Mechanism of immune checkpoint inhibitors related adverse events_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Wei ,  LIN Huayue

1. Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, P. R. China;

Corresponding author：

LIN Huayue, Email: linhy29@mail.sysu.edu.cn

Keywords：

immune checkpoint inhibitor; immune-related adverse event; epidemiology; pathogenic mechanism

DOI：

10.7507/1007-9424.202306015

Video：

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Most immune-related adverse event (irAE) associated with immune checkpoint inhibitors (ICIs) resulted from excessive immune response against normal organs. The severity, timing, and organs affected by these events were often unpredictable. Adverse reactions could cause treatment delays or interruptions, in rare cases, pose a life-threatening risk. The mechanisms underlying irAE involved immune cell dysregulation, imbalances in inflammatory factor expression, alterations in autoantibodies and complement activation, even dysbiosis of intestinal microorganisms. However, the mechanisms of irAE occurrence might differ slightly among organs due to variations in their structures and the functions of resident immune cells. Future research should focus on the development of targeted drugs for the prevention or treatment of irAE based on the mechanisms by which irAE occurs in different organs. A deeper understanding of the mechanisms underlying irAE occurrence would aid clinicians in effectively utilizing ICIs and provide valuable guidance for their clinical application.

Citation： ZHANG Wei, LIN Huayue. Mechanism of immune checkpoint inhibitors related adverse events. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2024, 31(1): 1-8. doi: 10.7507/1007-9424.202306015 Copy

1.	Gonzalez H, Hagerling C, Werb Z. Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev, 2018, 32(19-20): 1267-1284.
2.	Munn DH, Bronte V. Immune suppressive mechanisms in the tumor microenvironment. Curr Opin Immunol, 2016, 39: 1-6.
3.	Johnson DB, Nebhan CA, Moslehi JJ, et al. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol, 2022, 19(4): 254-267.
4.	Naimi A, Mohammed RN, Raji A, et al. Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons. Cell Commun Signal, 2022, 20(1): 44. doi: 10.1186/s12964-022-00854-y.
5.	Yang F, Shay C, Abousaud M, et al. Patterns of toxicity burden for FDA-approved immune checkpoint inhibitors in the United States. J Exp Clin Cancer Res, 2023, 42(1): 4. doi: 10.1186/s13046-022-02568-y.
6.	Ramos-Casals M, Brahmer JR, Callahan MK, et al. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers, 2020, 6(1): 38. doi: 10.1038/s41572-020-0160-6.
7.	Wang SJ, Dougan SK, Dougan M. Immune mechanisms of toxicity from checkpoint inhibitors. Trends Cancer, 2023, 9(7): 543-553.
8.	Liu Y, Zheng P. Preserving the CTLA-4 checkpoint for safer and more effective cancer immunotherapy. Trends Pharmacol Sci, 2020, 41(1): 4-12.
9.	Willsmore ZN, Coumbe BGT, Crescioli S, et al. Combined anti-PD-1 and anti-CTLA-4 checkpoint blockade: treatment of melanoma and immune mechanisms of action. Eur J Immunol, 2021, 51(3): 544-556.
10.	Jiang Y, Chen M, Nie H, et al. PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations. Hum Vaccin Immunother, 2019, 15(5): 1111-1122.
11.	Bertrand A, Kostine M, Barnetche T, et al. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med, 2015, 13: 211. doi: 10.1186/s12916-015-0455-8.
12.	Sonpavde GP, Grivas P, Lin Y, et al. Immune-related adverse events with PD-1 versus PD-L1 inhibitors: a meta-analysis of 8 730 patients from clinical trials. Future Oncol, 2021, 17(19): 2545-2558.
13.	Guo X, Chen S, Wang X, et al. Immune-related pulmonary toxicities of checkpoint inhibitors in non-small cell lung cancer: diagnosis, mechanism, and treatment strategies. Front Immunol, 2023, 14: 1138483. doi: 10.3389/fimmu.2023.1138483.
14.	Kim ST, Sheshadri A, Shannon V, et al. Distinct immunophenotypes of T cells in bronchoalveolar lavage fluid from leukemia patients with immune checkpoint inhibitors-related pulmonary complications. Front Immunol, 2021, 11: 590494. doi: 10.3389/fimmu.2020.590494.
15.	Franken A, Van Mol P, Vanmassenhove S, et al. Single-cell transcriptomics identifies pathogenic T-helper 17.1 cells and pro-inflammatory monocytes in immune checkpoint inhibitor-related pneumonitis. J Immunother Cancer, 2022, 10(9): e005323. doi: 10.1136/jitc-2022-005323.
16.	Suresh K, Naidoo J, Zhong Q, et al. The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis. J Clin Invest, 2019, 129(10): 4305-4315.
17.	Wang PM, Zhang ZW, Zhang S, et al. Characterization of immunomodulatory factors and cells in bronchoalveolar lavage fluid for immune checkpoint inhibitor-related pneumonitis. J Cancer Res Clin Oncol, 2023, 149(10): 8019-8026.
18.	Wang YN, Lou DF, Li DY, et al. Elevated levels of IL-17A and IL-35 in plasma and bronchoalveolar lavage fluid are associated with checkpoint inhibitor pneumonitis in patients with non-small cell lung cancer. Oncol Lett, 2020, 20(1): 611-622.
19.	Rubio-Infante N, Ramírez-Flores YA, Castillo EC, et al. Cardiotoxicity associated with immune checkpoint inhibitor therapy: a meta-analysis. Eur J Heart Fail, 2021, 23(10): 1739-1747.
20.	Chen R, Zhou M, Zhu F. Immune checkpoint inhibitors related to cardiotoxicity. J Cardiovasc Dev Dis, 2022, 9(11): 378. doi: 10.3390/jcdd9110378.
21.	Wang D, Bauersachs J, Berliner D. Immune checkpoint inhibitor associated myocarditis and cardiomyopathy: a translational review. Biology (Basel), 2023, 12(3): 472. doi: 10.1097/RHU.0000000000001874.
22.	Zhu H, Galdos FX, Lee D, et al. Identification of pathogenic immune cell subsets associated with checkpoint inhibitor-induced myocarditis. Circulation, 2022, 146(4): 316-335.
23.	Wei SC, Meijers WC, Axelrod ML, et al. A genetic mouse model recapitulates immune checkpoint inhibitor-associated myocarditis and supports a mechanism-based therapeutic intervention. Cancer Discov, 2021, 11(3): 614-625.
24.	Palaskas N, Lopez-Mattei J, Durand JB, et al. Immune checkpoint inhibitor myocarditis: pathophysiological characteristics, diagnosis, and treatment. J Am Heart Assoc, 2020, 9(2): e013757. doi: 10.1161/JAHA.119.013757.
25.	Rubio-Infante N, Ramírez-Flores YA, Castillo EC, et al. A systematic review of the mechanisms involved in immune checkpoint inhibitors cardiotoxicity and challenges to improve clinical safety. Front Cell Dev Biol, 2022, 10: 851032. doi: 10.3389/fcell.2022.851032.
26.	Taherian M, Chatterjee D, Wang H. Immune checkpoint inhibitor-induced hepatic injury: a clinicopathologic review. J Clin Transl Pathol, 2022, 2(3): 83-90.
27.	Ng KYY, Tan SH, Tan JJE, et al. Impact of immune-related adverse events on efficacy of immune checkpoint inhibitors in patients with advanced hepatocellular carcinoma. Liver Cancer, 2021, 11(1): 9-21.
28.	Shojaie L, Ali M, Iorga A, et al. Mechanisms of immune checkpoint inhibitor-mediated liver injury. Acta Pharm Sin B, 2021, 11(12): 3727-3739.
29.	Hercun J, Vincent C, Bilodeau M, et al. Immune-mediated hepatitis during immune checkpoint inhibitor cancer immunotherapy: lessons from autoimmune hepatitis and liver immunology. Front Immunol, 2022, 13: 907591. doi: 10.3389/fimmu.2022.907591.
30.	Siwicki M, Gort-Freitas NA, Messemaker M, et al. Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy. Sci Immunol, 2021, 6(61): eabi7083. doi: 10.1126/sciimmunol.abi7083.
31.	Oh DY, Cham J, Zhang L, et al. Immune toxicities elicted by CTLA-4 blockade in cancer patients are associated with early diversification of the T-cell repertoire. Cancer Res, 2017, 77(6): 1322-1330.
32.	Dong H, Xue C, Zheng Y, et al. Efficacy and safety of immune checkpoint inhibitors in patients with cancer and hepatitis B or C: a systematic review and meta-analysis. J Oncol, 2023, 2023: 2525903. doi: 10.1155/2023/2525903.
33.	Hagiwara S, Nishida N, Kudo M. Advances in immunotherapy for hepatocellular carcinoma. Cancers (Basel), 2023, 15(7): 2070. doi: 10.3390/cancers15072070.
34.	Papatheodoridis GV, Lekakis V, Voulgaris T, et al. Hepatitis B virus reactivation associated with new classes of immuno-suppressants and immunomodulators: a systematic review, meta-analysis, and expert opinion. J Hepatol, 2022, 77(6): 1670-1689.
35.	Losurdo G, Angelillo D, Favia N, et al. Checkpoint inhibitor-induced colitis: an update. Biomedicines, 2023, 11(5): 1496. doi: 10.3390/biomedicines11051496.
36.	Nielsen DL, Juhl CB, Chen IM, et al. Immune checkpoint inhibitor-induced diarrhea and colitis: incidence and management. a systematic review and meta-analysis. Cancer Treat Rev, 2022, 109: 102440.
37.	Sasson SC, Slevin SM, Cheung VTF, et al. Interferon-gamma-producing CD8⁺ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis. Gastroenterology, 2021, 161(4): 1229-1244. e9. doi: 10.1053/j.gastro.2021.06.025.
38.	Chaput N, Lepage P, Coutzac C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol, 2017, 28(6): 1368-1379.
39.	Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science, 2015, 350(6264): 1079-1084.
40.	Sprangers B, Leaf DE, Porta C, et al. Diagnosis and management of immune checkpoint inhibitor-associated acute kidney injury. Nat Rev Nephrol, 2022, 18(12): 794-805.
41.	Kanbay M, Copur S, Siriopol D, et al. The association between acute kidney injury and outcomes in cancer patients receiving immune checkpoint inhibitor therapy: a systematic review and meta-analysis. Clin Kidney J, 2022, 16(5): 817-826.
42.	Longhitano E, Muscolino P, Lo Re C, et al. Immune checkpoint inhibitors and the kidney: a focus on diagnosis and management for personalised medicine. Cancers (Basel), 2023, 15(6): 1891. doi: 10.3390/cancers15061891.
43.	Fadel F, El Karoui K, Knebelmann B. Anti-CTLA4 antibody-induced lupus nephritis. N Engl J Med, 2009, 361(2): 211-212.
44.	Koda R, Watanabe H, Tsuchida M, et al. Immune checkpoint inhibitor (nivolumab)-associated kidney injury and the importance of recognizing concomitant medications known to cause acute tubulointerstitial nephritis: a case report. BMC Nephrol, 2018, 19(1): 48. doi: 10.1186/s12882-018-0848-y.
45.	Watanabe T, Yamaguchi Y. Cutaneous manifestations associated with immune checkpoint inhibitors. Front Immunol, 2023, 14: 1071983. doi: 10.3389/fimmu.2023.1071983.
46.	Yamamoto T. Skin manifestation induced by immune checkpoint inhibitors. Clin Cosmet Investig Dermatol, 2022, 15: 829-841.
47.	Freeman-Keller M, Kim Y, Cronin H, et al. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res, 2016, 22(4): 886-894.
48.	Tsiogka A, Bauer JW, Patsatsi A. Bullous pemphigoid associated with anti-programmed cell death protein 1 and anti-programmed cell death ligand 1 therapy: a review of the literature. Acta Derm Venereol, 2021, 101(1): adv00377. doi: 10.2340/00015555-3740.
49.	Shi VJ, Rodic N, Gettinger S, et al. Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti-programmed cell death 1 and anti-programmed cell death ligand 1 immunotherapy. JAMA Dermatol, 2016, 152(10): 1128-1136.
50.	Muir CA, Tsang VHM, Menzies AM, et al. Immune related adverse events of the thyroid—a narrative review. Front Endocrinol (Lausanne), 2022, 13: 886930. doi: 10.3389/fendo.2022.886930.
51.	Chye A, Allen I, Barnet M, et al. Insights into the host contribution of endocrine associated immune-related adverse events to immune checkpoint inhibition therapy. Front Oncol, 2022, 12: 894015. doi: 10.3389/fonc.2022.894015.
52.	Yasuda Y, Iwama S, Sugiyama D, et al. CD4⁺ T cells are essential for the development of destructive thyroiditis induced by anti-PD-1 antibody in thyroglobulin-immunized mice. Sci Transl Med, 2021, 13(593): eabb7495. doi: 10.1126/scitranslmed.abb7495.
53.	Iwama S, Kobayashi T, Arima H. Clinical characteristics, management, and potential biomarkers of endocrine dysfunction induced by immune checkpoint inhibitors. Endocrinol Metab (Seoul), 2021, 36(2): 312-321.
54.	Haanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol, 2022, 33(12): 1217-1238.
55.	Thompson JA, Schneider BJ, Brahmer J, et al. NCCN guidelines insights: management of immunotherapy-related toxicities, version 1.2020. J Natl Compr Canc Netw, 2020, 18(3): 230-241.
56.	Verheijden RJ, van Eijs MJM, May AM, et al. Immunosuppression for immune-related adverse events during checkpoint inhibition: an intricate balance. NPJ Precis Oncol, 2023, 7(1): 41. doi: 10.1038/s41698-023-00380-1.
57.	Petrelli F, Signorelli D, Ghidini M, et al. Association of steroids use with survival in patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Cancers (Basel), 2020, 12(3): 546. doi: 10.3390/cancers12030546.

1. Gonzalez H, Hagerling C, Werb Z. Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev, 2018, 32(19-20): 1267-1284.
2. Munn DH, Bronte V. Immune suppressive mechanisms in the tumor microenvironment. Curr Opin Immunol, 2016, 39: 1-6.
3. Johnson DB, Nebhan CA, Moslehi JJ, et al. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol, 2022, 19(4): 254-267.
4. Naimi A, Mohammed RN, Raji A, et al. Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons. Cell Commun Signal, 2022, 20(1): 44. doi: 10.1186/s12964-022-00854-y.
5. Yang F, Shay C, Abousaud M, et al. Patterns of toxicity burden for FDA-approved immune checkpoint inhibitors in the United States. J Exp Clin Cancer Res, 2023, 42(1): 4. doi: 10.1186/s13046-022-02568-y.
6. Ramos-Casals M, Brahmer JR, Callahan MK, et al. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers, 2020, 6(1): 38. doi: 10.1038/s41572-020-0160-6.
7. Wang SJ, Dougan SK, Dougan M. Immune mechanisms of toxicity from checkpoint inhibitors. Trends Cancer, 2023, 9(7): 543-553.
8. Liu Y, Zheng P. Preserving the CTLA-4 checkpoint for safer and more effective cancer immunotherapy. Trends Pharmacol Sci, 2020, 41(1): 4-12.
9. Willsmore ZN, Coumbe BGT, Crescioli S, et al. Combined anti-PD-1 and anti-CTLA-4 checkpoint blockade: treatment of melanoma and immune mechanisms of action. Eur J Immunol, 2021, 51(3): 544-556.
10. Jiang Y, Chen M, Nie H, et al. PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations. Hum Vaccin Immunother, 2019, 15(5): 1111-1122.
11. Bertrand A, Kostine M, Barnetche T, et al. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med, 2015, 13: 211. doi: 10.1186/s12916-015-0455-8.
12. Sonpavde GP, Grivas P, Lin Y, et al. Immune-related adverse events with PD-1 versus PD-L1 inhibitors: a meta-analysis of 8 730 patients from clinical trials. Future Oncol, 2021, 17(19): 2545-2558.
13. Guo X, Chen S, Wang X, et al. Immune-related pulmonary toxicities of checkpoint inhibitors in non-small cell lung cancer: diagnosis, mechanism, and treatment strategies. Front Immunol, 2023, 14: 1138483. doi: 10.3389/fimmu.2023.1138483.
14. Kim ST, Sheshadri A, Shannon V, et al. Distinct immunophenotypes of T cells in bronchoalveolar lavage fluid from leukemia patients with immune checkpoint inhibitors-related pulmonary complications. Front Immunol, 2021, 11: 590494. doi: 10.3389/fimmu.2020.590494.
15. Franken A, Van Mol P, Vanmassenhove S, et al. Single-cell transcriptomics identifies pathogenic T-helper 17.1 cells and pro-inflammatory monocytes in immune checkpoint inhibitor-related pneumonitis. J Immunother Cancer, 2022, 10(9): e005323. doi: 10.1136/jitc-2022-005323.
16. Suresh K, Naidoo J, Zhong Q, et al. The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis. J Clin Invest, 2019, 129(10): 4305-4315.
17. Wang PM, Zhang ZW, Zhang S, et al. Characterization of immunomodulatory factors and cells in bronchoalveolar lavage fluid for immune checkpoint inhibitor-related pneumonitis. J Cancer Res Clin Oncol, 2023, 149(10): 8019-8026.
18. Wang YN, Lou DF, Li DY, et al. Elevated levels of IL-17A and IL-35 in plasma and bronchoalveolar lavage fluid are associated with checkpoint inhibitor pneumonitis in patients with non-small cell lung cancer. Oncol Lett, 2020, 20(1): 611-622.
19. Rubio-Infante N, Ramírez-Flores YA, Castillo EC, et al. Cardiotoxicity associated with immune checkpoint inhibitor therapy: a meta-analysis. Eur J Heart Fail, 2021, 23(10): 1739-1747.
20. Chen R, Zhou M, Zhu F. Immune checkpoint inhibitors related to cardiotoxicity. J Cardiovasc Dev Dis, 2022, 9(11): 378. doi: 10.3390/jcdd9110378.
21. Wang D, Bauersachs J, Berliner D. Immune checkpoint inhibitor associated myocarditis and cardiomyopathy: a translational review. Biology (Basel), 2023, 12(3): 472. doi: 10.1097/RHU.0000000000001874.
22. Zhu H, Galdos FX, Lee D, et al. Identification of pathogenic immune cell subsets associated with checkpoint inhibitor-induced myocarditis. Circulation, 2022, 146(4): 316-335.
23. Wei SC, Meijers WC, Axelrod ML, et al. A genetic mouse model recapitulates immune checkpoint inhibitor-associated myocarditis and supports a mechanism-based therapeutic intervention. Cancer Discov, 2021, 11(3): 614-625.
24. Palaskas N, Lopez-Mattei J, Durand JB, et al. Immune checkpoint inhibitor myocarditis: pathophysiological characteristics, diagnosis, and treatment. J Am Heart Assoc, 2020, 9(2): e013757. doi: 10.1161/JAHA.119.013757.
25. Rubio-Infante N, Ramírez-Flores YA, Castillo EC, et al. A systematic review of the mechanisms involved in immune checkpoint inhibitors cardiotoxicity and challenges to improve clinical safety. Front Cell Dev Biol, 2022, 10: 851032. doi: 10.3389/fcell.2022.851032.
26. Taherian M, Chatterjee D, Wang H. Immune checkpoint inhibitor-induced hepatic injury: a clinicopathologic review. J Clin Transl Pathol, 2022, 2(3): 83-90.
27. Ng KYY, Tan SH, Tan JJE, et al. Impact of immune-related adverse events on efficacy of immune checkpoint inhibitors in patients with advanced hepatocellular carcinoma. Liver Cancer, 2021, 11(1): 9-21.
28. Shojaie L, Ali M, Iorga A, et al. Mechanisms of immune checkpoint inhibitor-mediated liver injury. Acta Pharm Sin B, 2021, 11(12): 3727-3739.
29. Hercun J, Vincent C, Bilodeau M, et al. Immune-mediated hepatitis during immune checkpoint inhibitor cancer immunotherapy: lessons from autoimmune hepatitis and liver immunology. Front Immunol, 2022, 13: 907591. doi: 10.3389/fimmu.2022.907591.
30. Siwicki M, Gort-Freitas NA, Messemaker M, et al. Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy. Sci Immunol, 2021, 6(61): eabi7083. doi: 10.1126/sciimmunol.abi7083.
31. Oh DY, Cham J, Zhang L, et al. Immune toxicities elicted by CTLA-4 blockade in cancer patients are associated with early diversification of the T-cell repertoire. Cancer Res, 2017, 77(6): 1322-1330.
32. Dong H, Xue C, Zheng Y, et al. Efficacy and safety of immune checkpoint inhibitors in patients with cancer and hepatitis B or C: a systematic review and meta-analysis. J Oncol, 2023, 2023: 2525903. doi: 10.1155/2023/2525903.
33. Hagiwara S, Nishida N, Kudo M. Advances in immunotherapy for hepatocellular carcinoma. Cancers (Basel), 2023, 15(7): 2070. doi: 10.3390/cancers15072070.
34. Papatheodoridis GV, Lekakis V, Voulgaris T, et al. Hepatitis B virus reactivation associated with new classes of immuno-suppressants and immunomodulators: a systematic review, meta-analysis, and expert opinion. J Hepatol, 2022, 77(6): 1670-1689.
35. Losurdo G, Angelillo D, Favia N, et al. Checkpoint inhibitor-induced colitis: an update. Biomedicines, 2023, 11(5): 1496. doi: 10.3390/biomedicines11051496.
36. Nielsen DL, Juhl CB, Chen IM, et al. Immune checkpoint inhibitor-induced diarrhea and colitis: incidence and management. a systematic review and meta-analysis. Cancer Treat Rev, 2022, 109: 102440.
37. Sasson SC, Slevin SM, Cheung VTF, et al. Interferon-gamma-producing CD8⁺ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis. Gastroenterology, 2021, 161(4): 1229-1244. e9. doi: 10.1053/j.gastro.2021.06.025.
38. Chaput N, Lepage P, Coutzac C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol, 2017, 28(6): 1368-1379.
39. Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science, 2015, 350(6264): 1079-1084.
40. Sprangers B, Leaf DE, Porta C, et al. Diagnosis and management of immune checkpoint inhibitor-associated acute kidney injury. Nat Rev Nephrol, 2022, 18(12): 794-805.
41. Kanbay M, Copur S, Siriopol D, et al. The association between acute kidney injury and outcomes in cancer patients receiving immune checkpoint inhibitor therapy: a systematic review and meta-analysis. Clin Kidney J, 2022, 16(5): 817-826.
42. Longhitano E, Muscolino P, Lo Re C, et al. Immune checkpoint inhibitors and the kidney: a focus on diagnosis and management for personalised medicine. Cancers (Basel), 2023, 15(6): 1891. doi: 10.3390/cancers15061891.
43. Fadel F, El Karoui K, Knebelmann B. Anti-CTLA4 antibody-induced lupus nephritis. N Engl J Med, 2009, 361(2): 211-212.
44. Koda R, Watanabe H, Tsuchida M, et al. Immune checkpoint inhibitor (nivolumab)-associated kidney injury and the importance of recognizing concomitant medications known to cause acute tubulointerstitial nephritis: a case report. BMC Nephrol, 2018, 19(1): 48. doi: 10.1186/s12882-018-0848-y.
45. Watanabe T, Yamaguchi Y. Cutaneous manifestations associated with immune checkpoint inhibitors. Front Immunol, 2023, 14: 1071983. doi: 10.3389/fimmu.2023.1071983.
46. Yamamoto T. Skin manifestation induced by immune checkpoint inhibitors. Clin Cosmet Investig Dermatol, 2022, 15: 829-841.
47. Freeman-Keller M, Kim Y, Cronin H, et al. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res, 2016, 22(4): 886-894.
48. Tsiogka A, Bauer JW, Patsatsi A. Bullous pemphigoid associated with anti-programmed cell death protein 1 and anti-programmed cell death ligand 1 therapy: a review of the literature. Acta Derm Venereol, 2021, 101(1): adv00377. doi: 10.2340/00015555-3740.
49. Shi VJ, Rodic N, Gettinger S, et al. Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti-programmed cell death 1 and anti-programmed cell death ligand 1 immunotherapy. JAMA Dermatol, 2016, 152(10): 1128-1136.
50. Muir CA, Tsang VHM, Menzies AM, et al. Immune related adverse events of the thyroid—a narrative review. Front Endocrinol (Lausanne), 2022, 13: 886930. doi: 10.3389/fendo.2022.886930.
51. Chye A, Allen I, Barnet M, et al. Insights into the host contribution of endocrine associated immune-related adverse events to immune checkpoint inhibition therapy. Front Oncol, 2022, 12: 894015. doi: 10.3389/fonc.2022.894015.
52. Yasuda Y, Iwama S, Sugiyama D, et al. CD4⁺ T cells are essential for the development of destructive thyroiditis induced by anti-PD-1 antibody in thyroglobulin-immunized mice. Sci Transl Med, 2021, 13(593): eabb7495. doi: 10.1126/scitranslmed.abb7495.
53. Iwama S, Kobayashi T, Arima H. Clinical characteristics, management, and potential biomarkers of endocrine dysfunction induced by immune checkpoint inhibitors. Endocrinol Metab (Seoul), 2021, 36(2): 312-321.
54. Haanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol, 2022, 33(12): 1217-1238.
55. Thompson JA, Schneider BJ, Brahmer J, et al. NCCN guidelines insights: management of immunotherapy-related toxicities, version 1.2020. J Natl Compr Canc Netw, 2020, 18(3): 230-241.
56. Verheijden RJ, van Eijs MJM, May AM, et al. Immunosuppression for immune-related adverse events during checkpoint inhibition: an intricate balance. NPJ Precis Oncol, 2023, 7(1): 41. doi: 10.1038/s41698-023-00380-1.
57. Petrelli F, Signorelli D, Ghidini M, et al. Association of steroids use with survival in patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Cancers (Basel), 2020, 12(3): 546. doi: 10.3390/cancers12030546.

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Mechanism of immune checkpoint inhibitors related adverse events

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