Role of tumor associated macrophage in primary liver cancer and its related therapeutic application_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

CHEN Jiachuan ,  HU Zongqiang , CHEN Gang , JIANG Jie , XU Yuantong , YAN Chuntao

Department of Hepatobiliary Surgery, The First People’s Hospital of Kunming, Kuming 650051, P. R. China;

Corresponding author：

HU Zongqiang, Email: 2509484088@qq.com

Keywords：

tumor associated macrophages; primary liver cancer; mechanism; review

DOI：

10.7507/1007-9424.202105026

Video：

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Objective To understand the role and mechanism of tumor associated macrophages (TAM) on the occurrence and development of primary liver cancer, and its application in the treatment. Method The related literatures about the researches of relation between TAM and primary liver cancer at home and abroad in recent years were collected, sorted out, and made a review. Results Under different stimulating factors, TAM could be polarized to anti-tumor type 1 TAMs or tumor-promoting type 2 TAMs, and type 2 TAMs was the main part in the tumor microenvironment. Through some mechanisms such as vascularity-promoting, invasion-promoting, and immunosuppression to promote the occurrence and development of tumors, and potential treatment plans for primary liver cancer could be found by targeting TAM from different perspectives. Conclusion TAM has a wide range of effects on primary liver cancer, and their mechanisms are complex, understanding the relation between them and make an effective control of TAM could provide new therapeutic ideas and plans for clinical treatment of primary liver cancer.

Citation： CHEN Jiachuan, HU Zongqiang, CHEN Gang, JIANG Jie, XU Yuantong, YAN Chuntao. Role of tumor associated macrophage in primary liver cancer and its related therapeutic application. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(3): 389-395. doi: 10.7507/1007-9424.202105026 Copy

1.	Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet, 2018, 391(10127): 1301-1314.
2.	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
3.	Ahmed O, Pillai A. Hepatocellular carcinoma: a contemporary approach to locoregional therapy. Am J Gastroenterol, 2020, 115(11): 1733-1736.
4.	Elkhenany H, Shekshek A, Abdel-Daim M, et al. Stem cell therapy for hepatocellular carcinoma: future perspectives. Adv Exp Med Biol, 2020, 1237: 97-119.
5.	何玲华, 刘凯敏, 佟虹兴, 等. 肝细胞肝癌免疫检查点阻断治疗疗效相关生物标志物的研究进展. 中国普外基础与临床杂志, 2022, 29(1): 112-117.
6.	Ming Y, Li B, Fu R, et al. Bovine serum albumin nanoparticle-mediated delivery of sorafenib for improving hepatocellular carcinoma therapy. J Nanosci Nanotechnol, 2021, 21(10): 5075-5082.
7.	Wang L, He T, Liu J, et al. Pan-cancer analysis reveals tumor-associated macrophage communication in the tumor microenvironment. Exp Hematol Oncol, 2021, 10(1): 31. doi: 10.1186/s40164-021-00226-1 .
8.	Mu X, Li Y, Fan GC. Tissue-resident macrophages in the control of infection and resolution of inflammation. Shock, 2021, 55(1): 14-23.
9.	徐洋, 麻勇. Kupffer细胞在肝脏疾病中的研究进展. 中国普外基础与临床杂志, 2021, 28(5): 673-677.
10.	郭世朋, 张文锋, 龚建平. Kupffer 细胞起源及其免疫学功能的研究进展. 生理科学进展, 2016, 47(1): 57-60.
11.	Avila MA, Berasain C. Targeting CCL2/CCR2 in tumor-infiltrating macrophages: a tool emerging out of the box against hepatocellular carcinoma. Cell Mol Gastroenterol Hepatol, 2019, 7(2): 293-294.
12.	陆进, 杨月, 俞鹏, 等. 肝细胞癌组织CC趋化因子配体23(CCL23)表达的生物信息学分析及意义. 细胞与分子免疫学杂志, 2019, 35(10): 903-909.
13.	Lu C, Rong D, Zhang B, et al. Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities. Mol Cancer, 2019, 18(1): 130. doi: 10.1186/s12943-019-1047-6 .
14.	Wang YR, Zhang XN, Meng FG, et al. Targeting macrophage polarization by Nrf2 agonists for treating various xenobiotics-induced toxic responses. Toxicol Mech Methods, 2021, 31(5): 334-342.
15.	An Y, Liu F, Chen Y, et al. Crosstalk between cancer-associated fibroblasts and immune cells in cancer. J Cell Mol Med, 2020, 24(1): 13-24.
16.	Gok Yavuz B, Gunaydin G, Gedik ME, et aL. Cancer associated fibroblasts sculpt tumour microenvironment by recruiting monocytes and inducing immunosuppressive PD-1⁺ TAMs. Sci Rep, 2019, 9(1): 3172. doi: 10.1038/s41598-019-39553-z.
17.	中华预防医学会肝胆胰疾病预防与控制专业委员会, 中国研究型医院学会肝病专业委员会, 中华医学会肝病学分会, 等. 原发性肝癌的分层筛查与监测指南(2020版). 中华肿瘤防治杂志, 2021, 28(2): 83-99.
18.	Kitano Y, Okabe H, Yamashita YI, et al. Tumour-infiltrating inflammatory and immune cells in patients with extrahepatic cholangiocarcinoma. Br J Cancer, 2018, 118(2): 171-180.
19.	Petty AJ, Li A, Wang X, et al. Hedgehog signaling promotes tumor-associated macrophage polarization to suppress intratumoral CD8⁺ T cell recruitment. J Clin Invest, 2019, 129(12): 5151-5162.
20.	Zhang P, Zhang Y, Wang L, et al. Tumor-regulated macrophage type 2 differentiation promotes immunosuppression in laryngeal squamous cell carcinoma. Life Sci, 2021, 267: 118798. doi: 10.1016/j.lfs.2020.118798.
21.	Zong Z, Zou J, Mao R, et al. M1 macrophages induce PD-L1 expression in hepatocellular carcinoma cells through IL-1β signaling. Front Immunol, 2019, 10: 1643. doi: 10.3389/fimmu.2019.01643.
22.	Russo M, Giavazzi R. Anti-angiogenesis for cancer: current status and prospects. Thromb Res, 2018, 164 Suppl 1: S3-S6.
23.	Goradel NH, Mohammadi N, Haghi-Aminjan H, et al. Regulation of tumor angiogenesis by microRNAs: state of the art. J Cell Physiol, 2019, 234(2): 1099-1110.
24.	Nio K, Yamashita T, Kaneko S. The evolving concept of liver cancer stem cells. Mol Cancer, 2017, 16(1): 4. doi: 10.1186/s12943-016-0572-9.
25.	Zhang Y, Wang S, Liu Z, et al. Increased Six1 expression in macrophages promotes hepatocellular carcinoma growth and invasion by regulating MMP-9. J Cell Mol Med, 2019, 23(7): 4523-4533.
26.	Lin Q , Zhou CR , Bai MJ, et al. Exosome-mediated miRNA delivery promotes liver cancer EMT and metastasis. Am J Transl Res, 2020, 12(3): 1080-1095.
27.	Suarez-Carmona M, Lesage J, Cataldo D, et al. EMT and inflammation: inseparable actors of cancer progression. Mol Oncol, 2017, 11(7): 805-823.
28.	Umansky V, Adema GJ, Baran J, et al. Interactions among myeloid regulatory cells in cancer. Cancer Immunol Immunother, 2019, 68(4): 645-660.
29.	Wang H, Wang X, Li X, et al. CD68⁺HLA^–DR⁺ M1-like macrophages promote motility of HCC cells via NF-κB/FAK pathway. Cancer Letters, 2014, 345(1): 91-99.
30.	Teng KY, Han J, Zhang X, et al. Blocking the CCL2-CCR2 axis using CCL2-neutralizing antibody is an effective therapy for hepatocellular cancer in a mouse model. Mol Cancer Ther, 2017, 16(2): 312-322.
31.	Li X, Yao W, Yuan Y, et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut, 2017, 66(1): 157-167.
32.	Li X, Bu W, Meng L, et al. CXCL12/CXCR4 pathway orchestrates CSC-like properties by CAF recruited tumor associated macrophage in OSCC. Exp Cell Res, 2019, 378(2): 131-138.
33.	Yang J, Zhang L, Jiang Z, et al. TCF12 promotes the tumorigenesis and metastasis of hepatocellular carcinoma via upregulation of CXCR4 expression. Theranostics, 2019, 9(20): 5810-5827.
34.	Quintana E, Schulze CJ, Myers DR, et al. Allosteric inhibition of SHP2 stimulates antitumor immunity by transforming the immunosuppressive environment. Cancer Res, 2020, 80(13): 2889-2902.
35.	Belgiovine C, Bello E, Liguori M, et al. Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models. Br J Cancer, 2017, 117(5): 628-638.
36.	Furudate S, Fujimura T, Kakizaki A, et al. Tumor-associated M2 macrophages in mycosis fungoides acquire immunomodulatory function by interferon alpha and interferon gamma. J Dermatol Sci, 2016, 83(3): 182-189.
37.	Zhang Z, Zhu Y, Xu D, et al. IFN-α facilitates the effect of sorafenib via shifting the M2-like polarization of TAM in hepatocellular carcinoma. Am J Transl Res, 2021, 13(1): 301-313.
38.	Chen J, Zheng DX, Yu XJ, et al. Macrophages induce CD47 upregulation via IL-6 and correlate with poor survival in hepatocellular carcinoma patients. Oncoimmunology, 2019, 8(11): e1652540. doi: 10.1080/2162402X.2019.1652540.
39.	Kim H, Bang S, Jee S, et al. Clinicopathological significance of CD47 expression in hepatocellular carcinoma. J Clin Pathol, 2021, 74(2): 111-115.
40.	Lo J, Lau EY, So FT, et al. Anti-CD47 antibody suppresses tumour growth and augments the effect of chemotherapy treatment in hepatocellular carcinoma. Liver Int, 2016, 36(5): 737-745.
41.	de Graaff P, Govers C, Wichers HJ, et al. Consumption of β-glucans to spice up T cell treatment of tumors: a review. Expert Opin Biol Ther, 2018, 18(10): 1023-1040.

1. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet, 2018, 391(10127): 1301-1314.
2. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
3. Ahmed O, Pillai A. Hepatocellular carcinoma: a contemporary approach to locoregional therapy. Am J Gastroenterol, 2020, 115(11): 1733-1736.
4. Elkhenany H, Shekshek A, Abdel-Daim M, et al. Stem cell therapy for hepatocellular carcinoma: future perspectives. Adv Exp Med Biol, 2020, 1237: 97-119.
5. 何玲华, 刘凯敏, 佟虹兴, 等. 肝细胞肝癌免疫检查点阻断治疗疗效相关生物标志物的研究进展. 中国普外基础与临床杂志, 2022, 29(1): 112-117.
6. Ming Y, Li B, Fu R, et al. Bovine serum albumin nanoparticle-mediated delivery of sorafenib for improving hepatocellular carcinoma therapy. J Nanosci Nanotechnol, 2021, 21(10): 5075-5082.
7. Wang L, He T, Liu J, et al. Pan-cancer analysis reveals tumor-associated macrophage communication in the tumor microenvironment. Exp Hematol Oncol, 2021, 10(1): 31. doi: 10.1186/s40164-021-00226-1 .
8. Mu X, Li Y, Fan GC. Tissue-resident macrophages in the control of infection and resolution of inflammation. Shock, 2021, 55(1): 14-23.
9. 徐洋, 麻勇. Kupffer细胞在肝脏疾病中的研究进展. 中国普外基础与临床杂志, 2021, 28(5): 673-677.
10. 郭世朋, 张文锋, 龚建平. Kupffer 细胞起源及其免疫学功能的研究进展. 生理科学进展, 2016, 47(1): 57-60.
11. Avila MA, Berasain C. Targeting CCL2/CCR2 in tumor-infiltrating macrophages: a tool emerging out of the box against hepatocellular carcinoma. Cell Mol Gastroenterol Hepatol, 2019, 7(2): 293-294.
12. 陆进, 杨月, 俞鹏, 等. 肝细胞癌组织CC趋化因子配体23(CCL23)表达的生物信息学分析及意义. 细胞与分子免疫学杂志, 2019, 35(10): 903-909.
13. Lu C, Rong D, Zhang B, et al. Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities. Mol Cancer, 2019, 18(1): 130. doi: 10.1186/s12943-019-1047-6 .
14. Wang YR, Zhang XN, Meng FG, et al. Targeting macrophage polarization by Nrf2 agonists for treating various xenobiotics-induced toxic responses. Toxicol Mech Methods, 2021, 31(5): 334-342.
15. An Y, Liu F, Chen Y, et al. Crosstalk between cancer-associated fibroblasts and immune cells in cancer. J Cell Mol Med, 2020, 24(1): 13-24.
16. Gok Yavuz B, Gunaydin G, Gedik ME, et aL. Cancer associated fibroblasts sculpt tumour microenvironment by recruiting monocytes and inducing immunosuppressive PD-1⁺ TAMs. Sci Rep, 2019, 9(1): 3172. doi: 10.1038/s41598-019-39553-z.
17. 中华预防医学会肝胆胰疾病预防与控制专业委员会, 中国研究型医院学会肝病专业委员会, 中华医学会肝病学分会, 等. 原发性肝癌的分层筛查与监测指南(2020版). 中华肿瘤防治杂志, 2021, 28(2): 83-99.
18. Kitano Y, Okabe H, Yamashita YI, et al. Tumour-infiltrating inflammatory and immune cells in patients with extrahepatic cholangiocarcinoma. Br J Cancer, 2018, 118(2): 171-180.
19. Petty AJ, Li A, Wang X, et al. Hedgehog signaling promotes tumor-associated macrophage polarization to suppress intratumoral CD8⁺ T cell recruitment. J Clin Invest, 2019, 129(12): 5151-5162.
20. Zhang P, Zhang Y, Wang L, et al. Tumor-regulated macrophage type 2 differentiation promotes immunosuppression in laryngeal squamous cell carcinoma. Life Sci, 2021, 267: 118798. doi: 10.1016/j.lfs.2020.118798.
21. Zong Z, Zou J, Mao R, et al. M1 macrophages induce PD-L1 expression in hepatocellular carcinoma cells through IL-1β signaling. Front Immunol, 2019, 10: 1643. doi: 10.3389/fimmu.2019.01643.
22. Russo M, Giavazzi R. Anti-angiogenesis for cancer: current status and prospects. Thromb Res, 2018, 164 Suppl 1: S3-S6.
23. Goradel NH, Mohammadi N, Haghi-Aminjan H, et al. Regulation of tumor angiogenesis by microRNAs: state of the art. J Cell Physiol, 2019, 234(2): 1099-1110.
24. Nio K, Yamashita T, Kaneko S. The evolving concept of liver cancer stem cells. Mol Cancer, 2017, 16(1): 4. doi: 10.1186/s12943-016-0572-9.
25. Zhang Y, Wang S, Liu Z, et al. Increased Six1 expression in macrophages promotes hepatocellular carcinoma growth and invasion by regulating MMP-9. J Cell Mol Med, 2019, 23(7): 4523-4533.
26. Lin Q , Zhou CR , Bai MJ, et al. Exosome-mediated miRNA delivery promotes liver cancer EMT and metastasis. Am J Transl Res, 2020, 12(3): 1080-1095.
27. Suarez-Carmona M, Lesage J, Cataldo D, et al. EMT and inflammation: inseparable actors of cancer progression. Mol Oncol, 2017, 11(7): 805-823.
28. Umansky V, Adema GJ, Baran J, et al. Interactions among myeloid regulatory cells in cancer. Cancer Immunol Immunother, 2019, 68(4): 645-660.
29. Wang H, Wang X, Li X, et al. CD68⁺HLA^–DR⁺ M1-like macrophages promote motility of HCC cells via NF-κB/FAK pathway. Cancer Letters, 2014, 345(1): 91-99.
30. Teng KY, Han J, Zhang X, et al. Blocking the CCL2-CCR2 axis using CCL2-neutralizing antibody is an effective therapy for hepatocellular cancer in a mouse model. Mol Cancer Ther, 2017, 16(2): 312-322.
31. Li X, Yao W, Yuan Y, et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut, 2017, 66(1): 157-167.
32. Li X, Bu W, Meng L, et al. CXCL12/CXCR4 pathway orchestrates CSC-like properties by CAF recruited tumor associated macrophage in OSCC. Exp Cell Res, 2019, 378(2): 131-138.
33. Yang J, Zhang L, Jiang Z, et al. TCF12 promotes the tumorigenesis and metastasis of hepatocellular carcinoma via upregulation of CXCR4 expression. Theranostics, 2019, 9(20): 5810-5827.
34. Quintana E, Schulze CJ, Myers DR, et al. Allosteric inhibition of SHP2 stimulates antitumor immunity by transforming the immunosuppressive environment. Cancer Res, 2020, 80(13): 2889-2902.
35. Belgiovine C, Bello E, Liguori M, et al. Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models. Br J Cancer, 2017, 117(5): 628-638.
36. Furudate S, Fujimura T, Kakizaki A, et al. Tumor-associated M2 macrophages in mycosis fungoides acquire immunomodulatory function by interferon alpha and interferon gamma. J Dermatol Sci, 2016, 83(3): 182-189.
37. Zhang Z, Zhu Y, Xu D, et al. IFN-α facilitates the effect of sorafenib via shifting the M2-like polarization of TAM in hepatocellular carcinoma. Am J Transl Res, 2021, 13(1): 301-313.
38. Chen J, Zheng DX, Yu XJ, et al. Macrophages induce CD47 upregulation via IL-6 and correlate with poor survival in hepatocellular carcinoma patients. Oncoimmunology, 2019, 8(11): e1652540. doi: 10.1080/2162402X.2019.1652540.
39. Kim H, Bang S, Jee S, et al. Clinicopathological significance of CD47 expression in hepatocellular carcinoma. J Clin Pathol, 2021, 74(2): 111-115.
40. Lo J, Lau EY, So FT, et al. Anti-CD47 antibody suppresses tumour growth and augments the effect of chemotherapy treatment in hepatocellular carcinoma. Liver Int, 2016, 36(5): 737-745.
41. de Graaff P, Govers C, Wichers HJ, et al. Consumption of β-glucans to spice up T cell treatment of tumors: a review. Expert Opin Biol Ther, 2018, 18(10): 1023-1040.

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Role of tumor associated macrophage in primary liver cancer and its related therapeutic application

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