Advances in immunophenotyping of hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIU Jiarui , XIAO Heng ,  DU Chengyou

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P. R. China;

Corresponding author：

DU Chengyou, Email: duchengyou@126.com

Keywords：

hepatocellular carcinoma; tumor microenvironment; immunophenotype; immunotherapy; review

DOI：

10.7507/1007-9424.202011062

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the research progress of hepatocellular carcinoma (HCC) based on tumor microenvironment immunophenotyping.Method The related literatures of basic and clinical studies on HCC immunophenotyping in the recent years were reviewed.Results HCC could be divided into different immunophenotypes based on tumor microenvironment, and it showed different immune molecular characteristics, immune cell infiltration characteristics, and anti-tumor ability. At the same time, the HCC immunophenotype was significantly associated with patients’ survival and had been proved to be able to better evaluate the prognosis of HCC patients. According to the relevant molecular characteristics in the HCC immune microenvironment, it could provide guidance for the drug regimen of immunotherapy.Conclusion HCC immunophenotyping is still in the early stage of research, and its clinical application value has been preliminarily shown for the evaluation of patients’ prognosis and immunotherapy decision-making, which is a new idea of individualized treatment of HCC in the future.

Citation： LIU Jiarui, XIAO Heng, DU Chengyou. Advances in immunophenotyping of hepatocellular carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(9): 1237-1242. doi: 10.7507/1007-9424.202011062 Copy

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2.	Thimme R, Neagu M, Boettler T, et al. Comprehensive analysis of the alpha-fetoprotein-specific CD8⁺ T cell responses in patients with hepatocellular carcinoma. Hepatology, 2008, 48(6): 1821-1833.
3.	McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis, 2015, 19(2): 223-238.
4.	Llovet JM, Zucman-Rossi J, Pikarsky E, et al. Hepatocellular carcinoma. Nat Rev Dis Primers, 2016, 2: 16018.
5.	Zucman-Rossi J, Villanueva A, Nault JC, et al. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology, 2015, 149(5): 1226-1239.
6.	Kirkwood JM, Butterfield LH, Tarhini AA, et al. Immunotherapy of cancer in 2012. CA Cancer J Clin, 2012, 62(5): 309-335.
7.	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.
8.	El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet, 2017, 389(10088): 2492-2502.
9.	Rizvi S, Wang J, El-Khoueiry AB. Liver cancer immunity. Hepatology, 2021, 73 Suppl 1: 86-103.
10.	中华人民共和国国家卫生健康委员会医政医管局. 原发性肝癌诊疗规范 (2019年版). 中国实用外科杂志, 2020, 40(2): 121-138.
11.	赵洋, 张勇, 燕蒙, 等. 基于转录组的肝细胞癌分子分型研究进展. 中国科学: 生命科学, 2019, 49(1): 10-17.
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13.	Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol, 2015, 12(12): 681-700.
14.	Sia D, Jiao Y, Martinez-Quetglas I, et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology, 2017, 153(3): 812-826.
15.	Park BV, Freeman ZT, Ghasemzadeh A, et al. TGFβ1-mediated SMAD3 enhances PD-1 expression on antigen-specific T cells in cancer. Cancer Discov, 2016, 6(12): 1366-1381.
16.	Stephen TL, Rutkowski MR, Allegrezza MJ, et al. Transforming growth factor β-mediated suppression of antitumor T cells requires FoxP1 transcription factor expression. Immunity, 2014, 41(3): 427-439.
17.	Flavell RA, Sanjabi S, Wrzesinski SH, et al. The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol, 2010, 10(8): 554-567.
18.	吴志超, 林伯斌, 孙少杰, 等. 肝癌组织中TGF-β1、β-catenin和EMT相关蛋白表达水平及临床意义. 中国现代普通外科进展, 2019, 22(12): 930-934.
19.	樊嘉, 高强. 肝癌分子分型指导精准诊断与治疗的研究前沿. 中华消化外科杂志, 2020, 19(1): 28-31.
20.	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.
21.	Tsujikawa H, Masugi Y, Yamazaki K, et al. Immunohistochemical molecular analysis indicates hepatocellular carcinoma subgroups that reflect tumor aggressiveness. Hum Pathol, 2016, 50: 24-33.
22.	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.
23.	Peng D, Kryczek I, Nagarsheth N, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature, 2015, 527(7577): 249-253.
24.	Zhang Q, Lou Y, Yang J, et al. Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas. Gut, 2019, 68(11): 2019-2031.
25.	Geiger R, Rieckmann JC, Wolf T, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell, 2016, 167(3): 829-842.
26.	Garris CS, Arlauckas SP, Kohler RH, et al. Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12. Immunity, 2018, 49(6): 1148-1161.
27.	Takeda Y, Kataoka K, Yamagishi J, et al. A TLR3-specific adjuvant relieves innate resistance to PD-L1 blockade without cytokine toxicity in tumor vaccine immunotherapy. Cell Rep, 2017, 19(9): 1874-1887.
28.	Wang S, Campos J, Gallotta M, et al. Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8⁺ T cells. Proc Natl Acad Sci U S A, 2016, 113(46): E7240-E7249.
29.	Samson A, Scott KJ, Taggart D, et al. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci Transl Med, 2018, 10(422): eaam7577.
30.	Bourgeois-Daigneault MC, Roy DG, Aitken AS, et al. Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy. Sci Transl Med, 2018, 10(422): eaao1641.
31.	Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell, 2017, 170(6): 1109-1119.
32.	Wu C, Ning H, Liu M, et al. Spleen mediates a distinct hematopoietic progenitor response supporting tumor-promoting myelopoiesis. J Clin Invest, 2018, 128(8): 3425-3438.
33.	Allen E, Jabouille A, Rivera LB, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med, 2017, 9(385): eaak9679.
34.	Liu W, Putnam AL, Zhou XY, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4⁺ T reg cells. J Exp Med, 2006, 203(7): 1701-1711.
35.	Zheng C, Zheng L, Yoo JK, et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell, 2017, 169(7): 1342-1356.
36.	Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med, 2017, 377(25): 2500-2501.
37.	Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet, 2019, 51(2): 202-206.
38.	Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature, 2014, 515(7528): 568-571.
39.	Ma J, Zheng B, Goswami S, et al. PD1^Hi CD8⁺ T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma. J Immunother Cancer, 2019, 7(1): 331.
40.	Tian MX, Liu WR, Wang H, et al. Tissue-infiltrating lymphocytes signature predicts survival in patients with early/intermediate stage hepatocellular carcinoma. BMC Med, 2019, 17(1): 106.
41.	Wei L, Delin Z, Kefei Y, et al. A classification based on tumor budding and immune score for patients with hepatocellular carcinoma. Oncoimmunology, 2019, 9(1): 1672495.

1. 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.
2. Thimme R, Neagu M, Boettler T, et al. Comprehensive analysis of the alpha-fetoprotein-specific CD8⁺ T cell responses in patients with hepatocellular carcinoma. Hepatology, 2008, 48(6): 1821-1833.
3. McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis, 2015, 19(2): 223-238.
4. Llovet JM, Zucman-Rossi J, Pikarsky E, et al. Hepatocellular carcinoma. Nat Rev Dis Primers, 2016, 2: 16018.
5. Zucman-Rossi J, Villanueva A, Nault JC, et al. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology, 2015, 149(5): 1226-1239.
6. Kirkwood JM, Butterfield LH, Tarhini AA, et al. Immunotherapy of cancer in 2012. CA Cancer J Clin, 2012, 62(5): 309-335.
7. 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.
8. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet, 2017, 389(10088): 2492-2502.
9. Rizvi S, Wang J, El-Khoueiry AB. Liver cancer immunity. Hepatology, 2021, 73 Suppl 1: 86-103.
10. 中华人民共和国国家卫生健康委员会医政医管局. 原发性肝癌诊疗规范 (2019年版). 中国实用外科杂志, 2020, 40(2): 121-138.
11. 赵洋, 张勇, 燕蒙, 等. 基于转录组的肝细胞癌分子分型研究进展. 中国科学: 生命科学, 2019, 49(1): 10-17.
12. Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell, 2017, 169(7): 1327-1341.
13. Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol, 2015, 12(12): 681-700.
14. Sia D, Jiao Y, Martinez-Quetglas I, et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology, 2017, 153(3): 812-826.
15. Park BV, Freeman ZT, Ghasemzadeh A, et al. TGFβ1-mediated SMAD3 enhances PD-1 expression on antigen-specific T cells in cancer. Cancer Discov, 2016, 6(12): 1366-1381.
16. Stephen TL, Rutkowski MR, Allegrezza MJ, et al. Transforming growth factor β-mediated suppression of antitumor T cells requires FoxP1 transcription factor expression. Immunity, 2014, 41(3): 427-439.
17. Flavell RA, Sanjabi S, Wrzesinski SH, et al. The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol, 2010, 10(8): 554-567.
18. 吴志超, 林伯斌, 孙少杰, 等. 肝癌组织中TGF-β1、β-catenin和EMT相关蛋白表达水平及临床意义. 中国现代普通外科进展, 2019, 22(12): 930-934.
19. 樊嘉, 高强. 肝癌分子分型指导精准诊断与治疗的研究前沿. 中华消化外科杂志, 2020, 19(1): 28-31.
20. 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.
21. Tsujikawa H, Masugi Y, Yamazaki K, et al. Immunohistochemical molecular analysis indicates hepatocellular carcinoma subgroups that reflect tumor aggressiveness. Hum Pathol, 2016, 50: 24-33.
22. 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.
23. Peng D, Kryczek I, Nagarsheth N, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature, 2015, 527(7577): 249-253.
24. Zhang Q, Lou Y, Yang J, et al. Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas. Gut, 2019, 68(11): 2019-2031.
25. Geiger R, Rieckmann JC, Wolf T, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell, 2016, 167(3): 829-842.
26. Garris CS, Arlauckas SP, Kohler RH, et al. Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12. Immunity, 2018, 49(6): 1148-1161.
27. Takeda Y, Kataoka K, Yamagishi J, et al. A TLR3-specific adjuvant relieves innate resistance to PD-L1 blockade without cytokine toxicity in tumor vaccine immunotherapy. Cell Rep, 2017, 19(9): 1874-1887.
28. Wang S, Campos J, Gallotta M, et al. Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8⁺ T cells. Proc Natl Acad Sci U S A, 2016, 113(46): E7240-E7249.
29. Samson A, Scott KJ, Taggart D, et al. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci Transl Med, 2018, 10(422): eaam7577.
30. Bourgeois-Daigneault MC, Roy DG, Aitken AS, et al. Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy. Sci Transl Med, 2018, 10(422): eaao1641.
31. Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell, 2017, 170(6): 1109-1119.
32. Wu C, Ning H, Liu M, et al. Spleen mediates a distinct hematopoietic progenitor response supporting tumor-promoting myelopoiesis. J Clin Invest, 2018, 128(8): 3425-3438.
33. Allen E, Jabouille A, Rivera LB, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med, 2017, 9(385): eaak9679.
34. Liu W, Putnam AL, Zhou XY, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4⁺ T reg cells. J Exp Med, 2006, 203(7): 1701-1711.
35. Zheng C, Zheng L, Yoo JK, et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell, 2017, 169(7): 1342-1356.
36. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med, 2017, 377(25): 2500-2501.
37. Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet, 2019, 51(2): 202-206.
38. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature, 2014, 515(7528): 568-571.
39. Ma J, Zheng B, Goswami S, et al. PD1^Hi CD8⁺ T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma. J Immunother Cancer, 2019, 7(1): 331.
40. Tian MX, Liu WR, Wang H, et al. Tissue-infiltrating lymphocytes signature predicts survival in patients with early/intermediate stage hepatocellular carcinoma. BMC Med, 2019, 17(1): 106.
41. Wei L, Delin Z, Kefei Y, et al. A classification based on tumor budding and immune score for patients with hepatocellular carcinoma. Oncoimmunology, 2019, 9(1): 1672495.

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Advances in immunophenotyping of hepatocellular carcinoma

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