB. Finding the hot spot: identifying immune sensitive gastrointestinal tumors. Transl Gastroenterol Hepatol, 2020, 5: 48.
5.	Shan T, Chen S, Wu T, et al. PD-L1 expression in colon cancer and its relationship with clinical prognosis. Int J Clin Exp Pathol, 2019, 12(5): 1764-1769.
6.	Sun J, Zheng Y, Mamun M, et al. Research progress of PD-1/PD-L1 immunotherapy in gastrointestinal tumors. Biomed Pharmacother, 2020, 129: 110504.
7.	Gordon SR, Maute RL, Dulken BW, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature, 2017, 545(7655): 495-499.
8.	Yang Y, Li L, Xu C, et al. Cross-talk between the gut microbiota and monocyte-like macrophages mediates an inflammatory response to promote colitis-associated tumourigenesis. Gut, 2020, 70(8): 1495-1506.
9.	Jiang X, Cao G, Gao G, et al. Triptolide decreases tumor-associated macrophages infiltration and M2 polarization to remodel colon cancer immune microenvironment via inhibiting tumor-derived CXCL12. J Cell Physiol, 2021, 236(1): 193-204.
10.	Larionova I, Tuguzbaeva G, Ponomaryova A, et al. Tumor-associated macrophages in human breast, colorectal, lung, ovarian and prostate cancers. Front Oncol, 2020, 10: 566511.
11.	Molgora M, Esaulova E, Vermi W, et al. TREM2 modulation remodels the tumor myeloid landscape enhancing anti-PD-1 immunotherapy. Cell, 2020, 182(4): 886-900.e17.
12.	Franzè E, Laudisi F, Di Grazia A, et al. Macrophages produce and functionally respond to interleukin-34 in colon cancer. Cell Death Discov, 2020, 6(1): 117.
13.	DeNardo DG, Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy. Nat Rev Immunol, 2019, 19(6): 369-382.
14.	Azizi E, Carr AJ, Plitas G, et al. Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Cell, 2018, 174(5): 1293-1308.e36.
15.	Lambrechts D, Wauters E, Boeckx B, et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat Med, 2018, 24(8): 1277-1289.
16.	Zhang L, Li Z, Skrzypczynska KM, et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer. Cell, 2020, 181(2): 442-459.e29.
17.	Mantovani A, Marchesi F, Malesci A, et al. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol, 2017, 14(7): 399-416.
18.	Rodell CB, Arlauckas SP, Cuccarese MF, et al. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat Biomed Eng, 2018, 2(8): 578-588.
19.	Ma J, Liu L, Che G, et al. The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time. BMC Cancer, 2010, 10: 112.
20.	Guo L, Wang C, Qiu X, et al Colorectal cancer immune infiltrates: significance in patient prognosis and immunotherapeutic efficacy. Front Immunol, 2020, 11: 1052.
21.	Zhao S, Mi Y, Guan B, et al. Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer. J Hematol Oncol, 2020, 13(1): 156.
22.	Lee CC, Lin JC, Hwang WL, et al. Macrophage-secreted interleukin-35 regulates cancer cell plasticity to facilitate metastatic colonization. Nat Commun, 2018, 9(1): 3763.
23.	Wei C, Yang C, Wang S, et al. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol Cancer, 2019, 18(1): 64.
24.	Cooks T, Pateras IS, Jenkins LM, et al. Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246. Nat Commun, 2018, 9(1): 771.
25.	Tagliamonte M, Petrizzo A, Tornesello ML, et al. Antigen-specific vaccines for cancer treatment. Hum Vaccin Immunother, 2014, 10(11): 3332-3346.
26.	Lin X, Wang S, Sun M, et al. miR-195-5p/NOTCH2-mediated EMT modulates IL-4 secretion in colorectal cancer to affect M2-like TAM polarization. J Hematol Oncol, 2019, 12(1): 20.
27.	Zhong Q, Fang Y, Lai Q, et al. CPEB3 inhibits epithelial-mesenchymal transition by disrupting the crosstalk between colorectal cancer cells and tumor-associated macrophages via IL-6R/STAT3 signaling. J Exp Clin Cancer Res, 2020, 39(1): 132.
28.	Liu Q, Yang C, Wang S, et al. Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression. Cell Commun Signal, 2020, 18(1): 51.
29.	Malesci A, Bianchi P, Celesti G, et al. Tumor-associated macrophages and response to 5-fluorouracil adjuvant therapy in stage III colorectal cancer. Oncoimmunology, 2017, 6(12): e1342918.
30.	Caux C, Ramos RN, Prendergast GC, et al. A milestone review on how macrophages affect tumor growth. Cancer Res, 2016, 76(22): 6439-6442.
31.	Wang N, Wang S, Wang X, et al. Research trends in pharmacological modulation of tumor-associated macrophages. Clin Transl Med, 2021, 11(1): e288.
32.	Rubio CA, Schmidt PT. Severe defects in the macrophage barrier to gut microflora in inflammatory bowel disease and colon cancer. Anticancer Res, 2018, 38(7): 3811-3815.
33.	Loke YL, Chew MT, Ngeow YF, et al. Colon carcinogenesis: the interplay between diet and gut microbiota. Front Cell Infect Microbiol, 2020, 10: 603086.
34.	Fidelle M, Yonekura S, Picard M, et al. Resolving the paradox of colon cancer through the integration of genetics, immunology, and the microbiota. Front Immunol, 2020, 11: 600886.
35.	Wan G, Xie M, Yu H, et al. Intestinal dysbacteriosis activates tumor-associated macrophages to promote epithelial-mesenchymal transition of colorectal cancer. Innate Immun, 2018, 24(8): 480-489.
36.	Molska M, Reguła J. Potential mechanisms of probiotics action in the prevention and treatment of colorectal cancer. Nutrients, 2019, 11(10): 2453.
37.	Mörkl S, Butler MI, Holl A, et al Probiotics and the microbiota-gut-brain axis: focus on psychiatry. Curr Nutr Rep, 2020, 9(3): 171-182.
38.	Zhou W, Cheng Y, Zhu P, et al. Implication of gut microbiota in cardiovascular diseases. Oxid Med Cell Longev, 2020, 2020: 5394096.
39.	Chang PV, Hao L, Offermanns S, et al. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A, 2014, 111(6): 2247-2252.
40.	Bader J, Carson M, Enos R, et al. High-fat diet-fed ovariectomized mice are susceptible to accelerated subcutaneous tumor growth potentially through adipose tissue inflammation, local insulin-like growth factor release, and tumor associated macrophages. Oncotarget, 2020, 11(49): 4554-4569.
41.	Ma J, Shayiti F, Ma J, et al. Tumor-associated macrophage-derived CCL5 promotes chemotherapy resistance and metastasis in prostatic cancer. Cell Biol Int, 2021, 45(10): 2054-2062.
42.	Mo X, Huang X, Feng Y, et al. Immune infiltration and immune gene signature predict the response to fluoropyrimidine-based chemotherapy in colorectal cancer patients. Oncoimmunology, 2020, 9(1): 1832347.
43.	Li J, Li L, Li Y, et al. Tumor-associated macrophage infiltration and prognosis in colorectal cancer: systematic review and meta-analysis. Int J Colorectal Dis, 2020, 35(7): 1203-1210.
44.	Yang Z, Zhang M, Peng R, et al. The prognostic and clinicopathological value of tumor-associated macrophages in patients with colorectal cancer: a systematic review and meta-analysis. Int J Colorectal Dis, 2020, 35(9): 1651-1661.
45.	Vitale I, Manic G, Coussens LM, et al. Macrophages and metabolism in the tumor microenvironment. Cell Metab, 2019, 30(1): 36-50.
46.	Rao G, Wang H, Li B, et al. Reciprocal interactions between tumor-associated macrophages and CD44-positive cancer cells via osteopontin/CD44 promote tumorigenicity in colorectal cancer. Clin Cancer Res, 2013, 19(4): 785-797.
47.	Limagne E, Thibaudin M, Nuttin L, et al. Trifluridine/Tipiracil plus oxaliplatin improves PD-1 blockade in colorectal cancer by inducing immunogenic cell death and depleting macrophages. Cancer Immunol Res, 2019, 7(12): 1958-1969.
48.	Huang YJ, Yang CK, Wei PL, et al. Ovatodiolide suppresses colon tumorigenesis and prevents polarization of M2 tumor-associated macrophages through YAP oncogenic pathways. J Hematol Oncol, 2017, 10(1): 60.
49.	Lee NY, Kim Y, Kim YS, et al. β-Carotene exerts anti-colon cancer effects by regulating M2 macrophages and activated fibroblasts. J Nutr Biochem, 2020, 82: 108402.

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin, 2020, 70(1): 7-30.
2. Angell HK, Bruni D, Barrett JC, et al. The immunoscore: colon cancer and beyond. Clin Cancer Res, 2020, 26(2): 332-339.
3. Hsu PC, Jablons DM, Yang CT, et al. Epidermal growth factor receptor (EGFR) pathway, yes-associated protein (YAP) and the regulation of programmed death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC). Int J Mol Sci, 2019, 20(15): 3821.
4. De Souza ALPB. Finding the hot spot: identifying immune sensitive gastrointestinal tumors. Transl Gastroenterol Hepatol, 2020, 5: 48.
5. Shan T, Chen S, Wu T, et al. PD-L1 expression in colon cancer and its relationship with clinical prognosis. Int J Clin Exp Pathol, 2019, 12(5): 1764-1769.
6. Sun J, Zheng Y, Mamun M, et al. Research progress of PD-1/PD-L1 immunotherapy in gastrointestinal tumors. Biomed Pharmacother, 2020, 129: 110504.
7. Gordon SR, Maute RL, Dulken BW, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature, 2017, 545(7655): 495-499.
8. Yang Y, Li L, Xu C, et al. Cross-talk between the gut microbiota and monocyte-like macrophages mediates an inflammatory response to promote colitis-associated tumourigenesis. Gut, 2020, 70(8): 1495-1506.
9. Jiang X, Cao G, Gao G, et al. Triptolide decreases tumor-associated macrophages infiltration and M2 polarization to remodel colon cancer immune microenvironment via inhibiting tumor-derived CXCL12. J Cell Physiol, 2021, 236(1): 193-204.
10. Larionova I, Tuguzbaeva G, Ponomaryova A, et al. Tumor-associated macrophages in human breast, colorectal, lung, ovarian and prostate cancers. Front Oncol, 2020, 10: 566511.
11. Molgora M, Esaulova E, Vermi W, et al. TREM2 modulation remodels the tumor myeloid landscape enhancing anti-PD-1 immunotherapy. Cell, 2020, 182(4): 886-900.e17.
12. Franzè E, Laudisi F, Di Grazia A, et al. Macrophages produce and functionally respond to interleukin-34 in colon cancer. Cell Death Discov, 2020, 6(1): 117.
13. DeNardo DG, Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy. Nat Rev Immunol, 2019, 19(6): 369-382.
14. Azizi E, Carr AJ, Plitas G, et al. Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Cell, 2018, 174(5): 1293-1308.e36.
15. Lambrechts D, Wauters E, Boeckx B, et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat Med, 2018, 24(8): 1277-1289.
16. Zhang L, Li Z, Skrzypczynska KM, et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer. Cell, 2020, 181(2): 442-459.e29.
17. Mantovani A, Marchesi F, Malesci A, et al. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol, 2017, 14(7): 399-416.
18. Rodell CB, Arlauckas SP, Cuccarese MF, et al. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat Biomed Eng, 2018, 2(8): 578-588.
19. Ma J, Liu L, Che G, et al. The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time. BMC Cancer, 2010, 10: 112.
20. Guo L, Wang C, Qiu X, et al Colorectal cancer immune infiltrates: significance in patient prognosis and immunotherapeutic efficacy. Front Immunol, 2020, 11: 1052.
21. Zhao S, Mi Y, Guan B, et al. Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer. J Hematol Oncol, 2020, 13(1): 156.
22. Lee CC, Lin JC, Hwang WL, et al. Macrophage-secreted interleukin-35 regulates cancer cell plasticity to facilitate metastatic colonization. Nat Commun, 2018, 9(1): 3763.
23. Wei C, Yang C, Wang S, et al. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol Cancer, 2019, 18(1): 64.
24. Cooks T, Pateras IS, Jenkins LM, et al. Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246. Nat Commun, 2018, 9(1): 771.
25. Tagliamonte M, Petrizzo A, Tornesello ML, et al. Antigen-specific vaccines for cancer treatment. Hum Vaccin Immunother, 2014, 10(11): 3332-3346.
26. Lin X, Wang S, Sun M, et al. miR-195-5p/NOTCH2-mediated EMT modulates IL-4 secretion in colorectal cancer to affect M2-like TAM polarization. J Hematol Oncol, 2019, 12(1): 20.
27. Zhong Q, Fang Y, Lai Q, et al. CPEB3 inhibits epithelial-mesenchymal transition by disrupting the crosstalk between colorectal cancer cells and tumor-associated macrophages via IL-6R/STAT3 signaling. J Exp Clin Cancer Res, 2020, 39(1): 132.
28. Liu Q, Yang C, Wang S, et al. Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression. Cell Commun Signal, 2020, 18(1): 51.
29. Malesci A, Bianchi P, Celesti G, et al. Tumor-associated macrophages and response to 5-fluorouracil adjuvant therapy in stage III colorectal cancer. Oncoimmunology, 2017, 6(12): e1342918.
30. Caux C, Ramos RN, Prendergast GC, et al. A milestone review on how macrophages affect tumor growth. Cancer Res, 2016, 76(22): 6439-6442.
31. Wang N, Wang S, Wang X, et al. Research trends in pharmacological modulation of tumor-associated macrophages. Clin Transl Med, 2021, 11(1): e288.
32. Rubio CA, Schmidt PT. Severe defects in the macrophage barrier to gut microflora in inflammatory bowel disease and colon cancer. Anticancer Res, 2018, 38(7): 3811-3815.
33. Loke YL, Chew MT, Ngeow YF, et al. Colon carcinogenesis: the interplay between diet and gut microbiota. Front Cell Infect Microbiol, 2020, 10: 603086.
34. Fidelle M, Yonekura S, Picard M, et al. Resolving the paradox of colon cancer through the integration of genetics, immunology, and the microbiota. Front Immunol, 2020, 11: 600886.
35. Wan G, Xie M, Yu H, et al. Intestinal dysbacteriosis activates tumor-associated macrophages to promote epithelial-mesenchymal transition of colorectal cancer. Innate Immun, 2018, 24(8): 480-489.
36. Molska M, Reguła J. Potential mechanisms of probiotics action in the prevention and treatment of colorectal cancer. Nutrients, 2019, 11(10): 2453.
37. Mörkl S, Butler MI, Holl A, et al Probiotics and the microbiota-gut-brain axis: focus on psychiatry. Curr Nutr Rep, 2020, 9(3): 171-182.
38. Zhou W, Cheng Y, Zhu P, et al. Implication of gut microbiota in cardiovascular diseases. Oxid Med Cell Longev, 2020, 2020: 5394096.
39. Chang PV, Hao L, Offermanns S, et al. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A, 2014, 111(6): 2247-2252.
40. Bader J, Carson M, Enos R, et al. High-fat diet-fed ovariectomized mice are susceptible to accelerated subcutaneous tumor growth potentially through adipose tissue inflammation, local insulin-like growth factor release, and tumor associated macrophages. Oncotarget, 2020, 11(49): 4554-4569.
41. Ma J, Shayiti F, Ma J, et al. Tumor-associated macrophage-derived CCL5 promotes chemotherapy resistance and metastasis in prostatic cancer. Cell Biol Int, 2021, 45(10): 2054-2062.
42. Mo X, Huang X, Feng Y, et al. Immune infiltration and immune gene signature predict the response to fluoropyrimidine-based chemotherapy in colorectal cancer patients. Oncoimmunology, 2020, 9(1): 1832347.
43. Li J, Li L, Li Y, et al. Tumor-associated macrophage infiltration and prognosis in colorectal cancer: systematic review and meta-analysis. Int J Colorectal Dis, 2020, 35(7): 1203-1210.
44. Yang Z, Zhang M, Peng R, et al. The prognostic and clinicopathological value of tumor-associated macrophages in patients with colorectal cancer: a systematic review and meta-analysis. Int J Colorectal Dis, 2020, 35(9): 1651-1661.
45. Vitale I, Manic G, Coussens LM, et al. Macrophages and metabolism in the tumor microenvironment. Cell Metab, 2019, 30(1): 36-50.
46. Rao G, Wang H, Li B, et al. Reciprocal interactions between tumor-associated macrophages and CD44-positive cancer cells via osteopontin/CD44 promote tumorigenicity in colorectal cancer. Clin Cancer Res, 2013, 19(4): 785-797.
47. Limagne E, Thibaudin M, Nuttin L, et al. Trifluridine/Tipiracil plus oxaliplatin improves PD-1 blockade in colorectal cancer by inducing immunogenic cell death and depleting macrophages. Cancer Immunol Res, 2019, 7(12): 1958-1969.
48. Huang YJ, Yang CK, Wei PL, et al. Ovatodiolide suppresses colon tumorigenesis and prevents polarization of M2 tumor-associated macrophages through YAP oncogenic pathways. J Hematol Oncol, 2017, 10(1): 60.
49. Lee NY, Kim Y, Kim YS, et al. β-Carotene exerts anti-colon cancer effects by regulating M2 macrophages and activated fibroblasts. J Nutr Biochem, 2020, 82: 108402.

West China Medical Journal

Research progress of tumor-associated macrophages in colorectal cancer

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