Research progress on the potential molecular mechanisms and predictive factors of hyperprogressive disease in hepatocellular carcinoma immunotherapy_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

PANG Beichuan ^1,2 , TAN Yiwei ^1,2 ,  LI Youwei ^1,2 ,  ZHANG Yu ³

1. Department of Hepatobiliary and Pancreatic Surgery, Deyang People's Hospital, Deyang 618000, China;
2. Digestive Disease Center, Deyang People's Hospital, Deyang 618000, China;
3. Department of Hepatobiliary and Pancreatic Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (Affiliated Hospital of University of Electronic Science and Technology of China), Chengdu 610072, China;

Corresponding author：

LI Youwei, Email: 279032902@qq.com; ZHANG Yu, Email: zhangyuqg@med.uestc.edu.cn

Keywords：

hepatocellular carcinoma; hyperprogressive disease; immune checkpoint inhibitor; biomarker

DOI：

10.7507/1007-9424.202412073

Video：

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Objective To summarize the clinical characteristics, potential molecular mechanisms, and predictive biomarkers of hyperprogressive disease (HPD) induced during the treatment of hepatocellular carcinoma (HCC) with immune checkpoint inhibitors and to explore its clinical implications. Methods Relevant domestic and international literature was reviewed to analyze the definition, mechanisms, and predictive factors of HPD. Particular attention was given to key factors affecting HPD development, including clinical characteristics, tumor microenvironment, genetic mutations, and inflammatory factors. Results HPD significantly reduces the survival of HCC patients. Its occurrence may be associated with individual variability, dysregulation of the tumor microenvironment, tumor-related genetic mutations, and elevated levels of inflammatory factors. Blood-based biomarkers such as neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), and alpha-fetoprotein (AFP) show potential value in predicting HPD. Conclusions Systematic investigation of the molecular mechanisms and predictive biomarkers of HPD is crucial for optimizing immunotherapy strategies and improving patient outcomes. Large-scale, multi-center studies are needed to achieve precise prediction and personalized intervention in the future.

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2.	Yang C, Zhang H, Zhang L, et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol, 2023, 20(4): 203-222.
3.	Pinter M, Scheiner B, Pinato DJ. Immune checkpoint inhibitors in hepatocellular carcinoma: emerging challenges in clinical practice. Lancet Gastroenterol Hepatol, 2023, 8(8): 760-770.
4.	杨鑫, 戴朝六, 徐锋. 肝细胞癌免疫治疗超进展的现状与应对策略. 中国实用外科杂志, 2023, 43(3): 354-360.
5.	Han X, Sun Q, Xu M, et al. Unraveling the complexities of immune checkpoint inhibitors in hepatocellular carcinoma. Semin Liver Dis, 2023, 43(4): 383-401.
6.	Kim CG, Kim KH, Pyo KH, et al. Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer. Ann Oncol, 2019, 30(7): 1104-1113.
7.	Wong DJ, Lee J, Choo SP, et al. Hyperprogressive disease in hepatocellular carcinoma with immune checkpoint inhibitor use: a case series. Immunotherapy, 2019, 11(3): 167-175.
8.	Alkader M, Altaha R, Alkhatib L, et al. Hyperprogressive disease in a metastatic renal cell carcinoma patient after receiving immune checkpoint inhibitors: a case report. Cureus, 2022, 14(10): e30194. doi: 10.7759/cureus.30194.
9.	Kim MJ, Hong SPD, Park Y, et al. Incidence of immunotherapy-related hyperprogressive disease (HPD) across HPD definitions and cancer types in observational studies: a systematic review and meta-analysis. Cancer Med, 2024, 13(3): e6970. doi: 10.1002/cam4.6970.
10.	中国医师协会肝癌专业委员会. 肝细胞癌免疫治疗中国专家共识(2021版). 中华医学杂志, 2021, 101(48): 3921-3931.
11.	Kim CG, Kim C, Yoon SE, et al. Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma. J Hepatol, 2021, 74(2): 350-359.
12.	徐磊, 张万广. 肝癌系统治疗中肿瘤超进展研究现状. 中国实用外科杂志, 2021, 41(3): 284-288.
13.	Ferrara R, Mezquita L, Texier M, et al. Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy. JAMA Oncol, 2018, 4(11): 1543-1552.
14.	Champiat S, Ferrara R, Massard C, et al. Hyperprogressive disease: recognizing a novel pattern to improve patient management. Nat Rev Clin Oncol, 2018, 15(12): 748-762.
15.	Arasanz H, Zuazo M, Bocanegra A, et al. Hyperprogressive disease: main features and key controversies. Int J Mol Sci, 2021, 22(7): 3736. doi: 10.3390/ijms22073736.
16.	Fujita M, Yamaguchi R, Hasegawa T, et al. Classification of primary liver cancer with immunosuppression mechanisms and correlation with genomic alterations. EBioMedicine, 2020, 102659. doi: 10.1016/j.ebiom.2020.102659.
17.	Liu X, Qiao L. Hyperprogressive disease in malignant carcinoma with immune checkpoint inhibitor use: a review. Front Nutr, 2022, 9: 810472. doi: 10.3389/fnut.2022.810472.
18.	Aoki T, Nishida N, Kudo M. Current perspectives on the immunosuppressive niche and role of fibrosis in hepatocellular carcinoma and the development of antitumor immunity. J Histochem Cytochem, 2022, 70(1): 53-81.
19.	Nishida N. Role of oncogenic pathways on the cancer immunosuppressive microenvironment and its clinical implications in hepatocellular carcinoma. Cancers (Basel), 2021, 13(15): 3666. doi: 10.3390/cancers13153666.
20.	Lebossé F, Gudd C, Tunc E, et al. CD8+T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction. EBioMedicine, 2019, 49: 258-268.
21.	Camelliti S, Le Noci V, Bianchi F, et al. Mechanisms of hyperprogressive disease after immune checkpoint inhibitor therapy: what we (don't) know. J Exp Clin Cancer Res, 2020, 39(1): 236.
22.	Yumita S, Ogasawara S, Nakagawa M, et al. Hyperprogressive disease during atezolizumab plus bevacizumab treatment in patients with advanced hepatocellular carcinoma from Japanese real-world practice. BMC Gastroenterol, 2023, 23(1): 101. doi: 10.1186/s12876-023-02731-5.
23.	Qiu XY, Hu DX, Chen WQ, et al. PD-L1 confers glioblastoma multiforme malignancy via Ras binding and Ras/Erk/EMT activation. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(5 Pt A): 1754-1769.
24.	Tanaka T, Koga H, Suzuki H, et al. Anti-PD-L1 antibodies promote cellular proliferation by activating the PD-L1-AXL signal relay in liver cancer cells. Hepatol Int, 2024, 18(3): 984-997.
25.	Wu L, Quan W, Luo Q, et al. Identification of an immune-related prognostic predictor in hepatocellular carcinoma. Front Mol Biosci, 2020, 7: 567950. doi: 10.3389/fmolb.2020.567950.
26.	Azer SA. MDM2-p53 interactions in human hepatocellular carcinoma: what is the role of nutlins and new therapeutic options?. J Clin Med, 2018, 7(4): 64. doi: 10.3390/jcm7040064.
27.	Sun Q, Shen M, Zhu S, et al. Targeting NAD+ metabolism of hepatocellular carcinoma cells by lenvatinib promotes M2 macrophages reverse polarization, suppressing the HCC progression. Hepatol Int, 2023, 17(6): 1444-1460.
28.	Kim KH, Kim CG, Shin EC. Peripheral blood immune cell-based biomarkers in anti-PD-1/PD-L1 therapy. Immune Netw, 2020, 20(1): e8. doi: 10.4110/in.2020.20.e8.
29.	Lo Russo G, Moro M, Sommariva M, et al. Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade. Clin Cancer Res, 2019, 25(3): 989-999.
30.	Kanjanapan Y, Day D, Wang L, et al. Hyperprogressive disease in early-phase immunotherapy trials: Clinical predictors and association with immune-related toxicities. Cancer, 2019, 125(8): 1341-1349.
31.	Zhang L, Wu L, Chen Q, et al. Predicting hyperprogressive disease in patients with advanced hepatocellular carcinoma treated with anti-programmed cell death 1 therapy. EClinicalMedicine, 2020, 31: 100673. doi: 10.1016/j.eclinm.2020.100673.
32.	Liu J, Wu Q, Wu S, et al. Investigation on potential biomarkers of hyperprogressive disease (HPD) triggered by immune checkpoint inhibitors (ICIs). Clin Transl Oncol, 2021, 23(9): 1782-1793.
33.	Yildirim HC, Guven DC, Aktepe OH, et al. Blood based biomarkers as predictive factors for hyperprogressive disease. J Clin Med, 2022, 11(17): 5171. doi: 10.3390/jcm11175171.
34.	Tian Y, Xiao H, Yang Y, et al. Crosstalk between 5-methylcytosine and N6-methyladenosine machinery defines disease progression, therapeutic response and pharmacogenomic landscape in hepatocellular carcinoma. Mol Cancer, 2023, 22(1): 5. doi: 10.1186/s12943-022-01706-6.
35.	Maesaka K, Sakamori R, Yamada R, et al. Hyperprogressive disease in patients with unresectable hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy. Hepatol Res, 2022, 52(3): 298-307.
36.	Choi WM, Kim JY, Choi J, et al. Kinetics of the neutrophil-lymphocyte ratio during PD-1 inhibition as a prognostic factor in advanced hepatocellular carcinoma. Liver Int, 2021, 41(9): 2189-2199.
37.	Yu B, Ma W. Biomarker discovery in hepatocellular carcinoma (HCC) for personalized treatment and enhanced prognosis. Cytokine Growth Factor Rev, 2024, 79: 29-38.
38.	Shigefuku R, Yoshikawa K, Tsukimoto M, et al. Hepatocellular carcinoma pseudoprogression involving the main portal vein, right ventricular invasion, and exacerbation of lung metastases in a patient on Atezolizumab plus Bevacizumab. Intern Med, 2023, 62(4): 539-543.
39.	Chen Z, Chen Y, Sun Y, et al. Predicting gastric cancer response to anti-HER2 therapy or anti-HER2 combined immunotherapy based on multi-modal data. Signal Transduct Target Ther, 2024, 9(1): 222. doi: 10.1038/s41392-024-01932-y.
40.	Li R, Li L, Xu Y, et al. Machine learning meets omics: applications and perspectives. Brief Bioinform, 2022, 23(1): bbab460. doi: 10.1093/bib/bbab460.

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. Yang C, Zhang H, Zhang L, et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol, 2023, 20(4): 203-222.
3. Pinter M, Scheiner B, Pinato DJ. Immune checkpoint inhibitors in hepatocellular carcinoma: emerging challenges in clinical practice. Lancet Gastroenterol Hepatol, 2023, 8(8): 760-770.
4. 杨鑫, 戴朝六, 徐锋. 肝细胞癌免疫治疗超进展的现状与应对策略. 中国实用外科杂志, 2023, 43(3): 354-360.
5. Han X, Sun Q, Xu M, et al. Unraveling the complexities of immune checkpoint inhibitors in hepatocellular carcinoma. Semin Liver Dis, 2023, 43(4): 383-401.
6. Kim CG, Kim KH, Pyo KH, et al. Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer. Ann Oncol, 2019, 30(7): 1104-1113.
7. Wong DJ, Lee J, Choo SP, et al. Hyperprogressive disease in hepatocellular carcinoma with immune checkpoint inhibitor use: a case series. Immunotherapy, 2019, 11(3): 167-175.
8. Alkader M, Altaha R, Alkhatib L, et al. Hyperprogressive disease in a metastatic renal cell carcinoma patient after receiving immune checkpoint inhibitors: a case report. Cureus, 2022, 14(10): e30194. doi: 10.7759/cureus.30194.
9. Kim MJ, Hong SPD, Park Y, et al. Incidence of immunotherapy-related hyperprogressive disease (HPD) across HPD definitions and cancer types in observational studies: a systematic review and meta-analysis. Cancer Med, 2024, 13(3): e6970. doi: 10.1002/cam4.6970.
10. 中国医师协会肝癌专业委员会. 肝细胞癌免疫治疗中国专家共识(2021版). 中华医学杂志, 2021, 101(48): 3921-3931.
11. Kim CG, Kim C, Yoon SE, et al. Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma. J Hepatol, 2021, 74(2): 350-359.
12. 徐磊, 张万广. 肝癌系统治疗中肿瘤超进展研究现状. 中国实用外科杂志, 2021, 41(3): 284-288.
13. Ferrara R, Mezquita L, Texier M, et al. Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy. JAMA Oncol, 2018, 4(11): 1543-1552.
14. Champiat S, Ferrara R, Massard C, et al. Hyperprogressive disease: recognizing a novel pattern to improve patient management. Nat Rev Clin Oncol, 2018, 15(12): 748-762.
15. Arasanz H, Zuazo M, Bocanegra A, et al. Hyperprogressive disease: main features and key controversies. Int J Mol Sci, 2021, 22(7): 3736. doi: 10.3390/ijms22073736.
16. Fujita M, Yamaguchi R, Hasegawa T, et al. Classification of primary liver cancer with immunosuppression mechanisms and correlation with genomic alterations. EBioMedicine, 2020, 102659. doi: 10.1016/j.ebiom.2020.102659.
17. Liu X, Qiao L. Hyperprogressive disease in malignant carcinoma with immune checkpoint inhibitor use: a review. Front Nutr, 2022, 9: 810472. doi: 10.3389/fnut.2022.810472.
18. Aoki T, Nishida N, Kudo M. Current perspectives on the immunosuppressive niche and role of fibrosis in hepatocellular carcinoma and the development of antitumor immunity. J Histochem Cytochem, 2022, 70(1): 53-81.
19. Nishida N. Role of oncogenic pathways on the cancer immunosuppressive microenvironment and its clinical implications in hepatocellular carcinoma. Cancers (Basel), 2021, 13(15): 3666. doi: 10.3390/cancers13153666.
20. Lebossé F, Gudd C, Tunc E, et al. CD8+T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction. EBioMedicine, 2019, 49: 258-268.
21. Camelliti S, Le Noci V, Bianchi F, et al. Mechanisms of hyperprogressive disease after immune checkpoint inhibitor therapy: what we (don't) know. J Exp Clin Cancer Res, 2020, 39(1): 236.
22. Yumita S, Ogasawara S, Nakagawa M, et al. Hyperprogressive disease during atezolizumab plus bevacizumab treatment in patients with advanced hepatocellular carcinoma from Japanese real-world practice. BMC Gastroenterol, 2023, 23(1): 101. doi: 10.1186/s12876-023-02731-5.
23. Qiu XY, Hu DX, Chen WQ, et al. PD-L1 confers glioblastoma multiforme malignancy via Ras binding and Ras/Erk/EMT activation. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(5 Pt A): 1754-1769.
24. Tanaka T, Koga H, Suzuki H, et al. Anti-PD-L1 antibodies promote cellular proliferation by activating the PD-L1-AXL signal relay in liver cancer cells. Hepatol Int, 2024, 18(3): 984-997.
25. Wu L, Quan W, Luo Q, et al. Identification of an immune-related prognostic predictor in hepatocellular carcinoma. Front Mol Biosci, 2020, 7: 567950. doi: 10.3389/fmolb.2020.567950.
26. Azer SA. MDM2-p53 interactions in human hepatocellular carcinoma: what is the role of nutlins and new therapeutic options?. J Clin Med, 2018, 7(4): 64. doi: 10.3390/jcm7040064.
27. Sun Q, Shen M, Zhu S, et al. Targeting NAD+ metabolism of hepatocellular carcinoma cells by lenvatinib promotes M2 macrophages reverse polarization, suppressing the HCC progression. Hepatol Int, 2023, 17(6): 1444-1460.
28. Kim KH, Kim CG, Shin EC. Peripheral blood immune cell-based biomarkers in anti-PD-1/PD-L1 therapy. Immune Netw, 2020, 20(1): e8. doi: 10.4110/in.2020.20.e8.
29. Lo Russo G, Moro M, Sommariva M, et al. Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade. Clin Cancer Res, 2019, 25(3): 989-999.
30. Kanjanapan Y, Day D, Wang L, et al. Hyperprogressive disease in early-phase immunotherapy trials: Clinical predictors and association with immune-related toxicities. Cancer, 2019, 125(8): 1341-1349.
31. Zhang L, Wu L, Chen Q, et al. Predicting hyperprogressive disease in patients with advanced hepatocellular carcinoma treated with anti-programmed cell death 1 therapy. EClinicalMedicine, 2020, 31: 100673. doi: 10.1016/j.eclinm.2020.100673.
32. Liu J, Wu Q, Wu S, et al. Investigation on potential biomarkers of hyperprogressive disease (HPD) triggered by immune checkpoint inhibitors (ICIs). Clin Transl Oncol, 2021, 23(9): 1782-1793.
33. Yildirim HC, Guven DC, Aktepe OH, et al. Blood based biomarkers as predictive factors for hyperprogressive disease. J Clin Med, 2022, 11(17): 5171. doi: 10.3390/jcm11175171.
34. Tian Y, Xiao H, Yang Y, et al. Crosstalk between 5-methylcytosine and N6-methyladenosine machinery defines disease progression, therapeutic response and pharmacogenomic landscape in hepatocellular carcinoma. Mol Cancer, 2023, 22(1): 5. doi: 10.1186/s12943-022-01706-6.
35. Maesaka K, Sakamori R, Yamada R, et al. Hyperprogressive disease in patients with unresectable hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy. Hepatol Res, 2022, 52(3): 298-307.
36. Choi WM, Kim JY, Choi J, et al. Kinetics of the neutrophil-lymphocyte ratio during PD-1 inhibition as a prognostic factor in advanced hepatocellular carcinoma. Liver Int, 2021, 41(9): 2189-2199.
37. Yu B, Ma W. Biomarker discovery in hepatocellular carcinoma (HCC) for personalized treatment and enhanced prognosis. Cytokine Growth Factor Rev, 2024, 79: 29-38.
38. Shigefuku R, Yoshikawa K, Tsukimoto M, et al. Hepatocellular carcinoma pseudoprogression involving the main portal vein, right ventricular invasion, and exacerbation of lung metastases in a patient on Atezolizumab plus Bevacizumab. Intern Med, 2023, 62(4): 539-543.
39. Chen Z, Chen Y, Sun Y, et al. Predicting gastric cancer response to anti-HER2 therapy or anti-HER2 combined immunotherapy based on multi-modal data. Signal Transduct Target Ther, 2024, 9(1): 222. doi: 10.1038/s41392-024-01932-y.
40. Li R, Li L, Xu Y, et al. Machine learning meets omics: applications and perspectives. Brief Bioinform, 2022, 23(1): bbab460. doi: 10.1093/bib/bbab460.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Latest ArticlesResearch progress on the potential molecular mechanisms and predictive factors of hyperprogressive disease in hepatocellular carcinoma immunotherapy

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