Research progress on the role of immune components in tumor microenvironment in hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIAO Tianyi ^1,2 , LIU Shuo ^1,2 , ZHANG Xiang ^1,2 ,  CAI Hui ^1,2,3

1. The First Clinical Medical College, Lanzhou University, Lanzhou 730000, P. R. China;
2. Key Laboratory of Tumor Molecular Diagnosis and Precision Medicine in Surgery of Gansu Province, Gansu Provincial People’s Hospital, Lanzhou 730000, P. R. China;
3. Department of General Surgery, Gansu Provincial People’s Hospital, Lanzhou 730000, P. R. China;

Corresponding author：

CAI Hui, Email: caialonteam@163.com

Keywords：

hepatocellular carcinoma; immunotherapy; tumor microenvironment

DOI：

10.7507/1007-9424.202304033

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To introduce the research status of the immunomodulatory role of various immune cells and stromal cells in the tumor microenvironment in the progression of hepatocellular carcinoma. Method The related basic and clinical research literatures on the correlation between various immune cells and stromal cells in the tumor microenvironment and the occurrence, development and prognosis of hepatocellular carcinoma were reviewed and summarized. Results Immune cells and stromal cells in the tumor microenvironment have obvious complexity and diversity. Inhibitory immune cells in various immunosuppressive environments and stimulating immune cells that exert anti-tumor effects jointly promote or inhibit the occurrence and progression of hepatocellular carcinoma. Conclusions The exact role of various immune cells in the tumor microenvironment in hepatocellular carcinoma remains to be further studied. With the continuous accumulation of relevant research results, more patients with hepatocellular carcinoma will benefit from immunotherapy.

Citation： LIAO Tianyi, LIU Shuo, ZHANG Xiang, CAI Hui. Research progress on the role of immune components in tumor microenvironment in hepatocellular carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(8): 1008-1014. doi: 10.7507/1007-9424.202304033 Copy

1.	Vogel A, Meyer T, Sapisochin G, et al. Hepatocellular carcinoma. Lancet, 2022, 400(10360): 1345-1362.
2.	Duan R, Gong F, Wang Y, et al. Transarterial chemoembolization (TACE) plus tyrosine kinase inhibitors versus TACE in patients with hepatocellular carcinoma: a systematic review and meta-analysis. World J Surg Oncol, 2023, 21(1): 120. doi: 10.1186/s12957-023-02961-7.
3.	Sheng J, Kohno S, Okada N, et al. Treatment of retinoblastoma 1-intact hepatocellular carcinoma with cyclin-dependent kinase 4/6 inhibitor combination therapy. Hepatology, 2021, 74(4): 1971-1993.
4.	Lang L, Teng Y. Fibroblast growth factor receptor 4 targeting in cancer: new insights into mechanisms and therapeutic strategies. Cells, 2019, 8(1): 31. doi: 10.3390/cells8010031.
5.	Kurebayashi Y, Ojima H, Tsujikawa H, et al. Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification. Hepatology, 2018, 68(3): 1025-1041.
6.	何玲华, 陈刚, 佟虹兴, 等. 肿瘤相关中性粒细胞在肝细胞癌中的作用研究进展. 中国普外基础与临床杂志, 2022, 29(8): 1109-1114.
7.	Szefel J, Danielak A, Kruszewski WJ. Metabolic pathways of L-arginine and therapeutic consequences in tumors. Adv Med Sci, 2019, 64(1): 104-110.
8.	Wang L, Kuang Z, Zhang D, et al. Reactive oxygen species in immune cells: a new antitumor target. Biomed Pharmacother, 2021, 133: 110978. doi: 10.1016/j.biopha.2020.110978.
9.	Dysthe M, Parihar R. Myeloid-derived suppressor cells in the tumor microenvironment. Adv Exp Med Biol, 2020, 1224: 117-140.
10.	Boral B, Ballı HT, Sözütok S, et al. Clinical and prognostic significance of CD14⁺HLA-DR^-/low myeloid-derived suppressor cells in patients with hepatocellular carcinoma received transarterial radioembolization with Yttrium-90. Scand J Immunol, 2022, 95(3): e13132. doi: 10.1111/sji.13132.
11.	Nielsen SR, Schmid MC. Macrophages as key drivers of cancer progression and metastasis. Mediators Inflamm, 2017, 2017: 9624760. doi: 10.1155/2017/9624760.
12.	文静, 黄洁, 李云云, 等. 肿瘤相关巨噬细胞相关性miR-99a 对子宫内膜癌细胞生长和侵袭的调控作用. 中国癌症杂志, 2020, 30(8): 561-569.
13.	陈家川, 胡宗强, 陈刚, 等. 原发性肝癌中肿瘤相关巨噬细胞的作用和相关治疗应用. 中国普外基础与临床杂志, 2022, 29(3): 389-395.
14.	Zhang Q, He Y, Luo N, et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell, 2019, 179(4): 829-845.
15.	Mantovani A, Allavena P, Marchesi F, et al. Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discov, 2022, 21(11): 799-820.
16.	Fathi F, Saidi RF, Banafshe HR, et al. Changes in immune profile affect disease progression in hepatocellular carcinoma. Int J Immunopathol Pharmacol, 2022, 36: 3946320221078476. doi: 10.1177/03946320221078476.
17.	Wang S, Gao S, Zhou D, et al. The role of the CD39-CD73-adenosine pathway in liver disease. J Cell Physiol, 2021, 236(2): 851-862.
18.	Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1”versus “N2” TAN. Cancer Cell, 2009, 16(3): 183-194.
19.	Laschtowitz A, Lambrecht J, Puengel T, et al. Serum CXCL5 detects early hepatocellular carcinoma and indicates tumor progression. Int J Mol Sci, 2023, 24(6): 5295. doi: 10.3390/ijms24065295.
20.	Zhou SL, Yin D, Hu ZQ, et al. A positive feedback loop between cancer stem-like cells and tumor-associated neutrophils controls hepatocellular carcinoma progression. Hepatology, 2019, 70(4): 1214-1230.
21.	Zhou SL, Zhou ZJ, Hu ZQ, et al. Tumor-associated neutrophils recruit macrophages and t-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology, 2016, 150(7): 1646-1658.
22.	Pathni A, Özçelikkale A, Rey-Suarez I, et al. Cytotoxic T lymphocyte activation signals modulate cytoskeletal dynamics and mechanical force generation. Front Immunol, 2022, 13: 779888. doi: 10.3389/fimmu.2022.779888.
23.	Yu Y, You S, Fan R, et al. UCK2 regulated by miR-139-3p regulates the progression of hepatocellular carcinoma cells. Future Oncol, 2022, 18(8): 979-990.
24.	Ning Z, Liu K, Xiong H. Roles of BTLA in immunity and immune disorders. Front Immunol, 2021, 12: 654960. doi: 10.3389/fimmu.2021.654960.
25.	Granito A, Muratori L, Lalanne C, et al. Hepatocellular carcinoma in viral and autoimmune liver diseases: role of CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells in the immune microenvironment. World J Gastroenterol, 2021, 27(22): 2994-3009.
26.	Yu Y. The function of NK cells in tumor metastasis and NK cell-based immunotherapy. Cancers (Basel), 2023, 15(8) : 2323. doi: 10.3390/cancers15082323.
27.	Chen Z, Yang Y, Liu LL, et al. Strategies to augment natural killer (NK) cell activity against solid tumors. Cancers (Basel), 2019, 11(7): 1040. doi: 10.3390/cancers11071040.
28.	Leone K, Poggiana C, Zamarchi R. The interplay between circulating tumor cells and the immune system: from immune escape to cancer immunotherapy. Diagnostics (Basel), 2018, 8(3): 59. doi: 10.3390/diagnostics8030059.
29.	Sprinzl MF, Galle PR. Immune control in hepatocellular carcinoma development and progression: role of stromal cells. Semin Liver Dis, 2014, 34(4): 376-388.
30.	Xiang X, Niu YR, Wang ZH, et al. Cancer-associated fibroblasts: vital suppressors of the immune response in the tumor microenvironment. Cytokine Growth Factor Rev, 2022, 67: 35-48.
31.	凌煜玮, 康骅. 肿瘤相关成纤维细胞在肿瘤微环境中免疫调节作用的研究现状. 中国普外基础与临床杂志, 2020, 27(12): 1593-1597.
32.	Akkız H. Emerging role of cancer-associated fibroblasts in progression and treatment of hepatocellular carcinoma. Int J Mol Sci, 2023, 24(4): 3941. doi: 10.3390/ijms24043941.
33.	Lin L, Chen S, Wang H, et al. SPTBN1 inhibits inflammatory responses and hepatocarcinogenesis via the stabilization of SOCS1 and downregulation of p65 in hepatocellular carcinoma. Theranostics, 2021, 11(9): 4232-4250.
34.	Quiroz Reyes AG, Lozano Sepulveda SA, Martinez-Acuña N, et al. Cancer stem cell and hepatic stellate cells in hepatocellular carcinoma. Technol Cancer Res Treat, 2023, 22: 15330338231163677. doi: 10.1177/15330338231163677.
35.	Hsieh CC, Hung CH, Chiang M, et al. Hepatic stellate cells enhance liver cancer progression by inducing myeloid-derived suppressor cells through interleukin-6 signaling. Int J Mol Sci, 2019, 20(20): 5079. doi: 10.3390/ijms20205079.
36.	Dunham RM, Thapa M, Velazquez VM, et al. Hepatic stellate cells preferentially induce Foxp3⁺ regulatory T cells by production of retinoic acid. J Immunol, 2013, 190(5): 2009-2016.
37.	Li H. Intercellular crosstalk of liver sinusoidal endothelial cells in liver fibrosis, cirrhosis and hepatocellular carcinoma. Dig Liver Dis, 2022, 54(5): 598-613.
38.	Lurje I, Hammerich L, Tacke F. Dendritic cell and T cell crosstalk in liver fibrogenesis and hepatocarcinogenesis: implications for prevention and therapy of liver cancer. Int J Mol Sci, 2020, 21(19): 7378. doi: 10.3390/ijms21197378.
39.	Wculek SK, Cueto FJ, Mujal AM, et al. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol, 2020, 20(1): 7-24.
40.	Andrews TS, Kiselev VY, McCarthy D, et al. Tutorial: guidelines for the computational analysis of single-cell RNA sequencing data. Nat Protoc, 2021, 16(1): 1-9.
41.	Li XY, Shen Y, Zhang L, et al. Understanding initiation and progression of hepatocellular carcinoma through single cell sequencing. Biochim Biophys Acta Rev Cancer, 2022, 1877(3): 188720. doi: 10.1016/j.bbcan.2022.188720.
42.	Sangro B, Sarobe P, Hervás-Stubbs S, et al. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol, 2021, 18(8): 525-543.
43.	Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol, 2018, 19(7): 940-952.
44.	Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase Ⅲ trial. J Clin Oncol, 2020, 38(3): 193-202.

1. Vogel A, Meyer T, Sapisochin G, et al. Hepatocellular carcinoma. Lancet, 2022, 400(10360): 1345-1362.
2. Duan R, Gong F, Wang Y, et al. Transarterial chemoembolization (TACE) plus tyrosine kinase inhibitors versus TACE in patients with hepatocellular carcinoma: a systematic review and meta-analysis. World J Surg Oncol, 2023, 21(1): 120. doi: 10.1186/s12957-023-02961-7.
3. Sheng J, Kohno S, Okada N, et al. Treatment of retinoblastoma 1-intact hepatocellular carcinoma with cyclin-dependent kinase 4/6 inhibitor combination therapy. Hepatology, 2021, 74(4): 1971-1993.
4. Lang L, Teng Y. Fibroblast growth factor receptor 4 targeting in cancer: new insights into mechanisms and therapeutic strategies. Cells, 2019, 8(1): 31. doi: 10.3390/cells8010031.
5. Kurebayashi Y, Ojima H, Tsujikawa H, et al. Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification. Hepatology, 2018, 68(3): 1025-1041.
6. 何玲华, 陈刚, 佟虹兴, 等. 肿瘤相关中性粒细胞在肝细胞癌中的作用研究进展. 中国普外基础与临床杂志, 2022, 29(8): 1109-1114.
7. Szefel J, Danielak A, Kruszewski WJ. Metabolic pathways of L-arginine and therapeutic consequences in tumors. Adv Med Sci, 2019, 64(1): 104-110.
8. Wang L, Kuang Z, Zhang D, et al. Reactive oxygen species in immune cells: a new antitumor target. Biomed Pharmacother, 2021, 133: 110978. doi: 10.1016/j.biopha.2020.110978.
9. Dysthe M, Parihar R. Myeloid-derived suppressor cells in the tumor microenvironment. Adv Exp Med Biol, 2020, 1224: 117-140.
10. Boral B, Ballı HT, Sözütok S, et al. Clinical and prognostic significance of CD14⁺HLA-DR^-/low myeloid-derived suppressor cells in patients with hepatocellular carcinoma received transarterial radioembolization with Yttrium-90. Scand J Immunol, 2022, 95(3): e13132. doi: 10.1111/sji.13132.
11. Nielsen SR, Schmid MC. Macrophages as key drivers of cancer progression and metastasis. Mediators Inflamm, 2017, 2017: 9624760. doi: 10.1155/2017/9624760.
12. 文静, 黄洁, 李云云, 等. 肿瘤相关巨噬细胞相关性miR-99a 对子宫内膜癌细胞生长和侵袭的调控作用. 中国癌症杂志, 2020, 30(8): 561-569.
13. 陈家川, 胡宗强, 陈刚, 等. 原发性肝癌中肿瘤相关巨噬细胞的作用和相关治疗应用. 中国普外基础与临床杂志, 2022, 29(3): 389-395.
14. Zhang Q, He Y, Luo N, et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell, 2019, 179(4): 829-845.
15. Mantovani A, Allavena P, Marchesi F, et al. Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discov, 2022, 21(11): 799-820.
16. Fathi F, Saidi RF, Banafshe HR, et al. Changes in immune profile affect disease progression in hepatocellular carcinoma. Int J Immunopathol Pharmacol, 2022, 36: 3946320221078476. doi: 10.1177/03946320221078476.
17. Wang S, Gao S, Zhou D, et al. The role of the CD39-CD73-adenosine pathway in liver disease. J Cell Physiol, 2021, 236(2): 851-862.
18. Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1”versus “N2” TAN. Cancer Cell, 2009, 16(3): 183-194.
19. Laschtowitz A, Lambrecht J, Puengel T, et al. Serum CXCL5 detects early hepatocellular carcinoma and indicates tumor progression. Int J Mol Sci, 2023, 24(6): 5295. doi: 10.3390/ijms24065295.
20. Zhou SL, Yin D, Hu ZQ, et al. A positive feedback loop between cancer stem-like cells and tumor-associated neutrophils controls hepatocellular carcinoma progression. Hepatology, 2019, 70(4): 1214-1230.
21. Zhou SL, Zhou ZJ, Hu ZQ, et al. Tumor-associated neutrophils recruit macrophages and t-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology, 2016, 150(7): 1646-1658.
22. Pathni A, Özçelikkale A, Rey-Suarez I, et al. Cytotoxic T lymphocyte activation signals modulate cytoskeletal dynamics and mechanical force generation. Front Immunol, 2022, 13: 779888. doi: 10.3389/fimmu.2022.779888.
23. Yu Y, You S, Fan R, et al. UCK2 regulated by miR-139-3p regulates the progression of hepatocellular carcinoma cells. Future Oncol, 2022, 18(8): 979-990.
24. Ning Z, Liu K, Xiong H. Roles of BTLA in immunity and immune disorders. Front Immunol, 2021, 12: 654960. doi: 10.3389/fimmu.2021.654960.
25. Granito A, Muratori L, Lalanne C, et al. Hepatocellular carcinoma in viral and autoimmune liver diseases: role of CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells in the immune microenvironment. World J Gastroenterol, 2021, 27(22): 2994-3009.
26. Yu Y. The function of NK cells in tumor metastasis and NK cell-based immunotherapy. Cancers (Basel), 2023, 15(8) : 2323. doi: 10.3390/cancers15082323.
27. Chen Z, Yang Y, Liu LL, et al. Strategies to augment natural killer (NK) cell activity against solid tumors. Cancers (Basel), 2019, 11(7): 1040. doi: 10.3390/cancers11071040.
28. Leone K, Poggiana C, Zamarchi R. The interplay between circulating tumor cells and the immune system: from immune escape to cancer immunotherapy. Diagnostics (Basel), 2018, 8(3): 59. doi: 10.3390/diagnostics8030059.
29. Sprinzl MF, Galle PR. Immune control in hepatocellular carcinoma development and progression: role of stromal cells. Semin Liver Dis, 2014, 34(4): 376-388.
30. Xiang X, Niu YR, Wang ZH, et al. Cancer-associated fibroblasts: vital suppressors of the immune response in the tumor microenvironment. Cytokine Growth Factor Rev, 2022, 67: 35-48.
31. 凌煜玮, 康骅. 肿瘤相关成纤维细胞在肿瘤微环境中免疫调节作用的研究现状. 中国普外基础与临床杂志, 2020, 27(12): 1593-1597.
32. Akkız H. Emerging role of cancer-associated fibroblasts in progression and treatment of hepatocellular carcinoma. Int J Mol Sci, 2023, 24(4): 3941. doi: 10.3390/ijms24043941.
33. Lin L, Chen S, Wang H, et al. SPTBN1 inhibits inflammatory responses and hepatocarcinogenesis via the stabilization of SOCS1 and downregulation of p65 in hepatocellular carcinoma. Theranostics, 2021, 11(9): 4232-4250.
34. Quiroz Reyes AG, Lozano Sepulveda SA, Martinez-Acuña N, et al. Cancer stem cell and hepatic stellate cells in hepatocellular carcinoma. Technol Cancer Res Treat, 2023, 22: 15330338231163677. doi: 10.1177/15330338231163677.
35. Hsieh CC, Hung CH, Chiang M, et al. Hepatic stellate cells enhance liver cancer progression by inducing myeloid-derived suppressor cells through interleukin-6 signaling. Int J Mol Sci, 2019, 20(20): 5079. doi: 10.3390/ijms20205079.
36. Dunham RM, Thapa M, Velazquez VM, et al. Hepatic stellate cells preferentially induce Foxp3⁺ regulatory T cells by production of retinoic acid. J Immunol, 2013, 190(5): 2009-2016.
37. Li H. Intercellular crosstalk of liver sinusoidal endothelial cells in liver fibrosis, cirrhosis and hepatocellular carcinoma. Dig Liver Dis, 2022, 54(5): 598-613.
38. Lurje I, Hammerich L, Tacke F. Dendritic cell and T cell crosstalk in liver fibrogenesis and hepatocarcinogenesis: implications for prevention and therapy of liver cancer. Int J Mol Sci, 2020, 21(19): 7378. doi: 10.3390/ijms21197378.
39. Wculek SK, Cueto FJ, Mujal AM, et al. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol, 2020, 20(1): 7-24.
40. Andrews TS, Kiselev VY, McCarthy D, et al. Tutorial: guidelines for the computational analysis of single-cell RNA sequencing data. Nat Protoc, 2021, 16(1): 1-9.
41. Li XY, Shen Y, Zhang L, et al. Understanding initiation and progression of hepatocellular carcinoma through single cell sequencing. Biochim Biophys Acta Rev Cancer, 2022, 1877(3): 188720. doi: 10.1016/j.bbcan.2022.188720.
42. Sangro B, Sarobe P, Hervás-Stubbs S, et al. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol, 2021, 18(8): 525-543.
43. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol, 2018, 19(7): 940-952.
44. Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase Ⅲ trial. J Clin Oncol, 2020, 38(3): 193-202.

Previous Article
Research progress of hepatocellular carcinoma with lung metastasis
Next Article
Current status and prospect of treatment of advanced gastric cancer

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research progress on the role of immune components in tumor microenvironment in hepatocellular carcinoma

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content