Research progress on relation of immune cell infiltration and prognosis of hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

SHEN Bingbing , ZHU Wenjie ,  JIANG Jianxin

Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, P. R. China;

Corresponding author：

JIANG Jianxin, Email: rm002979@whu.edu.cn

Keywords：

hepatocellular carcinoma; immune cell; prognosis; progression

DOI：

10.7507/1007-9424.202110106

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the relation between various kinds of immune cells infiltration in tumor microenvironment and prognosis of hepatocellular carcinoma (HCC). Method Literatures on the relation between immune cell infiltration in tumor microenvironment and prognosis of HCC in recent years were collected and reviewed. Results The immune cell infiltration in the tumor microenvironment of HCC was inextricably linked with the progression of HCC. CD4⁺ T cells, CD8⁺ T cells, M1 macrophages, B cells, and memory T cells might be associated with a good prognosis in patients with HCC, while regulatory T cells, regulatory B cells, and M2 macrophages might be related to the poor prognosis of patients with HCC. Conclusion The study of immune cell infiltration in HCC can provide new ideas for precise immunotherapy of HCC.

Citation： SHEN Bingbing, ZHU Wenjie, JIANG Jianxin. Research progress on relation of immune cell infiltration and prognosis of hepatocellular carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(7): 953-957. doi: 10.7507/1007-9424.202110106 Copy

1.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2.	Chen Z, Xie H, Hu M, et al. Recent progress in treatment of hepatocellular carcinoma. Am J Cancer Res, 2020, 10(9): 2993-3036.
3.	Anderson NM, Simon MC. The tumor microenvironment. Curr Biol, 2020, 30(16): R921-R925. doi: 10.1016/j.cub.2020.06.081.
4.	Fu Y, Liu S, Zeng S, et al. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J Exp Clin Cancer Res, 2019, 38(1): 396. doi: 10.1186/s13046-019-1396-4.
5.	Rohr-Udilova N, Klinglmüller F, Schulte-Hermann R, et al. Deviations of the immune cell landscape between healthy liver and hepatocellular carcinoma. Sci Rep, 2018, 8(1): 6220. doi: 10.1038/s41598-018-24437-5.
6.	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.
7.	Lim CJ, Lee YH, Pan L, et al. Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma. Gut, 2019, 68(5): 916-927.
8.	Zhang YL, Li Q, Yang XM, et al. SPON2 promotes M1-like macrophage recruitment and inhibits hepatocellular carcinoma metastasis by distinct integrin-rho GTPase-Hippo pathways. Cancer Res, 2018, 78(9): 2305-2317.
9.	Jin Z, Lei L, Lin D, et al. IL-33 released in the liver inhibits tumor growth via promotion of CD4⁺ and CD8⁺ T cell responses in hepatocellular carcinoma. J Immunol, 2018, 201(12): 3770-3779.
10.	Xu X, Tan Y, Qian Y, et al. Clinicopathologic and prognostic significance of tumor-infiltrating CD8⁺ T cells in patients with hepatocellular carcinoma: a meta-analysis. Medicine (Baltimore), 2019, 98(2): e13923. doi: 10.1097/MD.0000000000013923.
11.	Brunner SM, Itzel T, Rubner C, et al. Tumor-infiltrating B cells producing antitumor active immunoglobulins in resected HCC prolong patient survival. Oncotarget, 2017, 8(41): 71002-71011.
12.	Chen Y, Wen H, Zhou C, et al. TNF-α derived from M2 tumor-associated macrophages promotes epithelial-mesenchymal transition and cancer stemness through the Wnt/β-catenin pathway in SMMC-7721 hepatocellular carcinoma cells. Exp Cell Res, 2019, 378(1): 41-50.
13.	Park H, Jung JH, Jung MK, et al. Effects of transarterial chemoembolization on regulatory T cell and its subpopulations in patients with hepatocellular carcinoma. Hepatol Int, 2020, 14(2): 249-258.
14.	Shao Y, Lo CM, Ling CC, et al. Regulatory B cells accelerate hepatocellular carcinoma progression via CD40/CD154 signaling pathway. Cancer Lett, 2014, 355(2): 264-272.
15.	Tian Z, Hou X, Liu W, et al. Macrophages and hepatocellular carcinoma. Cell Biosci, 2019, 9: 79. doi: 10.1186/s13578-019-0342-7.
16.	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.
17.	Sica A, Invernizzi P, Mantovani A. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology, 2014, 59(5): 2034-2042.
18.	Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol, 2011, 12(11): 1035-1044.
19.	Yin Z, Ma T, Lin Y, et al. IL-6/STAT3 pathway intermediates M1/M2 macrophage polarization during the development of hepatocellular carcinoma. J Cell Biochem, 2018, 119(11): 9419-9432.
20.	Zhou B, Li C, Yang Y, et al. RIG-Ⅰ promotes cell death in hepatocellular carcinoma by inducing m1 polarization of perineal macrophages through the RIG-Ⅰ/MAVS/NF-κB pathway. Onco Targets Ther, 2020, 13: 8783-8794.
21.	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.
22.	Zhao X, Wang X, You Y, et al. Nogo-B fosters HCC progression by enhancing Yap/Taz-mediated tumor-associated macrophages M2 polarization. Exp Cell Res, 2020, 391(1): 111979. doi: 10.1016/j.yexcr.2020.111979.
23.	Xun X, Zhang C, Wang S, et al. Cyclooxygenase-2 expressed hepatocellular carcinoma induces cytotoxic T lymphocytes exhaustion through M2 macrophage polarization. Am J Transl Res, 2021, 13(5): 4360-4375.
24.	Xu D, Wang Y, Wu J, et al. ECT2 overexpression promotes the polarization of tumor-associated macrophages in hepatocellular carcinoma via the ECT2/PLK1/PTEN pathway. Cell Death Dis, 2021, 12(2): 162. doi: 10.1038/s41419-021-03450-z.
25.	Li W, Xin X, Li X, et al. Exosomes secreted by M2 macrophages promote cancer stemness of hepatocellular carcinoma via the miR-27a-3p/TXNIP pathways. Int Immunopharmacol, 2021, 101(Pt A): 107585. doi: 10.1016/j.intimp.2021.107585.
26.	Wang L, Fu Y, Chu Y. Regulatory B cells. Adv Exp Med Biol, 2020, 1254: 87-103.
27.	Garnelo M, Tan A, Her Z, et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut, 2017, 66(2): 342-351.
28.	Largeot A, Pagano G, Gonder S, et al. The B-side of cancer immunity: the underrated tune. Cells, 2019, 8(5): 449. doi: 10.3390/cells8050449.
29.	Xue H, Lin F, Tan H, et al. Overrepresentation of IL-10-expressing B cells suppresses cytotoxic CD4⁺ T cell activity in HBV-induced hepatocellular carcinoma. PLoS One, 2016, 11(5): e0154815. doi: 10.1371/journal.pone.0154815.
30.	Hao J, Li M, Zhang T, et al. Prognostic value of tumor-infiltrating lymphocytes differs depending on lymphocyte subsets in esophageal squamous cell carcinoma: an updated meta-analysis. Front Oncol, 2020, 10: 614. doi: 10.3389/fonc.2020.00614.
31.	Zhao Y, Ge X, He J, et al. The prognostic value of tumor-infiltrating lymphocytes in colorectal cancer differs by anatomical subsite: a systematic review and meta-analysis. World J Surg Oncol, 2019, 17(1): 85. doi: 10.1186/s12957-019-1621-9.
32.	Yarchoan M, Xing D, Luan L, et al. Characterization of the immune microenvironment in hepatocellular carcinoma. Clin Cancer Res, 2017, 23(23): 7333-7339.
33.	Huo J, Wu L, Zang Y. Identification and validation of a novel immune-related signature associated with macrophages and CD8 T cell infiltration predicting overall survival for hepatocellular carcinoma. BMC Med Genomics, 2021, 14(1): 232. doi: 10.1186/12920-021-01081-z.
34.	Hofmann M, Tauber C, Hensel N, et al. CD8⁺T cell responses during HCV infection and HCC. J Clin Med, 2021, 10(5): 991. doi: 10.3390/jcm10050991.
35.	Ma C, Kesarwala AH, Eggert T, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature, 2016, 531(7593): 253-257.
36.	Mossanen JC, Kohlhepp M, Wehr A, et al. CXCR6 inhibits hepatocarcinogenesis by promoting natural killer T- and CD4 ⁺ T-cell-dependent control of senescence. Gastroenterology, 2019, 156(6): 1877-1889.e4.
37.	Brown ZJ, Fu Q, Ma C, et al. Carnitine palmitoyltransferase gene upregulation by linoleic acid induces CD4⁺ T cell apoptosis promoting HCC development. Cell Death Dis, 2018, 9(6): 620. doi: 10.1038/s41419-018-0687-6.
38.	Qi X, Yang M, Ma L, et al. Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response. J Immunother Cancer, 2020, 8(2): e001038. doi: 10.1136/jitc-2020-001038.
39.	Gao Q, Zhou J, Wang XY, et al. Infiltrating memory/senescent T cell ratio predicts extrahepatic metastasis of hepatocellular carcinoma. Ann Surg Oncol, 2012, 19(2): 455-466.
40.	Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression-implications for anticancer therapy. Nat Rev Clin Oncol, 2019, 16(6): 356-371.
41.	Zhang S, Gan X, Qiu J, et al. IL-10 derived from hepatocarcinoma cells improves human induced regulatory T cells function via JAK1/STAT5 pathway in tumor microenvironment. Mol Immunol, 2021, 133: 163-172.
42.	Ren Z, Yue Y, Zhang Y, et al. Changes in the peripheral blood Treg cell proportion in hepatocellular carcinoma patients after transarterial chemoembolization with microparticles. Front Immunol, 2021, 12: 624789. doi: 10.3389/fimmu.2021.624789.
43.	Macek Jilkova Z, Aspord C, Decaens T. Predictive factors for response to PD-1/PD-L1 checkpoint inhibition in the field of hepatocellular carcinoma: current status and challenges. Cancers (Basel), 2019, 11(10): 1554. doi: 10.3390/cancers11101554.
44.	Ma LJ, Feng FL, Dong LQ, et al. Clinical significance of PD-1/PD-Ls gene amplification and overexpression in patients with hepatocellular carcinoma. Theranostics, 2018, 8(20): 5690-5702.
45.	Deng H, Kan A, Lyu N, et al. Dual vascular endothelial growth factor receptor and fibroblast growth factor receptor inhibition elicits antitumor immunity and enhances programmed cell death-1 checkpoint blockade in hepatocellular carcinoma. Liver Cancer, 2020, 9(3): 338-357.
46.	Huang CY, Wang Y, Luo GY, et al. Relationship between PD-L1 expression and CD8⁺ T-cell immune responses in hepatocellular carcinoma. J Immunother, 2017, 40(9): 323-333.
47.	Xiao X, Lao XM, Chen MM, et al. PD-1hi identifies a novel regulatory B-cell population in human hepatoma that promotes disease progression. Cancer Discov, 2016, 6(5): 546-559.
48.	Xu G, Feng D, Yao Y, et al. Listeria-based hepatocellular carcinoma vaccine facilitates anti-PD-1 therapy by regulating macrophage polarization. Oncogene, 2020, 39(7): 1429-1444.
49.	Park DJ, Sung PS, Lee GW, et al. Preferential expression of programmed death ligand 1 protein in tumor-associated macrophages and its potential role in immunotherapy for hepatocellular carcinoma. Int J Mol Sci, 2021, 22(9): 4710. doi: 10.3390/ijms22094710.

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2. Chen Z, Xie H, Hu M, et al. Recent progress in treatment of hepatocellular carcinoma. Am J Cancer Res, 2020, 10(9): 2993-3036.
3. Anderson NM, Simon MC. The tumor microenvironment. Curr Biol, 2020, 30(16): R921-R925. doi: 10.1016/j.cub.2020.06.081.
4. Fu Y, Liu S, Zeng S, et al. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J Exp Clin Cancer Res, 2019, 38(1): 396. doi: 10.1186/s13046-019-1396-4.
5. Rohr-Udilova N, Klinglmüller F, Schulte-Hermann R, et al. Deviations of the immune cell landscape between healthy liver and hepatocellular carcinoma. Sci Rep, 2018, 8(1): 6220. doi: 10.1038/s41598-018-24437-5.
6. 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.
7. Lim CJ, Lee YH, Pan L, et al. Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma. Gut, 2019, 68(5): 916-927.
8. Zhang YL, Li Q, Yang XM, et al. SPON2 promotes M1-like macrophage recruitment and inhibits hepatocellular carcinoma metastasis by distinct integrin-rho GTPase-Hippo pathways. Cancer Res, 2018, 78(9): 2305-2317.
9. Jin Z, Lei L, Lin D, et al. IL-33 released in the liver inhibits tumor growth via promotion of CD4⁺ and CD8⁺ T cell responses in hepatocellular carcinoma. J Immunol, 2018, 201(12): 3770-3779.
10. Xu X, Tan Y, Qian Y, et al. Clinicopathologic and prognostic significance of tumor-infiltrating CD8⁺ T cells in patients with hepatocellular carcinoma: a meta-analysis. Medicine (Baltimore), 2019, 98(2): e13923. doi: 10.1097/MD.0000000000013923.
11. Brunner SM, Itzel T, Rubner C, et al. Tumor-infiltrating B cells producing antitumor active immunoglobulins in resected HCC prolong patient survival. Oncotarget, 2017, 8(41): 71002-71011.
12. Chen Y, Wen H, Zhou C, et al. TNF-α derived from M2 tumor-associated macrophages promotes epithelial-mesenchymal transition and cancer stemness through the Wnt/β-catenin pathway in SMMC-7721 hepatocellular carcinoma cells. Exp Cell Res, 2019, 378(1): 41-50.
13. Park H, Jung JH, Jung MK, et al. Effects of transarterial chemoembolization on regulatory T cell and its subpopulations in patients with hepatocellular carcinoma. Hepatol Int, 2020, 14(2): 249-258.
14. Shao Y, Lo CM, Ling CC, et al. Regulatory B cells accelerate hepatocellular carcinoma progression via CD40/CD154 signaling pathway. Cancer Lett, 2014, 355(2): 264-272.
15. Tian Z, Hou X, Liu W, et al. Macrophages and hepatocellular carcinoma. Cell Biosci, 2019, 9: 79. doi: 10.1186/s13578-019-0342-7.
16. 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.
17. Sica A, Invernizzi P, Mantovani A. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology, 2014, 59(5): 2034-2042.
18. Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol, 2011, 12(11): 1035-1044.
19. Yin Z, Ma T, Lin Y, et al. IL-6/STAT3 pathway intermediates M1/M2 macrophage polarization during the development of hepatocellular carcinoma. J Cell Biochem, 2018, 119(11): 9419-9432.
20. Zhou B, Li C, Yang Y, et al. RIG-Ⅰ promotes cell death in hepatocellular carcinoma by inducing m1 polarization of perineal macrophages through the RIG-Ⅰ/MAVS/NF-κB pathway. Onco Targets Ther, 2020, 13: 8783-8794.
21. 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.
22. Zhao X, Wang X, You Y, et al. Nogo-B fosters HCC progression by enhancing Yap/Taz-mediated tumor-associated macrophages M2 polarization. Exp Cell Res, 2020, 391(1): 111979. doi: 10.1016/j.yexcr.2020.111979.
23. Xun X, Zhang C, Wang S, et al. Cyclooxygenase-2 expressed hepatocellular carcinoma induces cytotoxic T lymphocytes exhaustion through M2 macrophage polarization. Am J Transl Res, 2021, 13(5): 4360-4375.
24. Xu D, Wang Y, Wu J, et al. ECT2 overexpression promotes the polarization of tumor-associated macrophages in hepatocellular carcinoma via the ECT2/PLK1/PTEN pathway. Cell Death Dis, 2021, 12(2): 162. doi: 10.1038/s41419-021-03450-z.
25. Li W, Xin X, Li X, et al. Exosomes secreted by M2 macrophages promote cancer stemness of hepatocellular carcinoma via the miR-27a-3p/TXNIP pathways. Int Immunopharmacol, 2021, 101(Pt A): 107585. doi: 10.1016/j.intimp.2021.107585.
26. Wang L, Fu Y, Chu Y. Regulatory B cells. Adv Exp Med Biol, 2020, 1254: 87-103.
27. Garnelo M, Tan A, Her Z, et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut, 2017, 66(2): 342-351.
28. Largeot A, Pagano G, Gonder S, et al. The B-side of cancer immunity: the underrated tune. Cells, 2019, 8(5): 449. doi: 10.3390/cells8050449.
29. Xue H, Lin F, Tan H, et al. Overrepresentation of IL-10-expressing B cells suppresses cytotoxic CD4⁺ T cell activity in HBV-induced hepatocellular carcinoma. PLoS One, 2016, 11(5): e0154815. doi: 10.1371/journal.pone.0154815.
30. Hao J, Li M, Zhang T, et al. Prognostic value of tumor-infiltrating lymphocytes differs depending on lymphocyte subsets in esophageal squamous cell carcinoma: an updated meta-analysis. Front Oncol, 2020, 10: 614. doi: 10.3389/fonc.2020.00614.
31. Zhao Y, Ge X, He J, et al. The prognostic value of tumor-infiltrating lymphocytes in colorectal cancer differs by anatomical subsite: a systematic review and meta-analysis. World J Surg Oncol, 2019, 17(1): 85. doi: 10.1186/s12957-019-1621-9.
32. Yarchoan M, Xing D, Luan L, et al. Characterization of the immune microenvironment in hepatocellular carcinoma. Clin Cancer Res, 2017, 23(23): 7333-7339.
33. Huo J, Wu L, Zang Y. Identification and validation of a novel immune-related signature associated with macrophages and CD8 T cell infiltration predicting overall survival for hepatocellular carcinoma. BMC Med Genomics, 2021, 14(1): 232. doi: 10.1186/12920-021-01081-z.
34. Hofmann M, Tauber C, Hensel N, et al. CD8⁺T cell responses during HCV infection and HCC. J Clin Med, 2021, 10(5): 991. doi: 10.3390/jcm10050991.
35. Ma C, Kesarwala AH, Eggert T, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature, 2016, 531(7593): 253-257.
36. Mossanen JC, Kohlhepp M, Wehr A, et al. CXCR6 inhibits hepatocarcinogenesis by promoting natural killer T- and CD4 ⁺ T-cell-dependent control of senescence. Gastroenterology, 2019, 156(6): 1877-1889.e4.
37. Brown ZJ, Fu Q, Ma C, et al. Carnitine palmitoyltransferase gene upregulation by linoleic acid induces CD4⁺ T cell apoptosis promoting HCC development. Cell Death Dis, 2018, 9(6): 620. doi: 10.1038/s41419-018-0687-6.
38. Qi X, Yang M, Ma L, et al. Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response. J Immunother Cancer, 2020, 8(2): e001038. doi: 10.1136/jitc-2020-001038.
39. Gao Q, Zhou J, Wang XY, et al. Infiltrating memory/senescent T cell ratio predicts extrahepatic metastasis of hepatocellular carcinoma. Ann Surg Oncol, 2012, 19(2): 455-466.
40. Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression-implications for anticancer therapy. Nat Rev Clin Oncol, 2019, 16(6): 356-371.
41. Zhang S, Gan X, Qiu J, et al. IL-10 derived from hepatocarcinoma cells improves human induced regulatory T cells function via JAK1/STAT5 pathway in tumor microenvironment. Mol Immunol, 2021, 133: 163-172.
42. Ren Z, Yue Y, Zhang Y, et al. Changes in the peripheral blood Treg cell proportion in hepatocellular carcinoma patients after transarterial chemoembolization with microparticles. Front Immunol, 2021, 12: 624789. doi: 10.3389/fimmu.2021.624789.
43. Macek Jilkova Z, Aspord C, Decaens T. Predictive factors for response to PD-1/PD-L1 checkpoint inhibition in the field of hepatocellular carcinoma: current status and challenges. Cancers (Basel), 2019, 11(10): 1554. doi: 10.3390/cancers11101554.
44. Ma LJ, Feng FL, Dong LQ, et al. Clinical significance of PD-1/PD-Ls gene amplification and overexpression in patients with hepatocellular carcinoma. Theranostics, 2018, 8(20): 5690-5702.
45. Deng H, Kan A, Lyu N, et al. Dual vascular endothelial growth factor receptor and fibroblast growth factor receptor inhibition elicits antitumor immunity and enhances programmed cell death-1 checkpoint blockade in hepatocellular carcinoma. Liver Cancer, 2020, 9(3): 338-357.
46. Huang CY, Wang Y, Luo GY, et al. Relationship between PD-L1 expression and CD8⁺ T-cell immune responses in hepatocellular carcinoma. J Immunother, 2017, 40(9): 323-333.
47. Xiao X, Lao XM, Chen MM, et al. PD-1hi identifies a novel regulatory B-cell population in human hepatoma that promotes disease progression. Cancer Discov, 2016, 6(5): 546-559.
48. Xu G, Feng D, Yao Y, et al. Listeria-based hepatocellular carcinoma vaccine facilitates anti-PD-1 therapy by regulating macrophage polarization. Oncogene, 2020, 39(7): 1429-1444.
49. Park DJ, Sung PS, Lee GW, et al. Preferential expression of programmed death ligand 1 protein in tumor-associated macrophages and its potential role in immunotherapy for hepatocellular carcinoma. Int J Mol Sci, 2021, 22(9): 4710. doi: 10.3390/ijms22094710.

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Research progress on relation of immune cell infiltration and prognosis of hepatocellular carcinoma

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