Research advances of biomarkers related to the efficacy of immune checkpoint blockade therapy for hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

HE Linghua , LIU Kaimin , TONG Hongxing , YANG Chao ,  CHEN Gang

Department of Hepatobiliary Surgery, The First People’s Hospital of Kunming/The Affiliated Ganmei Hospital of Kunming Medical University, Kunming 650011, P. R. China;

Corresponding author：

CHEN Gang, Email: kmcg123@163.com

Keywords：

hepatocellular carcinoma; immune checkpoint inhibition; biomarker

DOI：

10.7507/1007-9424.202103044

Video：

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Objective To summarize the biomarkers related to the efficacy of immune checkpoint inhibitors for hepatocellular carcinoma (HCC).Method Reviewed and summarized the literatures on the basic and clinical application of biomarkers related to programmed cell death protein 1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors and their combination with targeted therapy.Results The combination of immunotherapy and targeted therapy had brought great hope for the treatment of patients with advanced HCC, but there were still some patients who could not benefit from it. Recent studies had shown that expression of PD-L1 in tumor tissue, tumor mutational burden, tumor-infiltrating lymphocytes, peripheral immune cells, circulating tumor DNA, gut microbiome, and so on, could predict the efficacy of immunotherapy or targeted therapy combined with immunotherapy for HCC.Conclusions There is no specific biomarker to predict the efficacy of immunotherapy and its combination regimen for HCC. More prospective studies are needed to confirm the predictive value of these biomarkers and to establish a multi-factor predictive model or immune score to screen patients who may benefit, which is of great significance for precise immunotherapy of HCC.

Citation： HE Linghua, LIU Kaimin, TONG Hongxing, YANG Chao, CHEN Gang. Research advances of biomarkers related to the efficacy of immune checkpoint blockade therapy for hepatocellular carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(1): 112-117. doi: 10.7507/1007-9424.202103044 Copy

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2.	郑荣寿, 孙可欣, 张思维, 等. 2015 年中国恶性肿瘤流行情况分析. 中华肿瘤杂志, 2019, 41(1): 19-28.
3.	Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet, 2018, 391(10127): 1301-1314.
4.	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.
5.	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.
6.	Korman AJ, Peggs KS, Allison JP. Checkpoint blockade in cancer immunotherapy. Adv Immunol, 2006, 90: 297-339.
7.	Honjo T. Seppuku and autoimmunity. Science, 1992, 258(5082): 591-592.
8.	Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science, 2018, 359(6382): 1350-1355.
9.	Pinato DJ, Mauri FA, Spina P, et al. Clinical implications of heterogeneity in PD-L1 immunohistochemical detection in hepatocellular carcinoma: the Blueprint-HCC study. Br J Cancer, 2019, 120(11): 1033-1036.
10.	Feun LG, Li YY, Wu C, et al. Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma. Cancer, 2019, 125(20): 3603-3614.
11.	Tang H, Liang Y, Anders RA, et al. PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression. J Clin Invest, 2018, 128(2): 580-588.
12.	Davis AA, Patel VG. The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J Immunother Cancer, 2019, 7(1): 278.
13.	Goodman AM, Kato S, Bazhenova L, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther, 2017, 16(11): 2598-2608.
14.	Huo J, Wu L, Zang Y. A prognostic model of 15 immune-related gene pairs associated with tumor mutation burden for hepatocellular carcinoma. Front Mol Biosci, 2020, 7: 581354.
15.	Durgeau A, Virk Y, Corgnac S, et al. Recent advances in targeting CD8 T-cell immunity for more effective cancer immunotherapy. Front Immunol, 2018, 9: 14.
16.	Garcia-Diaz A, Shin DS, Moreno BH, et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep, 2017, 19(6): 1189-1201.
17.	Harding JJ, Nandakumar S, Armenia J, et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin Cancer Res, 2019, 25(7): 2116-2126.
18.	Ma L, Hernandez MO, Zhao Y, et al. Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer. Cancer Cell, 2019, 36(4): 418-430.e6.
19.	Yang X, Shi J, Chen X, et al. Efficacy of cabozantinib and nivolumab in treating hepatocellular carcinoma with RET amplification, high tumor mutational burden, and PD-L1 expression. Oncologist, 2020, 25(6): 470-474.
20.	Li J, Zhou J, Kai S, et al. Functional and clinical characterization of tumor-infiltrating T cell subpopulations in hepatocellular carcinoma. Front Genet, 2020, 11: 586415.
21.	Kaseb AO, Vence L, Blando J, et al. Immunologic correlates of pathologic complete response to preoperative immunotherapy in hepatocellular carcinoma. Cancer Immunol Res, 2019, 7(9): 1390-1395.
22.	Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature, 2014, 515(7528): 568-571.
23.	Kim HD, Song GW, Park S, et al. Association between expression level of PD1 by tumor-infiltrating CD8⁺T cells and features of hepatocellular carcinoma. Gastroenterology, 2018, 155(6): 1936-1950.
24.	Kamada T, Togashi Y, Tay C, et al. PD-1⁺ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci U S A, 2019, 116(20): 9999-10008.
25.	Peng G, Li S, Wu W, et al. PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients. Mol Immunol, 2008, 45(4): 963-970.
26.	Gros A, Parkhurst MR, Tran E, et al. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med, 2016, 22(4): 433-438.
27.	Hopkins AC, Yarchoan M, Durham JN, et al. T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma. JCI Insight, 2018, 3(13): e122092.
28.	Mariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature, 2018, 554(7693): 544-548.
29.	Sun DW, An L, Huang HY, et al. Establishing peripheral PD-L1 as a prognostic marker in hepatocellular carcinoma patients: how long will it come true? Clin Transl Oncol, 2021, 23(1): 82-91.
30.	Wu X, Li J, Gassa A, et al. Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma. Int J Biol Sci, 2020, 16(9): 1551-1562.
31.	Cai Z, Chen G, Zeng Y, et al. Comprehensive liquid profiling of circulating tumor DNA and protein biomarkers in long-term follow-up patients with hepatocellular carcinoma. Clin Cancer Res, 2019, 25(17): 5284-5294.
32.	Ikeda S, Lim JS, Kurzrock R. Analysis of tissue and circulating tumor DNA by next-generation sequencing of hepatocellular carcinoma: implications for targeted therapeutics. Mol Cancer Ther, 2018, 17(5): 1114-1122.
33.	Khagi Y, Goodman AM, Daniels GA, et al. Hypermutated circulating tumor DNA: correlation with response to checkpoint inhibitor-based immunotherapy. Clin Cancer Res, 2017, 23(19): 5729-5736.
34.	von Felden J, Craig AJ, Garcia-Lezana T, et al. Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma. Oncogene, 2021, 40(1): 140-151.
35.	Zhou A, Tang L, Zeng S, et al. Gut microbiota: a new piece in understanding hepatocarcinogenesis. Cancer Lett, 2020, 474: 15-22.
36.	Zitvogel L, Ma Y, Raoult D, et al. The microbiome in cancer immunotherapy: diagnostic tools and therapeutic strategies. Science, 2018, 359(6382): 1366-1370.
37.	Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science, 2018, 359(6371): 91-97.
38.	Zheng Y, Wang T, Tu X, et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J Immunother Cancer, 2019, 7(1): 193.
39.	Li L, Ye J. Characterization of gut microbiota in patients with primary hepatocellular carcinoma received immune checkpoint inhibitors: a Chinese population-based study. Medicine (Baltimore), 2020, 99(37): e21788.
40.	Hack SP, Zhu AX, Wang Y. Augmenting anticancer immunity through combined targeting of angiogenic and PD-1/PD-L1 pathways: challenges and opportunities. Front Immunol, 2020, 11: 598877.
41.	Kato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8⁺ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One, 2019, 14(2): e0212513.
42.	Kimura T, Kato Y, Ozawa Y, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepato cellular carcinoma model. Cancer Sci, 2018, 109(12): 3993-4002.
43.	Shigeta K, Datta M, Hato T, et al. Dual programmed death receptor-1 and vascular endothelial growth factor receptor-2 blockade promotes vascular normalization and enhances antitumor immune responses in hepatocellular carcinoma. Hepatology, 2020, 71(4): 1247-1261.
44.	Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med, 2020, 382(20): 1894-1905.
45.	Zhu A, Guan Y, Abbas A, et al. Abstract CT044: genomic correlates of clinical benefits from atezolizumab combined with bevacizumab vs. atezolizumab alone in patients with advanced hepatocellular carcinoma (HCC). Cancer Res, 2020, 80: CT044.
46.	Koinis F, Vetsika EK, Aggouraki D, et al. Effect of first-line treatment on myeloid-derived suppressor cells’ subpopulations in the peripheral blood of patients with non-small cell lung cancer. J Thorac Oncol, 2016, 11(8): 1263-1272.

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. 郑荣寿, 孙可欣, 张思维, 等. 2015 年中国恶性肿瘤流行情况分析. 中华肿瘤杂志, 2019, 41(1): 19-28.
3. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet, 2018, 391(10127): 1301-1314.
4. 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.
5. 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.
6. Korman AJ, Peggs KS, Allison JP. Checkpoint blockade in cancer immunotherapy. Adv Immunol, 2006, 90: 297-339.
7. Honjo T. Seppuku and autoimmunity. Science, 1992, 258(5082): 591-592.
8. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science, 2018, 359(6382): 1350-1355.
9. Pinato DJ, Mauri FA, Spina P, et al. Clinical implications of heterogeneity in PD-L1 immunohistochemical detection in hepatocellular carcinoma: the Blueprint-HCC study. Br J Cancer, 2019, 120(11): 1033-1036.
10. Feun LG, Li YY, Wu C, et al. Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma. Cancer, 2019, 125(20): 3603-3614.
11. Tang H, Liang Y, Anders RA, et al. PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression. J Clin Invest, 2018, 128(2): 580-588.
12. Davis AA, Patel VG. The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J Immunother Cancer, 2019, 7(1): 278.
13. Goodman AM, Kato S, Bazhenova L, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther, 2017, 16(11): 2598-2608.
14. Huo J, Wu L, Zang Y. A prognostic model of 15 immune-related gene pairs associated with tumor mutation burden for hepatocellular carcinoma. Front Mol Biosci, 2020, 7: 581354.
15. Durgeau A, Virk Y, Corgnac S, et al. Recent advances in targeting CD8 T-cell immunity for more effective cancer immunotherapy. Front Immunol, 2018, 9: 14.
16. Garcia-Diaz A, Shin DS, Moreno BH, et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep, 2017, 19(6): 1189-1201.
17. Harding JJ, Nandakumar S, Armenia J, et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin Cancer Res, 2019, 25(7): 2116-2126.
18. Ma L, Hernandez MO, Zhao Y, et al. Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer. Cancer Cell, 2019, 36(4): 418-430.e6.
19. Yang X, Shi J, Chen X, et al. Efficacy of cabozantinib and nivolumab in treating hepatocellular carcinoma with RET amplification, high tumor mutational burden, and PD-L1 expression. Oncologist, 2020, 25(6): 470-474.
20. Li J, Zhou J, Kai S, et al. Functional and clinical characterization of tumor-infiltrating T cell subpopulations in hepatocellular carcinoma. Front Genet, 2020, 11: 586415.
21. Kaseb AO, Vence L, Blando J, et al. Immunologic correlates of pathologic complete response to preoperative immunotherapy in hepatocellular carcinoma. Cancer Immunol Res, 2019, 7(9): 1390-1395.
22. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature, 2014, 515(7528): 568-571.
23. Kim HD, Song GW, Park S, et al. Association between expression level of PD1 by tumor-infiltrating CD8⁺T cells and features of hepatocellular carcinoma. Gastroenterology, 2018, 155(6): 1936-1950.
24. Kamada T, Togashi Y, Tay C, et al. PD-1⁺ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci U S A, 2019, 116(20): 9999-10008.
25. Peng G, Li S, Wu W, et al. PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients. Mol Immunol, 2008, 45(4): 963-970.
26. Gros A, Parkhurst MR, Tran E, et al. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med, 2016, 22(4): 433-438.
27. Hopkins AC, Yarchoan M, Durham JN, et al. T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma. JCI Insight, 2018, 3(13): e122092.
28. Mariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature, 2018, 554(7693): 544-548.
29. Sun DW, An L, Huang HY, et al. Establishing peripheral PD-L1 as a prognostic marker in hepatocellular carcinoma patients: how long will it come true? Clin Transl Oncol, 2021, 23(1): 82-91.
30. Wu X, Li J, Gassa A, et al. Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma. Int J Biol Sci, 2020, 16(9): 1551-1562.
31. Cai Z, Chen G, Zeng Y, et al. Comprehensive liquid profiling of circulating tumor DNA and protein biomarkers in long-term follow-up patients with hepatocellular carcinoma. Clin Cancer Res, 2019, 25(17): 5284-5294.
32. Ikeda S, Lim JS, Kurzrock R. Analysis of tissue and circulating tumor DNA by next-generation sequencing of hepatocellular carcinoma: implications for targeted therapeutics. Mol Cancer Ther, 2018, 17(5): 1114-1122.
33. Khagi Y, Goodman AM, Daniels GA, et al. Hypermutated circulating tumor DNA: correlation with response to checkpoint inhibitor-based immunotherapy. Clin Cancer Res, 2017, 23(19): 5729-5736.
34. von Felden J, Craig AJ, Garcia-Lezana T, et al. Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma. Oncogene, 2021, 40(1): 140-151.
35. Zhou A, Tang L, Zeng S, et al. Gut microbiota: a new piece in understanding hepatocarcinogenesis. Cancer Lett, 2020, 474: 15-22.
36. Zitvogel L, Ma Y, Raoult D, et al. The microbiome in cancer immunotherapy: diagnostic tools and therapeutic strategies. Science, 2018, 359(6382): 1366-1370.
37. Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science, 2018, 359(6371): 91-97.
38. Zheng Y, Wang T, Tu X, et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J Immunother Cancer, 2019, 7(1): 193.
39. Li L, Ye J. Characterization of gut microbiota in patients with primary hepatocellular carcinoma received immune checkpoint inhibitors: a Chinese population-based study. Medicine (Baltimore), 2020, 99(37): e21788.
40. Hack SP, Zhu AX, Wang Y. Augmenting anticancer immunity through combined targeting of angiogenic and PD-1/PD-L1 pathways: challenges and opportunities. Front Immunol, 2020, 11: 598877.
41. Kato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8⁺ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One, 2019, 14(2): e0212513.
42. Kimura T, Kato Y, Ozawa Y, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepato cellular carcinoma model. Cancer Sci, 2018, 109(12): 3993-4002.
43. Shigeta K, Datta M, Hato T, et al. Dual programmed death receptor-1 and vascular endothelial growth factor receptor-2 blockade promotes vascular normalization and enhances antitumor immune responses in hepatocellular carcinoma. Hepatology, 2020, 71(4): 1247-1261.
44. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med, 2020, 382(20): 1894-1905.
45. Zhu A, Guan Y, Abbas A, et al. Abstract CT044: genomic correlates of clinical benefits from atezolizumab combined with bevacizumab vs. atezolizumab alone in patients with advanced hepatocellular carcinoma (HCC). Cancer Res, 2020, 80: CT044.
46. Koinis F, Vetsika EK, Aggouraki D, et al. Effect of first-line treatment on myeloid-derived suppressor cells’ subpopulations in the peripheral blood of patients with non-small cell lung cancer. J Thorac Oncol, 2016, 11(8): 1263-1272.

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Research advances of biomarkers related to the efficacy of immune checkpoint blockade therapy for hepatocellular carcinoma

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