Challenges and advances of immune checkpoint therapy

Abstract

Background and Objectives: Immuno-checkpoint therapy (ICT) significantly alters the clinical course of cancer patients, providing long-lasting clinical benefits and offering the potential for cure to some patients. However, response rates for different tumour types vary, and predictive biomarkers are needed to enhance patient selection for the purpose of optimising effectiveness and reducing toxicity. This has driven efforts to decipher the immune and non-immune factors that regulate ICT response.

Main Content: This review offers a thorough examination of the advantages and future challenges of immune checkpoint inhibitors in cancer therapy. Additionally, we explore ongoing efforts to address current challenges, such as guiding subsequent clinical trials, developing ICT combination therapy strategies and utilising epigenetics to enhance clinical efficacy.

Conclusion and Perspectives: Despite significant progress, ICT faces challenges including immune-related adverse events (irAEs) and resistance mechanisms. Ongoing research focuses on developing novel biomarkers, combination therapies, and epigenetic strategies to improve the efficacy and safety of ICT for cancer patients worldwide. Future studies are required to validate these findings across different tumor types and treatment settings.

Keywords

biomarkers / clinical trials / CTLA-4 / immune checkpoint therapy / PD-1

References

[1] SharmaP, Goswami S, RaychaudhuriD, et al. Immune checkpoint therapy-current perspectives and future directions. Cell. 2023;186(8):1652-1669.

[2] WeiSC, DuffyCR, AllisonJP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 2018;8(9):1069-1086.

[3] ChristofiT, Baritaki S, FalzoneL, et al. Current perspectives in cancer immunotherapy. Cancers (Basel). 2019;11(10):1472.

[4] KumarV, Chaudhary N, GargM, et al. Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol. 2017;8:49.

[5] LiuYH, ZangXY, WangJC, et al. Diagnosis and management of immune related adverse events (irAEs) in cancer immunotherapy. Biomed Pharmacother. 2019;120:109437.

[6] ChenH, YangM, WangQ, et al. The new identified biomarkers determine sensitivity to immune check-point blockade therapies in melanoma. Oncoimmunology. 2019;8(8):1608132.

[7] RizzoA, RicciAD. Biomarkers for breast cancer immunotherapy: pD-L1, TILs, and beyond. Expert Opin Investig Drugs. 2022;31(6):549-555.

[8] LiT, FanJ, WangB, et al. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 2017;77(21):e108-e110.

[9] LiT, FuJ, ZengZ, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020;48(W1):W509-W514.

[10] WallJA, Meza-Perez S, ScaliseCB, et al. Manipulating the Wnt/beta-catenin signaling pathway to promote anti-tumor immune infiltration into the TME to sensitize ovarian cancer to ICB therapy. Gynecol Oncol. 2021;160(1):285-294.

[11] SaibilSD, OhashiPS. Targeting T cell activation in immuno-oncology. Curr Oncol. 2020;27(2):S98-S105. Suppl.

[12] WillsmoreZN, CoumbeB, CrescioliS, 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.

[13] AsrirA, Tardiveau C, CoudertJ, et al. Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy. Cancer Cell. 2022;40(3):318-334.

[14] QinS, XuL, YiM, et al. Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Mol Cancer. 2019;18(1):155.

[15] WangDR, WuXL, SunYL. Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response. Signal Transduct Target Ther. 2022;7(1):331.

[16] SuzukiH, TakagiH, OwadaY, et al. I. History of immunotherapy and cancer vaccine for lung cancer. Gan To Kagaku Ryoho. 2017;44(8):646-649.

[17] GajewskiTF, Schumacher T. Cancer immunotherapy. Curr Opin Immunol. 2013;25(2):259-260.

[18] Justiz VaillantAA, Nessel TA, PatelP, ZitoPM. Immunotherapy. StatPearls. StatPearls Publishing; 2024. April 21.

[19] RummelT, Batchelder J, FlahertyP, et al. CD28 costimulation is required for the expression of T-cell-dependent cell-mediated immunity against blood-stage Plasmodium chabaudi malaria parasites. Infect Immun. 2004;72(10):5768-5774.

[20] ZhangY, DuX, LiuM, et al. Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy. Cell Res. 2019;29(8):609-627.

[21] GoldsteinBL, Gedmintas L, ToddDJ. Drug-associated polymyalgia rheumatica/giant cell arteritis occurring in two patients after treatment with ipilimumab, an antagonist of ctla-4. Arthritis Rheumatol. 2014;66(3):768-769.

[22] RengaG, BelletMM, ParianoM, et al. Thymosin alpha1 protects from CTLA-4 intestinal immunopathology. Life Sci Alliance. 2020;3(10):e202000662.

[23] WalunasTL, Lenschow DJ, BakkerCY, et al. Pillars article: cTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994;1:405-413. J Immunol. 2011;187(7):3466-3474.

[24] ParryRV, Chemnitz JM, FrauwirthKA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25(21):9543-9553.

[25] KrummelMF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182(2):459-465.

[26] EagarTN, Karandikar NJ, BluestoneJA, et al. The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance. Eur J Immunol. 2002;32(4):972-981.

[27] LeachDR, Krummel MF, AllisonJP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734-1736.

[28] PatelV, GandhiH, UpaganlawarA. Ipilimumab: melanoma and beyond. J Pharm Bioallied Sci. 2011;3(4):546.

[29] RobertC, ThomasL, BondarenkoI, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517-2526.

[30] BhaveP, AhmedT, LoSN, et al. Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma. J Immunother Cancer. 2022;10(7):e004668.

[31] HuppertLA, DaudAI. Pembrolizumab and ipilimumab as second-line therapy for advanced melanoma. J Clin Oncol. 2021;39(24):2637-2639.

[32] KeirME, ButteMJ, FreemanGJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704.

[33] OkazakiT, Chikuma S, IwaiY, et al. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol. 2013;14(12):1212-1218.

[34] NieJ, WangC, LiuY, et al. Addition of low-dose decitabine to anti-PD-1 antibody camrelizumab in relapsed/refractory classical hodgkin lymphoma. J Clin Oncol. 2019;37(17):1479-1489.

[35] CaderFZ, HuX, GohWL, et al. A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma. Nat Med. 2020;26(9):1468-1479.

[36] ErricoA. Immunotherapy: pD-1-PD-L1 axis: efficient checkpoint blockade against cancer. Nat Rev Clin Oncol. 2015;12(2):63.

[37] SalihHR, Wintterle S, KruschM, et al. The role of leukemia-derived B7-H1 (PD-L1) in tumor-T-cell interactions in humans. Exp Hematol. 2006;34(7):888-894.

[38] DongH, StromeSE, SalomaoDR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800.

[39] CurielTJ, WeiS, DongH, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med. 2003;9(5):562-567.

[40] WangTW, Johmura Y, SuzukiN, et al. Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes. Nature. 2022;611(7935):358-364.

[41] TawbiHA, Schadendorf D, LipsonEJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34.

[42] AmariaRN, PostowM, BurtonEM, et al. Neoadjuvant relatlimab and nivolumab in resectable melanoma. Nature. 2022;611(7934):155-160.

[43] RobertC, Schachter J, LongGV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521-2532.

[44] LukeJJ, Rutkowski P, QueiroloP, et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716):a randomised, double-blind, phase 3 trial. Lancet. 2022;399(10336):1718-1729.

[45] SchmutzJL. Psoriasis and psoriatic arthritis induced by nivolumab (Opdivo((R))). Ann Dermatol Venereol. 2016;143(12):881-882.

[46] KodamaK, Djurian A, LimY. What is the importance of difference in LCM strategy in drug development?-learnings from Keytruda and Opdivo. Drug Discov Today. 2022;27(12):103390.

[47] NeumannM, MurphyN, SeetharamuN. The evolving role of PD-L1 inhibition in non-small cell lung cancer: a review of durvalumab and avelumab. Cancer Med J. 2022;5(1):31-45.

[48] SharmaA, Subudhi SK, BlandoJ, et al. Anti-CTLA-4 immunotherapy does not deplete FOXP3(+) regulatory T cells (Tregs) in human cancers. Clin Cancer Res. 2019;25(4):1233-1238.

[49] SobhaniN, Tardiel-Cyril DR, DavtyanA, et al. CTLA-4 in regulatory T cells for cancer immunotherapy. Cancers (Basel). 2021;13(6):1440.

[50] Pentcheva-HoangT, Egen JG, WojnoonskiK, et al. B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity. 2004;21(3):401-413.

[51] EngelhardtJJ, Sullivan TJ, AllisonJP. CTLA-4 overexpression inhibits T cell responses through a CD28-B7-dependent mechanism. J Immunol. 2006;177(2):1052-1061.

[52] KhalifaR, ElseseN, El-DesoukyK, et al. Immune checkpoint proteins (PD-L1 and CTLA-4) in endometrial carcinoma: prognostic role and correlation with CD4(+)/CD8(+) tumor infiltrating lymphocytes (TILs) ratio. J Immunoassay Immunochem. 2022;43(2):192-212.

[53] van PulKM, Notohardjo J, FransenMF, et al. Local delivery of low-dose anti-CTLA-4 to the melanoma lymphatic basin leads to systemic T(reg) reduction and effector T cell activation. Sci Immunol. 2022;7(73):eabn8097.

[54] WuX, GuZ, ChenY, et al. Application of PD-1 blockade in cancer immunotherapy. Comput Struct Biotechnol J. 2019;17:661-674.

[55] KuolN, Stojanovska L, NurgaliK, et al. PD-1/PD-L1 in disease. Immunotherapy. 2018;10(2):149-160.

[56] LarkinJ, MinorD, D’AngeloS, et al. Overall survival in patients with advanced melanoma who received nivolumab versus investigator’s choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018;36(4):383-390.

[57] BuchbinderEI, DesaiA. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98-106.

[58] RowshanravanB, Halliday N, SansomDM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58-67.

[59] RotteA. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res. 2019;38(1):255.

[60] BoutrosC, Tarhini A, RoutierE, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13(8):473-486.

[61] SeidelJA, OtsukaA, KabashimaK. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front Oncol. 2018;8:86.

[62] O’MalleyDM, Neffa M, MonkBJ, et al. Dual PD-1 and CTLA-4 checkpoint blockade using balstilimab and zalifrelimab combination as second-line treatment for advanced cervical cancer: an open-label phase II study. J Clin Oncol. 2022;40(7):762-771.

[63] DuraiswamyJ, KaluzaKM, FreemanGJ, et al. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 2013;73(12):3591-3603.

[64] Dorta-EstremeraS, Hegde VL, SlayRB, et al. Targeting interferon signaling and CTLA-4 enhance the therapeutic efficacy of anti-PD-1 immunotherapy in preclinical model of HPV(+) oral cancer. J Immunother Cancer. 2019;7(1):252.

[65] PatelSP, OthusM, ChaeYK, et al. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART SWOG 1609) in patients with nonpancreatic neuroendocrine tumors. Clin Cancer Res. 2020;26(10):2290-2296.

[66] DuerinckJ, Schwarze JK, AwadaG, et al. Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial. J Immunother Cancer. 2021;9(6):e002296.

[67] O’MalleyDM, Neffa M, MonkBJ, et al. Dual PD-1 and CTLA-4 checkpoint blockade using balstilimab and zalifrelimab combination as second-line treatment for advanced cervical cancer: an open-label phase II study. J Clin Oncol. 2022;40(7):762-771.

[68] HuuhtanenJ, Kasanen H, PeltolaK, et al. Single-cell characterization of anti-LAG-3 and anti-PD-1 combination treatment in patients with melanoma. J Clin Invest. 2023;133(6):e164809.

[69] RobertC. LAG-3 and PD-1 blockade raises the bar for melanoma. Nat Cancer. 2021;2(12):1251-1253.

[70] GestermannN, SaugyD, MartignierC, et al. LAG-3 and PD-1+LAG-3 inhibition promote anti-tumor immune responses in human autologous melanoma/T cell co-cultures. Oncoimmunology. 2020;9(1):1736792.

[71] JinHS, KoM, ChoiDS, et al. CD226(hi)CD8(+) T cells are a prerequisite for anti-TIGIT immunotherapy. Cancer Immunol Res. 2020;8(7):912-925.

[72] YeoJ, KoM, LeeDH, et al. TIGIT/CD226 axis regulates anti-tumor immunity. Pharmaceuticals (Basel). 2021;14(3):200.

[73] GuoQ, ChenC, WuZ, et al. Engineered PD-1/TIGIT dual-activating cell-membrane nanoparticles with dexamethasone act synergistically to shape the effector T cell/Treg balance and alleviate systemic lupus erythematosus. Biomaterials. 2022;285:121517.

[74] ChuX, TianW, WangZ, et al. Co-inhibition of TIGIT and PD-1/PD-L1 in cancer immunotherapy: mechanisms and clinical trials. Mol Cancer. 2023;22(1):93.

[75] HeL, LiH, WuA, et al. Functions of N6-methyladenosine and its role in cancer. Mol Cancer. 2019;18(1):176.

[76] ChenYG, ChenR, AhmadS, et al. N6-methyladenosine modification controls circular RNA immunity. Mol Cell. 2019;76(1):96-109.

[77] TongH, WeiH, SmithAO, et al. The role of m6A epigenetic modification in the treatment of colorectal cancer immune checkpoint inhibitors. Front Immunol. 2022;12:802049.

[78] PanY, ChenH, ZhangX, et al. METTL3 drives NAFLD-related hepatocellular carcinoma and is a therapeutic target for boosting immunotherapy. Cell Rep Med. 2023;4(8):101144.

[79] LuoL, FuS, DuW, et al. LRRC3B and its promoter hypomethylation status predicts response to anti-PD-1 based immunotherapy. Front Immunol. 2023;14:959868.

[80] BelkJA, DanielB, SatpathyAT. Epigenetic regulation of T cell exhaustion. Nat Immunol. 2022;23(6):848-860.

[81] KissickH, AhmedR. New epigenetic regulators of T cell exhaustion. Cancer Cell. 2022;40(7):708-710.

[82] YuJ, QinB, MoyerAM, et al. DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine. J Clin Invest. 2018;128(6):2376-2388.

[83] HanP, HouY, ZhaoY, et al. Low-dose decitabine modulates T-cell homeostasis and restores immune tolerance in immune thrombocytopenia. Blood. 2021;138(8):674-688.

[84] ZhangF, SuT, XiaoM. RUNX3-regulated circRNA METTL3 inhibits colorectal cancer proliferation and metastasis via miR-107/PER3 axis. Cell Death Dis. 2022;13(6):550.

[85] YoungA, NgiowSF, BarkauskasDS, et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell. 2016;30(3):391-403.

[86] WangF, FuK, WangY, et al. Small-molecule agents for cancer immunotherapy. Acta Pharm Sin B. 2024;14(3):905-952.

[87] XiaC, YinS, ToKKW, Fu L. CD39/CD73/A2AR pathway and cancer immunotherapy. Mol Cancer. 2023;22(1):44.

[88] Hsieh-WongJ, LiuJ, HuynhJ, et al. Immunotherapy in synchronous MSI-H rectal adenocarcinoma and upper tract urothelial carcinoma: a case report. J Gastrointest Oncol. 2022;13(3):1473-1480.

[89] TrojanJ, Stintzing S, HaaseO, et al. Complete pathological response after neoadjuvant short-course immunotherapy with ipilimumab and nivolumab in locally advanced MSI-H/dMMR rectal cancer. Oncologist. 2021;26(12):e2110-e2114.

[90] WangQX, XiaoBY, ChengY, et al. Anti-PD-1-based immunotherapy as curative-intent treatment in dMMR/MSI-H rectal cancer: a multicentre cohort study. Eur J Cancer. 2022;174:176-184.

[91] ChakrabartiS, Bucheit L, StarrJS, et al. Detection of microsatellite instability-high (MSI-H) by liquid biopsy predicts robust and durable response to immunotherapy in patients with pancreatic cancer. J Immunother Cancer. 2022;10(6):e004485.

[92] Cabezon-GutierrezL, Custodio-Cabello S, Palka-KotlowskaM, et al. Neoadjuvant immunotherapy for dMMR/MSI-H locally advanced rectal cancer: the future new standard approach?. Eur J Surg Oncol. 2023;49(2):323-328.

[93] CilonaM, Locatello LG, NovelliL, et al. The mismatch repair system (MMR) in head and neck carcinogenesis and its role in modulating the response to immunotherapy: a critical review. Cancers (Basel). 2020;12(10):3006.

[94] ShakerE, DoghimNN, HassanAM, et al. Immunotherapy in cutaneous warts: comparative clinical Study between MMR vaccine, tuberculin, and BCG Vaccine. J Cosmet Dermatol. 2021;20(8):2657-2666.

[95] LoteH, Starling N, PihlakR, et al. Advances in immunotherapy for MMR proficient colorectal cancer. Cancer Treat Rev. 2022;111:102480.

[96] HodiFS, Wolchok JD, SchadendorfD, et al. TMB and inflammatory gene expression associated with clinical outcomes following immunotherapy in advanced melanoma. Cancer Immunol Res. 2021;9(10):1202-1213.

[97] RizzoA, RicciAD. PD-L1, TMB, and other potential predictors of response to immunotherapy for hepatocellular carcinoma: how can they assist drug clinical trials?. Expert Opin Investig Drugs. 2022;31(4):415-423.

[98] BoumberY. Tumor mutational burden (TMB) as a biomarker of response to immunotherapy in small cell lung cancer. J Thorac Dis. 2018;10(8):4689-4693.

[99] HalbertB, Einstein DJ. Hot or not: tumor mutational burden (TMB) as a biomarker of immunotherapy response in genitourinary cancers. Urology. 2021;147:119-126.

[100] PengM, MoY, WangY, et al. Neoantigen vaccine: an emerging tumor immunotherapy. Mol Cancer. 2019;18(1):128.

[101] ZhangZ, LuM, QinY, et al. Neoantigen: a new breakthrough in tumor immunotherapy. Front Immunol. 2021;12:672356.

[102] WangC, YuM, ZhangW. Neoantigen discovery and applications in glioblastoma: an immunotherapy perspective. Cancer Lett. 2022;550:215945.

[103] LiuZ, LvJ, DangQ, et al. Engineering neoantigen vaccines to improve cancer personalized immunotherapy. Int J Biol Sci. 2022;18(15):5607-5623.

[104] HodiFS, Wolchok JD, SchadendorfD, et al. TMB and inflammatory gene expression associated with clinical outcomes following immunotherapy in advanced melanoma. Cancer Immunol Res. 2021;9(10):1202-1213.

[105] LiuL, BaiX, WangJ, et al. Combination of TMB and CNA stratifies prognostic and predictive responses to immunotherapy across metastatic cancer. Clin Cancer Res. 2019;25(24):7413-7423.

[106] HodiFS, Wolchok JD, SchadendorfD, et al. TMB and inflammatory gene expression associated with clinical outcomes following immunotherapy in advanced melanoma. Cancer Immunol Res. 2021;9(10):1202-1213.

[107] BoumberY. Tumor mutational burden (TMB) as a biomarker of response to immunotherapy in small cell lung cancer. J Thorac Dis. 2018;10(8):4689-4693.

[108] DiasESD, BorbaGB, BealJR, et al. Response to abemaciclib and immunotherapy rechallenge with nivolumab and ipilimumab in a heavily pretreated TMB-H metastatic squamous cell lung cancer with CDKN2A mutation, PIK3CA amplification and TPS 80%: a case report. Int J Mol Sci. 2023;24(4):4209.

[109] LiuY, WangS, WangY, et al. What makes TMB an ambivalent biomarker for immunotherapy? A subtle mismatch between the sample-based design of variant callers and real clinical cohort. Front Immunol. 2023;14:1151224.

[110] YostKE, Satpathy AT, WellsDK, et al. Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat Med. 2019;25(8):1251-1259.

[111] BlankC, Gajewski TF, MackensenA. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother. 2005;54(4):307-314.

[112] VeinaldeR, Pidelaserra-Marti G, MoulinC, et al. Oncolytic measles vaccines encoding PD-1 and PD-L1 checkpoint blocking antibodies to increase tumor-specific T cell memory. Mol Ther Oncolytics. 2022;24:43-58.

[113] SimonS, Labarriere N. PD-1 expression on tumor-specific T cells: friend or foe for immunotherapy?. Oncoimmunology. 2017;7(1):e1364828.

[114] EllmarkP, Mangsbo SM, FurebringC, et al. Tumor-directed immunotherapy can generate tumor-specific T cell responses through localized co-stimulation. Cancer Immunol Immunother. 2017;66(1):1-7.

[115] FerrariV, TarkeA, FieldsH, et al. Tumor-specific T cell-mediated upregulation of PD-L1 in myelodysplastic syndrome cells does not affect T-cell killing. Front Oncol. 2022;12:915629.

[116] BrogdenKA, Parashar D, HallierAR, et al. Correction to: genomics of NSCLC patients both affirm PD-L1 expression and predict their clinical responses to anti-PD-1 immunotherapy. BMC Cancer. 2018;18(1):413.

[117] Puig-SausC, Sennino B, PengS, et al. Neoantigen-targeted CD8(+) T cell responses with PD-1 blockade therapy. Nature. 2023;615(7953):697-704.

[118] PerryJA, Shallberg L, ClarkJT, et al. PD-L1-PD-1 interactions limit effector regulatory T cell populations at homeostasis and during infection. Nat Immunol. 2022;23(5):743-756.

[119] WeberJS, Levinson BA, LainoAS, et al. Clinical and immune correlate results from a phase 1b study of the histone deacetylase inhibitor mocetinostat with ipilimumab and nivolumab in unresectable stage III/IV melanoma. Melanoma Res. 2022;32(5):324-333.

[120] BlankCU, Rozeman EA, FanchiLF, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med. 2018;24(11):1655-1661.

[121] CarbonellC, Frigola J, PardoN, et al. Dynamic changes in circulating tumor DNA assessed by shallow whole-genome sequencing associate with clinical efficacy of checkpoint inhibitors in NSCLC. Mol Oncol. 2023;17(5):779-791.

[122] MomenS, Fassihi H, DaviesHR, et al. Dramatic response of metastatic cutaneous angiosarcoma to an immune checkpoint inhibitor in a patient with xeroderma pigmentosum: whole-genome sequencing aids treatment decision in end-stage disease. Cold Spring Harb Mol Case Stud. 2019;5(5):a004408.

[123] ImaiH, KairaK, KagamuH. Advanced research on immune checkpoint inhibitor therapy. J Clin Med. 2022;11(18):5392.

[124] CatalanoM, Roviello G, GalliIC, et al. Immune checkpoint inhibitor induced nephrotoxicity: an ongoing challenge. Front Med (Lausanne). 2022;9:1014257.

[125] GarassinoMC, Mazieres J, ReckM, et al. Durvalumab after sequential chemoradiotherapy in stage III, unresectable NSCLC: the phase 2 PACIFIC-6 trial. J Thorac Oncol. 2022;17(12):1415-1427.

[126] FitzpatrickO, NaidooJ. Immunotherapy for stage III NSCLC: durvalumab and beyond. Lung Cancer (Auckl). 2021;12:123-131.

[127] GrayJE, Villegas A, DanielD, et al. Three-year overall survival with durvalumab after chemoradiotherapy in stage III NSCLC-update from PACIFIC. J Thorac Oncol. 2020;15(2):288-293.

[128] NapolitanoM, Schipilliti FM, TruduL, et al. Immunotherapy in head and neck cancer: the great challenge of patient selection. Crit Rev Oncol Hematol. 2019;144:102829.

[129] Garcia-ArandaM, Redondo M. Immunotherapy: a challenge of breast cancer treatment. Cancers (Basel). 2019;11(12):1822.

[130] LiQ, HanJ, YangY, et al. PD-1/PD-L1 checkpoint inhibitors in advanced hepatocellular carcinoma immunotherapy. Front Immunol. 2022;13:1070961.

[131] LombardiR, Piciotti R, DongiovanniP, et al. PD-1/PD-L1 immuno-mediated therapy in NAFLD: advantages and obstacles in the treatment of advanced disease. Int J Mol Sci. 2022;23(5):2707.

[132] ZhangY, ZhengJ. Functions of immune checkpoint molecules beyond immune evasion. Adv Exp Med Biol. 2020;1248:201-226.

[133] ShiravandY, Khodadadi F, KashaniS, et al. Immune checkpoint inhibitors in cancer therapy. Curr Oncol. 2022;29(5):3044-3060.

[134] CarlinoMS, LarkinJ, LongGV. Immune checkpoint inhibitors in melanoma. Lancet. 2021;398(10304):1002-1014.

[135] LiB, ChanHL, ChenP. Immune checkpoint inhibitors: basics and challenges. Curr Med Chem. 2019;26(17):3009-3025.

[136] SharmaP, Allison JP. The future of immune checkpoint therapy. Science. 2015;348(6230):56-61.

[137] ZengS, SongH, ChenY, et al. B7-H4-mediated immunoresistance is supressed by PI3K/Akt/mTOR pathway inhibitors. Mol Biol (Mosk). 2016;50(6):1007-1013.

[138] ChoiSH, JungD, KimKY, et al. Combined use of cisplatin plus natural killer cells overcomes immunoresistance of cisplatin resistant ovarian cancer. Biochem Biophys Res Commun. 2021;563:40-46.

[139] RandrianV, EvrardC, TougeronD. Microsatellite instability in colorectal cancers: carcinogenesis, neo-antigens, immuno-resistance and emerging therapies. Cancers (Basel). 2021;13(12):3063.

[140] DossetM, VargasTR, LagrangeA, et al. PD-1/PD-L1 pathway: an adaptive immune resistance mechanism to immunogenic chemotherapy in colorectal cancer. Oncoimmunology. 2018;7(6):e1433981.

[141] PassarelliA, AietaM, SgambatoA, et al. Targeting immunometabolism mediated by CD73 pathway in EGFR-mutated non-small cell lung cancer: a new hope for overcoming immune resistance. Front Immunol. 2020;11:1479.

[142] MuraokaD, SeoN, HayashiT, et al. Antigen delivery targeted to tumor-associated macrophages overcomes tumor immune resistance. J Clin Invest. 2019;129(3):1278-1294.

[143] SpellaM, Stathopoulos GT. Immune resistance in lung adenocarcinoma. Cancers (Basel). 2021;13(3):384.

[144] TumehPC, Harview CL, YearleyJH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568-571.

[145] KimH, ParkS, HanKY, et al. Clonal expansion of resident memory T cells in peripheral blood of patients with non-small cell lung cancer during immune checkpoint inhibitor treatment. J Immunother Cancer. 2023;11(2):e005509.

[146] VeatchJR, Riddell SR. Immune checkpoint blockade provokes resident memory T cells to eliminate head and neck cancer. Cell. 2022;185(16):2848-2849.

[147] SassonSC, SlevinSM, CheungV, 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.

[148] JuddJ, Borghaei H. Combining immunotherapy and chemotherapy for non-small cell lung cancer. Thorac Surg Clin. 2020;30(2):199-206.

[149] YuWD, SunG, LiJ, et al. Mechanisms and therapeutic potentials of cancer immunotherapy in combination with radiotherapy and/or chemotherapy. Cancer Lett. 2019;452:66-70.

[150] KakejiY, Oshikiri T, TakiguchiG, et al. Multimodality approaches to control esophageal cancer: development of chemoradiotherapy, chemotherapy, and immunotherapy. Esophagus. 2021;18(1):25-32.

[151] HerreraFG, RonetC, OchoaDOM, et al. Low-dose radiotherapy reverses tumor immune desertification and resistance to immunotherapy. Cancer Discov. 2022;12(1):108-133.

[152] PointerKB, Pitroda SP, WeichselbaumRR. Radiotherapy and immunotherapy: open questions and future strategies. Trends Cancer. 2022;8(1):9-20.

[153] ZhangZ, LiuX, ChenD, et al. Radiotherapy combined with immunotherapy: the dawn of cancer treatment. Signal Transduct Target Ther. 2022;7(1):258.

[154] HidaT, Yamaguchi T. Advances in immunotherapy for stage III non-small cell lung cancer: moving immune checkpoint inhibitors to the front lines concurrently with chemoradiotherapy?. J Thorac Dis. 2020;12(8):4549-4552.

[155] FengCH, MellLK, SharabiAB, et al. Immunotherapy with radiotherapy and chemoradiotherapy for cervical cancer. Semin Radiat Oncol. 2020;30(4):273-280.

[156] ChalmersAW, PatelSB, AkerleyW. Immunotherapy after chemoradiotherapy in stage III non-small cell lung cancer: a new standard of care?. J Thorac Dis. 2018;10(3):1198-1200.

[157] NamikawaK, Yamazaki N. Targeted therapy and immunotherapy for melanoma in Japan. Curr Treat Options Oncol. 2019;20(1):7.

[158] NaylorEC, DesaniJK, ChungPK. Targeted therapy and immunotherapy for lung cancer. Surg Oncol Clin N Am. 2016;25(3):601-609.

[159] CaoD, SongQ, LiJ, et al. Opportunities and challenges in targeted therapy and immunotherapy for pancreatic cancer. Expert Rev Mol Med. 2021;23:e21.

[160] GuoCX, HuangX, XuJ, et al. Combined targeted therapy and immunotherapy for cancer treatment. World J Clin Cases. 2021;9(26):7643-7652.

[161] HsuC, Rimassa L, SunHC, et al. Immunotherapy in hepatocellular carcinoma: evaluation and management of adverse events associated with atezolizumab plus bevacizumab. Ther Adv Med Oncol. 2021;13:17524123.

[162] SongMJ, PanQZ, DingY, et al. The efficacy and safety of the combination of axitinib and pembrolizumab-activated autologous DC-CIK cell immunotherapy for patients with advanced renal cell carcinoma: a phase 2 study. Clin Transl Immunol. 2021;10(3):e1257.

[163] LeeMMP, ChanLL, ChanSL. The role of lenvatinib in the era of immunotherapy of hepatocellular carcinoma. J Liver Cancer. 2023;23(2):262-271.

[164] GuoDZ, ZhangSY, DongSY, et al. Circulating immune index predicting the prognosis of patients with hepatocellular carcinoma treated with lenvatinib and immunotherapy. Front Oncol. 2023;13:1109742.

[165] KlemenND, WangM, FeingoldPL, et al. Patterns of failure after immunotherapy with checkpoint inhibitors predict durable progression-free survival after local therapy for metastatic melanoma. J Immunother Cancer. 2019;7(1):196.

[166] LiuW, XieZ, ShenK, et al. Analysis of the safety and effectiveness of TACE combined with targeted immunotherapy in the treatment of intermediate and advanced hepatocellular carcinoma. Med Oncol. 2023;40(9):251.

[167] GlutschV, KneitzH, GesierichA, et al. Activity of ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma. Cancer Immunol Immunother. 2021;70(7):2087-2093.

[168] GlutschV, KneitzH, GoebelerM, et al. Breaking avelumab resistance with combined ipilimumab and nivolumab in metastatic Merkel cell carcinoma?. Ann Oncol. 2019;30(10):1667-1668.

[169] GlutschV, Schummer P, KneitzH, et al. Ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma: a multicenter study of the prospective skin cancer registry ADOREG. J Immunother Cancer. 2022;10(11):e005930.

[170] RecondoG, Mezquita L. Tiragolumab and atezolizumab in patients with PD-L1 positive non-small-cell lung cancer. Lancet Oncol. 2022;23(6):695-697.

[171] AuL, LarkinJ, TurajlicS. Relatlimab and nivolumab in the treatment of melanoma. Cell. 2022;185(26):4866-4869.

[172] TawbiHA, Schadendorf D, LipsonEJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34.

[173] ZeidanAM, Giagounidis A, SekeresMA, et al. STIMULUS-MDS2 design and rationale: a phase III trial with the anti-TIM-3 sabatolimab (MBG453) +azacitidine in higher risk MDS and CMML-2. Future Oncol. 2023;19(9):631-642.

[174] CuriglianoG, Gelderblom H, MachN, et al. Phase I/Ib clinical trial of sabatolimab, an anti-TIM-3 antibody, alone and in combination with spartalizumab, an anti-PD-1 antibody, in advanced solid tumors. Clin Cancer Res. 2021;27(13):3620-3629.

[175] LiY, ZhangY, CaoG, et al. Blockade of checkpoint receptor PVRIG unleashes anti-tumor immunity of NK cells in murine and human solid tumors. J Hematol Oncol. 2021;14(1):100.

[176] LiJ, WhelanS, KotturiMF, et al. PVRIG is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia. Haematologica. 2021;106(12):3115-3124.

[177] HuangX, ZhangX, LiE, et al. VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy. J Hematol Oncol. 2020;13(1):83.

[178] LiuJ, YuanY, ChenW, et al. Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. Proc Natl Acad Sci USA. 2015;112(21):6682-6687.

[179] WrightQ, Gonzalez CJ, WellsJW, et al. PD-1 and beyond to activate T cells in cutaneous squamous cell cancers: the case for 4-1BB and VISTA antibodies in combination therapy. Cancers (Basel). 2021;13(13):3310.

[180] KirchhammerN, TrefnyMP, AufDMP, et al. Combination cancer immunotherapies: emerging treatment strategies adapted to the tumor microenvironment. Sci Transl Med. 2022;14(670):eabo3605.

[181] KudoM. Durvalumab plus tremelimumab in unresectable hepatocellular carcinoma. Hepatobiliary Surg Nutr. 2022;11(4):592-596.

[182] WabitschS, McCallen JD, KamenyevaO, et al. Metformin treatment rescues CD8+T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD. J Hepatol. 2022;77(3):748-760.

[183] ChiangCH, ChenYJ, ChiangCH, et al. Effect of metformin on outcomes of patients treated with immune checkpoint inhibitors: a retrospective cohort study. Cancer Immunol Immunother. 2023;72(6):1951-1956.

[184] WangZ, LuC, ZhangK, et al. Metformin combining PD-1 inhibitor enhanced anti-tumor efficacy in STK11 mutant lung cancer through AXIN-1-dependent inhibition of STING ubiquitination. Front Mol Biosci. 2022;9:780200.

[185] YangJ, KimSH, JungEH, et al. The effect of metformin or dipeptidyl peptidase 4 inhibitors on clinical outcomes in metastatic non-small cell lung cancer treated with immune checkpoint inhibitors. Thorac Cancer. 2023;14(1):52-60.

[186] GoggiJL, Hartimath SV, KhanapurS, et al. Imaging memory T-cells stratifies response to adjuvant metformin combined with αPD-1 therapy. Int J Mol Sci. 2022;23(21):12892.

[187] AfzalMZ, Dragnev K, SarwarT, ShiraiK. Clinical outcomes in non-small-cell lung cancer patients receiving concurrent metformin and immune checkpoint inhibitors. Lung Cancer Manag. 2019;8(2):LMT11.

[188] JacobiO, Landman Y, ReinhornD, et al. The relationship of diabetes mellitus to efficacy of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer. Oncology. 2021;99(9):555-561.

[189] ZhangQ, YangZ, HaoX, et al. Niclosamide improves cancer immunotherapy by modulating RNA-binding protein HuR-mediated PD-L1 signaling. Cell Biosci. 2023;13(1):192.

[190] GuoY, ZhuH, XiaoY, et al. The anthelmintic drug niclosamide induces GSK-β-mediated β-catenin degradation to potentiate gemcitabine activity, reduce immune evasion ability and suppress pancreatic cancer progression. Cell Death Dis. 2022;13(2):112.

[191] LuoF, LuoM, RongQX, et al. Niclosamide, an antihelmintic drug, enhances efficacy of PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer. J Immunother Cancer. 2019;7(1):245.

[192] VaddepallyR, Doddamani R, SodavarapuS, et al. Review of immune-related adverse events (irAEs) in non-small-cell lung cancer (NSCLC)-their incidence, management, multiorgan irAEs, and rechallenge. Biomedicines. 2022;10(4):790.

[193] DarnellEP, Mooradian MJ, BaruchEN, et al. Immune-related adverse events (irAEs):diagnosis, management, and clinical pearls. Curr Oncol Rep. 2020;22(4):39.

[194] TengYS, YuS. Molecular mechanisms of cutaneous immune-related adverse events (irAEs) induced by immune checkpoint inhibitors. Curr Oncol. 2023;30(7):6805-6819.

[195] BlumSM, Rouhani SJ, SullivanRJ. Effects of immune-related adverse events (irAEs) and their treatment on antitumor immune responses. Immunol Rev. 2023;318(1):167-178.

[196] ChhabraN, Kennedy J. A review of cancer immunotherapy toxicity: immune checkpoint inhibitors. J Med Toxicol. 2021;17(4):411-424.

[197] Stein-MerlobAF, Rothberg MV, RibasA, et al. Cardiotoxicities of novel cancer immunotherapies. Heart. 2021;107(21):1694-1703.

[198] MichotJM, Lazarovici J, TieuA, et al. Haematological immune-related adverse events with immune checkpoint inhibitors, how to manage?. Eur J Cancer. 2019;122:72-90.

[199] EliaG, Ferrari SM, GaldieroMR, et al. New insight in endocrine-related adverse events associated to immune checkpoint blockade. Best Pract Res Clin Endocrinol Metab. 2020;34(1):101370.

[200] SznolM, PostowMA, DaviesMJ, et al. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev. 2017;58:70-76.

[201] JingY, ChenX, LiK, et al. Association of antibiotic treatment with immune-related adverse events in patients with cancer receiving immunotherapy. J Immunother Cancer. 2022;10(1):e003779.

[202] HarataniK, Hayashi H, ChibaY, et al. Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol. 2018;4(3):374-378.

[203] DarnellEP, Mooradian MJ, BaruchEN, et al. Immune-related adverse events (irAEs):diagnosis, management, and clinical pearls. Curr Oncol Rep. 2020;22(4):39.

[204] KumarV, Chaudhary N, GargM, et al. Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol. 2017;8:49.

[205] LiuYH, ZangXY, WangJC, et al. Diagnosis and management of immune related adverse events (irAEs) in cancer immunotherapy. Biomed Pharmacother. 2019;120:109437.

[206] HegdePS, ChenDS. Top 10 challenges in cancer immunotherapy. Immunity. 2020;52(1):17-35.

[207] SivanA, Corrales L, HubertN, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350(6264):1084-1089.

[208] VétizouM, PittJM, DaillèreR, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079-1084.

[209] RoutyB, Le Chatelier E, DerosaL, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91-97.

[210] GopalakrishnanV, Helmink BA, SpencerCN, ReubenA, WargoJA. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell. 2018;33(4):570-580.

[211] FjæstadKY, Rømer AMA, GoiteaV, et al. Blockade of beta-adrenergic receptors reduces cancer growth and enhances the response to anti-CTLA4 therapy by modulating the tumor microenvironment. Oncogene. 2022;41(9):1364-1375.

[212] KamiyaA, HayamaY, KatoS, et al. Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression [retracted in: Nat Neurosci. 2024 May; 27(5):1020]. Nat Neurosci. 2019;22(8):1289-1305.

[213] PowlesT, YuenKC, GillessenS, et al. Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Nat Med. 2022;28(1):144-153.

[214] MorseMD, McNeelDG. T cells localized to the androgen-deprived prostate are TH1 and TH17 biased. Prostate. 2012;72(11):1239-1247.

[215] TangS, MooreML, GraysonJM, Dubey P. Increased CD8+T-cell function following castration and immunization is countered by parallel expansion of regulatory T cells. Cancer Res. 2012;72(8):1975-1985.

RIGHTS & PERMISSIONS

2024 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.