Effect of PD<b>-</b>1 and PD<b>-</b>L1 preoperative treatment on rejection after liver transplantation of liver cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

XI Aoyao ¹ ,  LÜ Tao ²

1. West China Clinical Medical College, Sichuan University, Chengdu 610041, P. R. China;
2. Liver Transplant Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

LÜ Tao, Email: doclvtao@scu.edu.com

Keywords：

programmed cell death protein 1; programmed cell death protein-ligand 1; immune checkpoint inhibitor; liver cancer; liver transplantation; immune tolerance

DOI：

10.7507/1007-9424.202208066

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the research progress of programmed cell death protein 1 (PD-1)/programmed cell death protein-ligand 1 (PD-L1) inhibitors before liver transplantation of liver cancer. Method The literatures on the application of PD-1/PD-L1 inhibitors before liver transplantation of liver cancer were collected and reviewed. Results PD-1/PD-L1 inhibitors preoperatively treated liver transplantation recipients had a low incidence of postoperative rejection, and routine usage of hormone and immune tolerance induction therapy in liver transplantation recipients might reduce the incidence of rejection caused by PD-1/PD-L1 inhibitors. Conclusion Preoperative usage of PD-1/PD-L1 inhibitors have more benefits than risks for patients with advanced liver cancer.

Citation： XI Aoyao, LÜ Tao. Effect of PD-1 and PD-L1 preoperative treatment on rejection after liver transplantation of liver cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(3): 369-373. doi: 10.7507/1007-9424.202208066 Copy

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.	Maomao C, He L, Dianqin S, et al. Current cancer burden in China: epidemiology, etiology, and prevention. Cancer Biol Med, 2022, 19(8): 1121-1138.
3.	Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
4.	Martin JD, Cabral H, Stylianopoulos T, et al. Improving cancer immunotherapy using nanomedicines: progress, opportunities and challenges. Nat Rev Clin Oncol, 2020, 17(4): 251-266.
5.	Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res, 2020, 10(3): 727-742.
6.	Ibañez-Vega J, Vilchez C, Jimenez K, et al. Cellular and molecular regulation of the programmed death-1/programmed death ligand system and its role in multiple sclerosis and other autoimmune diseases. J Autoimmun, 2021, 123: 102702. doi: 10.1016/j.jaut.2021.102702.
7.	Tang Q, Chen Y, Li X, et al. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol, 2022, 13: 964442. doi: 10.3389/fimmu.2022.964442.
8.	Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med, 2012, 366(26): 2517-2519.
9.	Kumar V, Shinagare AB, Rennke HG, et al. The safety and efficacy of checkpoint inhibitors in transplant recipients: a case series and systematic review of literature. Oncologist, 2020, 25(6): 505-514.
10.	Abdel-Wahab N, Safa H, Abudayyeh A, et al. Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature. J Immunother Cancer, 2019, 7(1): 106. doi: 10.1186/s40425-019-0585-1.
11.	Ueki S, Castellaneta A, Yoshida O, et al. Hepatic B7 homolog 1 expression is essential for controlling cold ischemia/reperfusion injury after mouse liver transplantation. Hepatology, 2011, 54(1): 216-228.
12.	Morita M, Fujino M, Jiang G, et al. PD-1/B7-H1 interaction contribute to the spontaneous acceptance of mouse liver allograft. Am J Transplant, 2010, 10(1): 40-46.
13.	Munker S, De Toni EN. Use of checkpoint inhibitors in liver transplant recipients. United European Gastroenterol J, 2018, 6(7): 970-973.
14.	Liu Y, Liu S, Wu C, et al. PD-1-Mediated PI3K/Akt/mTOR, Caspase 9/Caspase 3 and ERK pathways are involved in regulating the apoptosis and proliferation of CD4⁺ and CD8⁺ T cells during BVDV infection in vitro. Front Immunol, 2020, 11: 467. doi: 10.3389/fimmu.2020.00467.
15.	Dai S, Jia R, Zhang X, et al. The PD-1/PD-Ls pathway and autoimmune diseases. Cell Immunol, 2014, 290(1): 72-79.
16.	Matinlauri IH, Nurminen MM, Höckerstedt KA, et al. Changes in liver graft rejections over time. Transplant Proc, 2006, 38(8): 2663-2666.
17.	Leung CS, Yang KY, Li X, et al. Single-cell transcriptomics reveal that PD-1 mediates immune tolerance by regulating proliferation of regulatory T cells. Genome Med, 2018, 10(1): 71. doi: 10.1186/s13073-018-0581-y.
18.	Heeren AM, Rotman J, Stam AGM, et al. Efficacy of PD-1 blockade in cervical cancer is related to a CD8⁺FoxP3⁺CD25⁺ T-cell subset with operational effector functions despite high immune checkpoint levels. J Immunother Cancer, 2019, 7(1): 43. doi: 10.1186/s40425-019-0526-z.
19.	Dyck L, Wilk MM, Raverdeau M, et al. Anti-PD-1 inhibits Foxp3⁺ Treg cell conversion and unleashes intratumoural effector T cells thereby enhancing the efficacy of a cancer vaccine in a mouse model. Cancer Immunol Immunother, 2016, 65(12): 1491-1498.
20.	Subrahmanyam PB, Dong Z, Gusenleitner D, et al. Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients. J Immunother Cancer, 2018, 6(1): 18. doi: 10.1186/s40425-018-0328-8.
21.	Edwards J, Wilmott JS, Madore J, et al. CD103⁺ tumor-resident CD8⁺ T Cells are associated with improved survival in immunotherapy-naïve melanoma patients and expand significantly during anti-PD-1 treatment. Clin Cancer Res, 2018, 24(13): 3036-3045.
22.	Ono Y, Perez-Gutierrez A, Nakao T, et al. Graft-infiltrating PD-L1^hi cross-dressed dendritic cells regulate antidonor T cell responses in mouse liver transplant tolerance. Hepatology, 2018, 67(4): 1499-1515.
23.	Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med, 2020, 382(20): 1894-1905.
24.	Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol, 2021, 22(7): 977-990.
25.	Andrew X. A phase Ⅰ b study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC). ASCO, Chicago, 2020.
26.	El-khoueiry A, Kim R. Phase Ⅰ b study of regorafenib (REG) plus pembrolizumab (PEMBRO) for first-line treatment of advanced hepatocellular carcinoma (HCC). ASCO-GI, San Francisco, 2020.
27.	Kudo M, Ikeda M, Motomura K, et al. Unresectable hepatocellular carcinoma (uHCC): Study 117. ASCO-GI, San Francisco, 2020.
28.	Xu J, Zhang Y, Jia R, et al. Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study. Clin Cancer Res, 2019, 25(2): 515-523.
29.	Tabrizian P, Florman SS, Schwartz ME. PD-1 inhibitor as bridge therapy to liver transplantation? Am J Transplant, 2021, 21(5): 1979-1980.
30.	段斌炜, 李文磊, 曹俊宁, 等. PD-1抑制剂联合TKIs治疗中晚期肝细胞癌后实施肝移植的可行性探讨. 中华肝胆外科杂志, 2022, 28(1): 28-32.
31.	崔春晓, 杨柳晓, 王颖, 等. 肝癌患者肝移植术前使用PD-1抑制剂对移植后排斥反应的影响. 中国临床医学, 2020, 27(3): 444-447.
32.	刘召波, 武聚山, 林栋栋, 等. PD-1抑制剂用于肝癌肝移植术前治疗的安全性探讨. 器官移植, 2021, 12(4): 445-449.
33.	Nordness MF, Hamel S, Godfrey CM, et al. Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: are checkpoint inhibitors safe for the pretransplant patient? Am J Transplant, 2020, 20(3): 879-883.
34.	宾阳阳, 李杰群, 李强, 等. PD-1单克隆抗体治疗实体器官移植术后恶性肿瘤的系统评价. 器官移植, 2020, 11(3): 384-390.
35.	Hu B, Yang XB, Sang XT. Liver graft rejection following immune checkpoint inhibitors treatment: a review. Med Oncol, 2019, 36(11): 94. doi: 10.1007/s12032-019-1316-7.
36.	Yamamoto N, Nokihara H, Yamada Y, et al. Phase Ⅰ study of Nivolumab, an anti-PD-1 antibody, in patients with malignant solid tumors. Invest New Drugs, 2017, 35(2): 207-216.
37.	Yamazaki N, Takenouchi T, Fujimoto M, et al. Phase Ⅰ b study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced melanoma (KEYNOTE-041). Cancer Chemother Pharmacol, 2017, 79(4): 651-660.
38.	Tang B, Yan X, Sheng X, et al. Safety and clinical activity with an anti-PD-1 antibody JS001 in advanced melanoma or urologic cancer patients. J Hematol Oncol, 2019, 12(1): 7. doi: 10.1186/s13045-018-0693-2.
39.	Compton F, He L, Sarode R, et al. Immune checkpoint inhibitor toxicity: a new indication for therapeutic plasma exchange? J Clin Apher, 2021, 36(4): 645-648.
40.	De Bruyn P, Van Gestel D, Ost P, et al. Immune checkpoint blockade for organ transplant patients with advanced cancer: how far can we go? Curr Opin Oncol, 2019, 31(2): 54-64.

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. Maomao C, He L, Dianqin S, et al. Current cancer burden in China: epidemiology, etiology, and prevention. Cancer Biol Med, 2022, 19(8): 1121-1138.
3. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
4. Martin JD, Cabral H, Stylianopoulos T, et al. Improving cancer immunotherapy using nanomedicines: progress, opportunities and challenges. Nat Rev Clin Oncol, 2020, 17(4): 251-266.
5. Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res, 2020, 10(3): 727-742.
6. Ibañez-Vega J, Vilchez C, Jimenez K, et al. Cellular and molecular regulation of the programmed death-1/programmed death ligand system and its role in multiple sclerosis and other autoimmune diseases. J Autoimmun, 2021, 123: 102702. doi: 10.1016/j.jaut.2021.102702.
7. Tang Q, Chen Y, Li X, et al. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol, 2022, 13: 964442. doi: 10.3389/fimmu.2022.964442.
8. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med, 2012, 366(26): 2517-2519.
9. Kumar V, Shinagare AB, Rennke HG, et al. The safety and efficacy of checkpoint inhibitors in transplant recipients: a case series and systematic review of literature. Oncologist, 2020, 25(6): 505-514.
10. Abdel-Wahab N, Safa H, Abudayyeh A, et al. Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature. J Immunother Cancer, 2019, 7(1): 106. doi: 10.1186/s40425-019-0585-1.
11. Ueki S, Castellaneta A, Yoshida O, et al. Hepatic B7 homolog 1 expression is essential for controlling cold ischemia/reperfusion injury after mouse liver transplantation. Hepatology, 2011, 54(1): 216-228.
12. Morita M, Fujino M, Jiang G, et al. PD-1/B7-H1 interaction contribute to the spontaneous acceptance of mouse liver allograft. Am J Transplant, 2010, 10(1): 40-46.
13. Munker S, De Toni EN. Use of checkpoint inhibitors in liver transplant recipients. United European Gastroenterol J, 2018, 6(7): 970-973.
14. Liu Y, Liu S, Wu C, et al. PD-1-Mediated PI3K/Akt/mTOR, Caspase 9/Caspase 3 and ERK pathways are involved in regulating the apoptosis and proliferation of CD4⁺ and CD8⁺ T cells during BVDV infection in vitro. Front Immunol, 2020, 11: 467. doi: 10.3389/fimmu.2020.00467.
15. Dai S, Jia R, Zhang X, et al. The PD-1/PD-Ls pathway and autoimmune diseases. Cell Immunol, 2014, 290(1): 72-79.
16. Matinlauri IH, Nurminen MM, Höckerstedt KA, et al. Changes in liver graft rejections over time. Transplant Proc, 2006, 38(8): 2663-2666.
17. Leung CS, Yang KY, Li X, et al. Single-cell transcriptomics reveal that PD-1 mediates immune tolerance by regulating proliferation of regulatory T cells. Genome Med, 2018, 10(1): 71. doi: 10.1186/s13073-018-0581-y.
18. Heeren AM, Rotman J, Stam AGM, et al. Efficacy of PD-1 blockade in cervical cancer is related to a CD8⁺FoxP3⁺CD25⁺ T-cell subset with operational effector functions despite high immune checkpoint levels. J Immunother Cancer, 2019, 7(1): 43. doi: 10.1186/s40425-019-0526-z.
19. Dyck L, Wilk MM, Raverdeau M, et al. Anti-PD-1 inhibits Foxp3⁺ Treg cell conversion and unleashes intratumoural effector T cells thereby enhancing the efficacy of a cancer vaccine in a mouse model. Cancer Immunol Immunother, 2016, 65(12): 1491-1498.
20. Subrahmanyam PB, Dong Z, Gusenleitner D, et al. Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients. J Immunother Cancer, 2018, 6(1): 18. doi: 10.1186/s40425-018-0328-8.
21. Edwards J, Wilmott JS, Madore J, et al. CD103⁺ tumor-resident CD8⁺ T Cells are associated with improved survival in immunotherapy-naïve melanoma patients and expand significantly during anti-PD-1 treatment. Clin Cancer Res, 2018, 24(13): 3036-3045.
22. Ono Y, Perez-Gutierrez A, Nakao T, et al. Graft-infiltrating PD-L1^hi cross-dressed dendritic cells regulate antidonor T cell responses in mouse liver transplant tolerance. Hepatology, 2018, 67(4): 1499-1515.
23. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med, 2020, 382(20): 1894-1905.
24. Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol, 2021, 22(7): 977-990.
25. Andrew X. A phase Ⅰ b study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC). ASCO, Chicago, 2020.
26. El-khoueiry A, Kim R. Phase Ⅰ b study of regorafenib (REG) plus pembrolizumab (PEMBRO) for first-line treatment of advanced hepatocellular carcinoma (HCC). ASCO-GI, San Francisco, 2020.
27. Kudo M, Ikeda M, Motomura K, et al. Unresectable hepatocellular carcinoma (uHCC): Study 117. ASCO-GI, San Francisco, 2020.
28. Xu J, Zhang Y, Jia R, et al. Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study. Clin Cancer Res, 2019, 25(2): 515-523.
29. Tabrizian P, Florman SS, Schwartz ME. PD-1 inhibitor as bridge therapy to liver transplantation? Am J Transplant, 2021, 21(5): 1979-1980.
30. 段斌炜, 李文磊, 曹俊宁, 等. PD-1抑制剂联合TKIs治疗中晚期肝细胞癌后实施肝移植的可行性探讨. 中华肝胆外科杂志, 2022, 28(1): 28-32.
31. 崔春晓, 杨柳晓, 王颖, 等. 肝癌患者肝移植术前使用PD-1抑制剂对移植后排斥反应的影响. 中国临床医学, 2020, 27(3): 444-447.
32. 刘召波, 武聚山, 林栋栋, 等. PD-1抑制剂用于肝癌肝移植术前治疗的安全性探讨. 器官移植, 2021, 12(4): 445-449.
33. Nordness MF, Hamel S, Godfrey CM, et al. Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: are checkpoint inhibitors safe for the pretransplant patient? Am J Transplant, 2020, 20(3): 879-883.
34. 宾阳阳, 李杰群, 李强, 等. PD-1单克隆抗体治疗实体器官移植术后恶性肿瘤的系统评价. 器官移植, 2020, 11(3): 384-390.
35. Hu B, Yang XB, Sang XT. Liver graft rejection following immune checkpoint inhibitors treatment: a review. Med Oncol, 2019, 36(11): 94. doi: 10.1007/s12032-019-1316-7.
36. Yamamoto N, Nokihara H, Yamada Y, et al. Phase Ⅰ study of Nivolumab, an anti-PD-1 antibody, in patients with malignant solid tumors. Invest New Drugs, 2017, 35(2): 207-216.
37. Yamazaki N, Takenouchi T, Fujimoto M, et al. Phase Ⅰ b study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced melanoma (KEYNOTE-041). Cancer Chemother Pharmacol, 2017, 79(4): 651-660.
38. Tang B, Yan X, Sheng X, et al. Safety and clinical activity with an anti-PD-1 antibody JS001 in advanced melanoma or urologic cancer patients. J Hematol Oncol, 2019, 12(1): 7. doi: 10.1186/s13045-018-0693-2.
39. Compton F, He L, Sarode R, et al. Immune checkpoint inhibitor toxicity: a new indication for therapeutic plasma exchange? J Clin Apher, 2021, 36(4): 645-648.
40. De Bruyn P, Van Gestel D, Ost P, et al. Immune checkpoint blockade for organ transplant patients with advanced cancer: how far can we go? Curr Opin Oncol, 2019, 31(2): 54-64.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Effect of PD-1 and PD-L1 preoperative treatment on rejection after liver transplantation of liver cancer

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