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Recent advancements in the B7/CD28 immune checkpoint families: new biology and clinical therapeutic strategies

Cellular & Molecular Immunology volume 20, pages 694–713 (2023)Cite this article

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Abstract

The B7/CD28 families of immune checkpoints play vital roles in negatively or positively regulating immune cells in homeostasis and various diseases. Recent basic and clinical studies have revealed novel biology of the B7/CD28 families and new therapeutics for cancer therapy. In this review, we discuss the newly discovered KIR3DL3/TMIGD2/HHLA2 pathways, PD-1/PD-L1 and B7-H3 as metabolic regulators, the glycobiology of PD-1/PD-L1, B7x (B7-H4) and B7-H3, and the recently characterized PD-L1/B7-1 cis-interaction. We also cover the tumor-intrinsic and -extrinsic resistance mechanisms to current anti-PD-1/PD-L1 and anti-CTLA-4 immunotherapies in clinical settings. Finally, we review new immunotherapies targeting B7-H3, B7x, PD-1/PD-L1, and CTLA-4 in current clinical trials.

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References

  1. Ledford H, Else H, Warren M. Cancer immunologists scoop medicine Nobel prize. Nature. 2018;562:20–1.

    Article  CAS  PubMed  Google Scholar 

  2. Zang X. 2018 Nobel prize in medicine awarded to cancer immunotherapy: Immune checkpoint blockade - a personal account. Genes Dis. 2018;5:302–3.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zhao R, Chinai JM, Buhl S, Scandiuzzi L, Ray A, Jeon H, et al. HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function. Proc Natl Acad Sci USA. 2013;110:9879–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zang X, Loke P, Kim J, Murphy K, Waitz R, Allison JP. B7x: A widely expressed B7 family member that inhibits T cell activation. Proc Natl Acad Sci USA. 2003;100:10388–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Janakiram M, Shah UA, Liu W, Zhao A, Schoenberg MP, Zang X. The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7-H3. Immunol Rev. 2017;276:26–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wei Y, Ren X, Galbo PM Jr, Moerdler S, Wang H, Sica RA, et al. KIR3DL3-HHLA2 is a human immunosuppressive pathway and a therapeutic target. Sci Immunol. 2021;6:eabf9792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. John P, Wei Y, Liu W, Du M, Guan F, Zang X. The B7x immune checkpoint pathway: From discovery to clinical trial. Trends Pharm Sci. 2019;40:883–96.

    Article  CAS  PubMed  Google Scholar 

  8. Picarda E, Ohaegbulam KC, Zang X. Molecular pathways: targeting B7-H3 (CD276) for human cancer immunotherapy. Clin Cancer Res. 2016;22:3425–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zang X. New immune checkpoint pathways: HHLA2 and its receptors including TMIGD2. Cold Spring Harbor Asia Conference on Precision Cancer Biology: From Targeted to Immune Therapies, Suzhou, China 18 to 22 September. 2017.

  10. Janakiram M, Chinai JM, Fineberg S, Fiser A, Montagna C, Medavarapu R, et al. Expression, clinical significance, and receptor identification of the newest B7 family member HHLA2 protein. Clin Cancer Res. 2015;21:2359–66.

    Article  CAS  PubMed  Google Scholar 

  11. Bhatt RS, Berjis A, Konge JC, Mahoney KM, Klee AN, Freeman SS, et al. KIR3DL3 Is an inhibitory receptor for HHLA2 that mediates an alternative immunoinhibitory pathway to PD-1. Cancer. Immunol Res. 2021;9:156–69.

    CAS  Google Scholar 

  12. Cheng H, Janakiram M, Borczuk A, Lin J, Qiu W, Liu H, et al. HHLA2, a new immune checkpoint member of the B7 Family, is widely expressed in human lung cancer and associated with EGFR mutational status. Clin Cancer Res. 2017;23:825–32.

    Article  CAS  PubMed  Google Scholar 

  13. Cheng H, Borczuk A, Janakiram M, Ren X, Lin J, Assal A, et al. Wide expression and significance of alternative immune checkpoint molecules, B7x and HHLA2, in PD-L1-negative human lung cancers. Clin Cancer Res. 2018;24:1954–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Koirala P, Roth ME, Gill J, Chinai JM, Ewart MR, Piperdi S, et al. HHLA2, a member of the B7 family, is expressed in human osteosarcoma and is associated with metastases and worse survival. Sci Rep. 2016;6:31154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Boor PPC, Sideras K, Biermann K, Hosein Aziz M, Levink IJM, Mancham S, et al. HHLA2 is expressed in pancreatic and ampullary cancers and increased expression is associated with better post-surgical prognosis. Br J Cancer. 2020;122:1211–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang Z, Liu J, Zhang C, Li F, Li L, Wang D, et al. Over-expression and prognostic significance of HHLA2, a new immune checkpoint molecule, in human clear cell renal cell carcinoma. Front Cell Dev Biol. 2020;8:280.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Yuan Z, Gardiner JC, Maggi EC, Huang S, Adem A, Bagdasarov S, et al. B7 immune-checkpoints as targets for the treatment of neuroendocrine tumors. Endocr Relat Cancer. 2021;28:135–49.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zhou Q, Li K, Lai Y, Yao K, Wang Q, Zhan X, et al. B7 score and T cell infiltration stratify immune status in prostate cancer. J Immunother Cancer. 2021;9:e002455.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Janakiram M, Chinai JM, Zhao A, Sparano JA, Zang X. HHLA2 and TMIGD2: New immunotherapeutic targets of the B7 and CD28 families. Oncoimmunology. 2015;4:e1026534.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lamb M, Wei Y, Ren X, O’Connor R, Dulak A, Rausch M, et al. NPX267, a first-in-class monoclonal antibody targeting KIR3DL3, blocks HHLA2-mediated immunosuppression and potentiates T and NK cell-mediated antitumor immunity. J Immunother Cancer. 2022;10:A510.

    Google Scholar 

  21. Zhu Y, Yao S, Iliopoulou BP, Han X, Augustine MM, Xu H, et al. B7-H5 costimulates human T cells via CD28H. Nat Commun. 2013;4:2043.

    Article  PubMed  Google Scholar 

  22. Luu K, Schwarz H, Lundqvist A. B7-H7 is inducible on T cells to regulate their immune response and serves as a marker for exhaustion. Front Immunol. 2021;12:682627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chen D, Chen W, Xu Y, Zhu M, Xiao Y, Shen Y, et al. Upregulated immune checkpoint HHLA2 in clear cell renal cell carcinoma: A novel prognostic biomarker and potential therapeutic target. J Med Genet. 2019;56:43–9.

    Article  CAS  PubMed  Google Scholar 

  24. Farrag M, Ibrahim E, El-Hadidy T, Akl M, Elsergany A, Abdelwahab H. Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) is a novel immune checkpoint protein in lung cancer which predicts survival. Asian Pac J Cancer Prev. 2021;22:1883–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jing CY, Fu YP, Yi Y, Zhang MX, Zheng SS, Huang JL, et al. HHLA2 in intrahepatic cholangiocarcinoma: An immune checkpoint with prognostic significance and wider expression compared with PD-L1. J Immunother Cancer. 2019;7:77.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Luo M, Lin Y, Liang R, Li Y, Ge L. Clinical significance of the HHLA2 protein in hepatocellular carcinoma and the tumor microenvironment. J Inflamm Res. 2021;14:4217–28.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Yan H, Qiu W, Koehne de Gonzalez AK, Wei JS, Tu M, Xi CH, et al. HHLA2 is a novel immune checkpoint protein in pancreatic ductal adenocarcinoma and predicts post-surgical survival. Cancer Lett. 2019;442:333–40.

    Article  CAS  PubMed  Google Scholar 

  28. Rahimi N, Rezazadeh K, Mahoney JE, Hartsough E, Meyer RD. Identification of IGPR-1 as a novel adhesion molecule involved in angiogenesis. Mol Biol Cell. 2012;23:1646–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Crespo J, Vatan L, Maj T, Liu R, Kryczek I, Zou W. Phenotype and tissue distribution of CD28H+ immune cell subsets. OncoImmunology. 2017;6:e1362529.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Zhuang X, Long EO. CD28 homolog is a strong activator of natural killer cells for lysis of B7-H7+ tumor cells. Cancer Immunol Res. 2019;7:939–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Leaton LA, Shortt J, Kichula KM, Tao S, Nemat-Gorgani N, Mentzer AJ, et al. Conservation, extensive heterozygosity, and convergence of signaling potential all indicate a critical role for KIR3DL3 in higher primates. Front Immunol. 2019;10:24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Trundley AE, Hiby SE, Chang C, Sharkey AM, Santourlidis S, Uhrberg M, et al. Molecular characterization of KIR3DL3. Immunogenetics. 2006;57:904–16.

    Article  CAS  PubMed  Google Scholar 

  33. Trompeter H-I, Gómez-Lozano N, Santourlidis S, Eisermann B, Wernet P, Vilches C, et al. Three structurally and functionally divergent kinds of promoters regulate expression of clonally distributed killer cell Ig-like receptors (KIR), of KIR2DL4, and of KIR3DL3. J Immunol. 2005;174:4135–43.

    Article  CAS  PubMed  Google Scholar 

  34. Steggerda SM, Bennett MK, Chen J, Emberley E, Huang T, Janes JR, et al. Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment. J Immunother Cancer. 2017;5:101.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Nutalai R, Gaudieri S, Jumnainsong A, Leelayuwat C. Regulation of KIR3DL3 expression via miRNA. Genes. 2019;10:603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Huang FX, Wu JW, Cheng XQ, Wang JH, Wen XZ, Li JJ, et al. HHLA2 predicts improved prognosis of anti-PD-1/PD-L1 immunotherapy in patients with melanoma. Front Immunol. 2022;13:902167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ramaswamy M, Kim T, Jones DC, Ghadially H, Mahmoud TI, Garcia A, et al. Immunomodulation of T- and NK-cell responses by a bispecific antibody targeting CD28 homolog and PD-L1. Cancer Immunol Res. 2022;10:200–14.

    Article  CAS  PubMed  Google Scholar 

  38. Chi H. Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol. 2012;12:325–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Siska PJ, Rathmell JC. T cell metabolic fitness in antitumor immunity. Trends Immunol. 2015;36:257–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Oestreich KJ, Yoon H, Ahmed R, Boss JM. NFATc1 regulates PD-1 expression upon T cell activation. J Immunol. 2008;181:4832–9.

    Article  CAS  PubMed  Google Scholar 

  41. Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004;574:37–41.

    Article  CAS  PubMed  Google Scholar 

  42. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004;173:945–54.

    Article  CAS  PubMed  Google Scholar 

  43. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25:9543–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol. 2009;10:1185–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M, et al. PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8 T cells. EMBO Mol Med. 2011;3:581–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012;209:1201–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal. 2012;5:ra46.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Patsoukis N, Li L, Sari D, Petkova V, Boussiotis VA. PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2. Mol Cell Biol. 2013;33:3091–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hui E, Cheung J, Zhu J, Su X, Taylor MJ, Wallweber HA, et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. 2017;355:1428–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015;6:6692.

    Article  CAS  PubMed  Google Scholar 

  51. Kew S, Mesa MD, Tricon S, Buckley R, Minihane AM, Yaqoob P. Effects of oils rich in eicosapentaenoic and docosahexaenoic acids on immune cell composition and function in healthy humans. Am J Clin Nutr. 2004;79:674–81.

    Article  CAS  PubMed  Google Scholar 

  52. Verlengia R, Gorjao R, Kanunfre CC, Bordin S, Martins De Lima T, Martins EF, et al. Comparative effects of eicosapentaenoic acid and docosahexaenoic acid on proliferation, cytokine production, and pleiotropic gene expression in Jurkat cells. J Nutr Biochem. 2004;15:657–65.

    Article  CAS  PubMed  Google Scholar 

  53. Jaudszus A, Gruen M, Watzl B, Ness C, Roth A, Lochner A, et al. Evaluation of suppressive and pro-resolving effects of EPA and DHA in human primary monocytes and T-helper cells. J Lipid Res. 2013;54:923–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Xu S, Chaudhary O, Rodriguez-Morales P, Sun X, Chen D, Zappasodi R, et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8 T cells in tumors. Immunity. 2021;54:1561–77 e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tkachev V, Goodell S, Opipari AW, Hao LY, Franchi L, Glick GD, et al. Programmed death-1 controls T cell survival by regulating oxidative metabolism. J Immunol. 2015;194:5789–800.

    Article  CAS  PubMed  Google Scholar 

  56. Chamoto K, Chowdhury PS, Kumar A, Sonomura K, Matsuda F, Fagarasan S, et al. Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proc Natl Acad Sci USA. 2017;114:E761–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kalia V, Yuzefpolskiy Y, Vegaraju A, Xiao H, Baumann F, Jatav S, et al. Metabolic regulation by PD-1 signaling promotes long-lived quiescent CD8 T cell memory in mice. Sci Transl Med. 2021;13:eaba6006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Johnnidis JB, Muroyama Y, Ngiow SF, Chen Z, Manne S, Cai Z, et al. Inhibitory signaling sustains a distinct early memory CD8 T cell precursor that is resistant to DNA damage. Sci Immunol. 2021;6:eabe3702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Qorraj M, Bruns H, Bottcher M, Weigand L, Saul D, Mackensen A, et al. The PD-1/PD-L1 axis contributes to immune metabolic dysfunctions of monocytes in chronic lymphocytic leukemia. Leukemia. 2017;31:470–8.

    Article  CAS  PubMed  Google Scholar 

  60. Strauss L, Mahmoud MAA, Weaver JD, Tijaro-Ovalle NM, Christofides A, Wang Q, et al. Targeted deletion of PD-1 in myeloid cells induces antitumor immunity. Sci Immunol. 2020;5:eaay1863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yu Y, Tsang JC, Wang C, Clare S, Wang J, Chen X, et al. Single-cell RNA-seq identifies a PD-1(hi) ILC progenitor and defines its development pathway. Nature. 2016;539:102–6.

    Article  CAS  PubMed  Google Scholar 

  62. Donnelly RP, Loftus RM, Keating SE, Liou KT, Biron CA, Gardiner CM, et al. mTORC1-dependent metabolic reprogramming is a prerequisite for NK cell effector function. J Immunol. 2014;193:4477–84.

    Article  CAS  PubMed  Google Scholar 

  63. Tan CL, Kuchroo JR, Sage PT, Liang D, Francisco LM, Buck J, et al. PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance. J Exp Med. 2021;218:e20182232.

    Article  CAS  PubMed  Google Scholar 

  64. Kamada T, Togashi Y, Tay C, Ha D, Sasaki A, Nakamura Y, et al. PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci USA. 2019;116:9999–10008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kumagai S, Togashi Y, Kamada T, Sugiyama E, Nishinakamura H, Takeuchi Y, et al. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat Immunol. 2020;21:1346–58.

    Article  CAS  PubMed  Google Scholar 

  66. Park HJ, Park JS, Jeong YH, Son J, Ban YH, Lee BH, et al. PD-1 upregulated on regulatory T cells during chronic virus infection enhances the suppression of CD8 T cell immune response via the interaction with PD-L1 expressed on CD8 T cells. J Immunol. 2015;194:5801–11.

    Article  CAS  PubMed  Google Scholar 

  67. Stathopoulou C, Gangaplara A, Mallett G, Flomerfelt FA, Liniany LP, Knight D, et al. PD-1 inhibitory receptor downregulates asparaginyl endopeptidase and maintains Foxp3 transcription factor stability in induced regulatory T cells. Immunity. 2018;49:247–63.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kim MJ, Kim K, Park HJ, Kim GR, Hong KH, Oh JH, et al. Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells. Nat Immunol. 2023;24:148–61.

    Article  CAS  PubMed  Google Scholar 

  69. Wang H, Franco F, Tsui YC, Xie X, Trefny MP, Zappasodi R, et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat Immunol. 2020;21:298–308.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Charbonnier LM, Cui Y, Stephen-Victor E, Harb H, Lopez D, Bleesing JJ, et al. Functional reprogramming of regulatory T cells in the absence of Foxp3. Nat Immunol. 2019;20:1208–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lim SA, Wei J, Nguyen TM, Shi H, Su W, Palacios G, et al. Lipid signalling enforces functional specialization of Treg cells in tumours. Nature. 2021;591:306–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Xu C, Fu Y, Liu S, Trittipo J, Lu X, Qi R, et al. BATF regulates T regulatory cell functional specification and fitness of triglyceride metabolism in restraining allergic responses. J Immunol. 2021;206:2088–100.

    Article  CAS  PubMed  Google Scholar 

  73. Itahashi K, Irie T, Yuda J, Kumagai S, Tanegashima T, Lin Y-T, et al. BATF epigenetically and transcriptionally controls the activation program of regulatory T cells in human tumors. Sci Immunol. 2022;7:eabk0957.

    Article  CAS  PubMed  Google Scholar 

  74. Chang CH, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015;162:1229–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wang S, Li J, Xie J, Liu F, Duan Y, Wu Y, et al. Programmed death ligand 1 promotes lymph node metastasis and glucose metabolism in cervical cancer by activating integrin beta4/SNAI1/SIRT3 signaling pathway. Oncogene. 2018;37:4164–80.

    Article  CAS  PubMed  Google Scholar 

  76. Kim S, Jang JY, Koh J, Kwon D, Kim YA, Paeng JC, et al. Programmed cell death ligand-1-mediated enhancement of hexokinase 2 expression is inversely related to T-cell effector gene expression in non-small-cell lung cancer. J Exp Clin Cancer Res. 2019;38:462.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Yu Y, Liang Y, Li D, Wang L, Liang Z, Chen Y, et al. Glucose metabolism involved in PD-L1-mediated immune escape in the malignant kidney tumour microenvironment. Cell Death Disco. 2021;7:15.

    Article  CAS  Google Scholar 

  78. Lin R, Zhang H, Yuan Y, He Q, Zhou J, Li S, et al. Fatty acid oxidation controls CD8 tissue-resident memory T cell survival in gastric adenocarcinoma. Cancer Immunol Res. 2020;8:479–92.

    Article  CAS  PubMed  Google Scholar 

  79. Lim S, Liu H, Madeira da Silva L, Arora R, Liu Z, Phillips JB, et al. Immunoregulatory protein B7-H3 reprograms glucose metabolism in cancer cells by ROS-mediated stabilization of HIF1-α. Cancer Res. 2016;76:2231–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Nunes-Xavier CE, Karlsen KF, Tekle C, Pedersen C, Øyjord T, Hongisto V, et al. Decreased expression of B7-H3 reduces the glycolytic capacity and sensitizes breast cancer cells to AKT/mTOR inhibitors. Oncotarget. 2016;7:6891–901.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Flem-Karlsen K, Tekle C, Andersson Y, Flatmark K, Fodstad Ø, Nunes-Xavier CE. Immunoregulatory protein B7-H3 promotes growth and decreases sensitivity to therapy in metastatic melanoma cells. Pigment Cell Melanoma Res. 2017;30:467–76.

    Article  CAS  PubMed  Google Scholar 

  82. Shi T, Ma Y, Cao L, Zhan S, Xu Y, Fu F, et al. B7-H3 promotes aerobic glycolysis and chemoresistance in colorectal cancer cells by regulating HK2. Cell Death Dis. 2019;10:308.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Luo D, Xiao H, Dong J, Li Y, Feng G, Cui M, et al. B7-H3 regulates lipid metabolism of lung cancer through SREBP1-mediated expression of FASN. Biochem Biophys Res Commun. 2017;482:1246–51.

    Article  CAS  PubMed  Google Scholar 

  84. Wu J, Wang F, Liu X, Zhang T, Liu F, Ge X, et al. Correlation of IDH1 and B7-H3 expression with prognosis of CRC patients. Eur J Surg Oncol. 2018;44:1254–60.

    Article  PubMed  Google Scholar 

  85. Picarda E, Galbo PM Jr., Zong H, Rajan MR, Wallenius V, Zheng D, et al. The immune checkpoint B7-H3 (CD276) regulates adipocyte progenitor metabolism and obesity development. Sci Adv. 2022;8:eabm7012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Peixoto A, Relvas-Santos M, Azevedo R, Santos LL, Ferreira JA. Protein glycosylation and tumor microenvironment alterations driving cancer hallmarks. Front Oncol. 2019;9:380.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Bartish M, del Rincón SV, Rudd CE, Saragovi HU. Aiming for the sweet spot: Glyco-immune checkpoints and γδ T cells in targeted immunotherapy. Front Immunol. 2020;11:564499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. de Haas P, Hendriks WJAJ, Lefeber DJ, Cambi A. Biological and technical challenges in unraveling the role of N-glycans in immune receptor regulation. Front Chem. 2020;8:55.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Munkley J. The glycosylation landscape of pancreatic cancer. Oncol Lett. 2019;17:2569–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Huang C, Fang M, Feng H, Liu L, Li Y, Xu X, et al. N-glycan fingerprint predicts alpha-fetoprotein negative hepatocellular carcinoma: A large-scale multicenter study. Int J Cancer. 2021;149:717–27.

    Article  CAS  PubMed  Google Scholar 

  91. Munkley J, Elliott DJ. Hallmarks of glycosylation in cancer. Oncotarget. 2016;7:35478–89.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Reily C, Stewart TJ, Renfrow MB, Novak J. Glycosylation in health and disease. Nat Rev Nephrol. 2019;15:346–66.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Stanley P, Tanwar A. Regulation of myeloid and lymphoid cell development by O-glycans on Notch. Front Mol Biosci. 2022;9:979724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. An HJ, Froehlich JW, Lebrilla CB. Determination of glycosylation sites and site-specific heterogeneity in glycoproteins. Curr Opin Chem Biol. 2009;13:421–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ma M, Han G, Wang Y, Zhao Z, Guan F, Li X. Role of FUT8 expression in clinicopathology and patient survival for various malignant tumor types: A systematic review and meta-analysis. Aging. 2020;13:2212–30.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Bastian K, Scott E, Elliott DJ, Munkley J. FUT8 Alpha-(1,6)-Fucosyltransferase in cancer. Int J Mol Sci. 2021;22:455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Varki A. Biological roles of glycans. Glycobiology. 2017;27:3–49.

    Article  CAS  PubMed  Google Scholar 

  98. Wang Y-N, Lee H-H, Hsu JL, Yu D, Hung M-C. The impact of PD-L1 N-linked glycosylation on cancer therapy and clinical diagnosis. J Biomed Sci. 2020;27:77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sun L, Li CW, Chung EM, Yang R, Kim YS, Park AH, et al. Targeting glycosylated PD-1 induces potent antitumor immunity. Cancer Res. 2020;80:2298–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Okada M, Chikuma S, Kondo T, Hibino S, Machiyama H, Yokosuka T, et al. Blockage of core fucosylation reduces cell-surface expression of PD-1 and promotes anti-tumor immune responses of T cells. Cell Rep. 2017;20:1017–28.

    Article  CAS  PubMed  Google Scholar 

  101. Tan S, Zhang H, Chai Y, Song H, Tong Z, Wang Q, et al. An unexpected N-terminal loop in PD-1 dominates binding by nivolumab. Nat Commun. 2017;8:14369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhou S, Zhu J, Xu J, Gu B, Zhao Q, Luo C, et al. Anti‐tumour potential of PD‐L1/PD‐1 post‐translational modifications. Immunology. 2022;167:471–81.

    Article  CAS  PubMed  Google Scholar 

  103. Zhang N, Li M, Xu X, Zhang Y, Liu Y, Zhao M, et al. Loss of core fucosylation enhances the anticancer activity of cytotoxic T lymphocytes by increasing PD-1 degradation. Eur J Immunol. 2020;50:1820–33.

    Article  CAS  PubMed  Google Scholar 

  104. Guzik K, Zak KM, Grudnik P, Magiera K, Musielak B, Törner R, et al. Small-molecule inhibitors of the programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) interaction via transiently induced protein states and dimerization of PD-L1. J Med Chem. 2017;60:5857–67.

    Article  CAS  PubMed  Google Scholar 

  105. Sun R, Kim AMJ, Lim SO. Glycosylation of immune receptors in cancer. Cells. 2021;10:1100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Liu K, Tan S, Jin W, Guan J, Wang Q, Sun H, et al. N-glycosylation of PD-1 promotes binding of camrelizumab. EMBO Rep. 2020;21:e51444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Shi X, Zhang D, Li F, Zhang Z, Wang S, Xuan Y, et al. Targeting glycosylation of PD-1 to enhance CAR-T cell cytotoxicity. J Hematol Oncol. 2019;12:127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Li C-W, Lim S-O, Xia W, Lee H-H, Chan L-C, Kuo C-W, et al. Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nat Commun. 2016;7:12632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Xiao L, Guan X, Xiang M, Wang Q, Long Q, Yue C, et al. B7 family protein glycosylation: promising novel targets in tumor treatment. Front Immunol. 2022;13:1088560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Li CW, Lim SO, Chung EM, Kim YS, Park AH, Yao J, et al. Eradication of triple-negative breast cancer cells by targeting glycosylated PD-L1. Cancer Cell. 2018;33:187–201.e10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Cha JH, Yang WH, Xia W, Wei Y, Chan LC, Lim SO, et al. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1. Mol Cell. 2018;71:606–20.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Lee HH, Wang YN, Xia W, Chen CH, Rau KM, Ye L, et al. Removal of N-linked glycosylation enhances PD-L1 detection and predicts anti-PD-1/PD-L1 therapeutic efficacy. Cancer Cell. 2019;36:168–78.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ou-Yang F, Li CL, Chen CC, Shen YC, Moi SH, Luo CW, et al. De-glycosylated membrane PD-L1 in tumor tissues as a biomarker for responsiveness to atezolizumab (Tecentriq) in advanced breast cancer patients. Am J Cancer Res. 2022;12:123–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Song X, Zhou Z, Li H, Xue Y, Lu X, Bahar I, et al. Pharmacologic suppression of B7-H4 glycosylation restores antitumor immunity in immune-cold breast cancers. Cancer Disco. 2020;10:1872–93.

    Article  CAS  Google Scholar 

  115. Rinis N, Golden JE, Marceau CD, Carette JE, Van Zandt MC, Gilmore R, et al. Editing N-glycan site occupancy with small-molecule oligosaccharyltransferase inhibitors. Cell Chem Biol. 2018;25:1231–41.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Chen JT, Chen CH, Ku KL, Hsiao M, Chiang CP, Hsu TL, et al. Glycoprotein B7-H3 overexpression and aberrant glycosylation in oral cancer and immune response. Proc Natl Acad Sci USA. 2015;112:13057–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Huang Y, Zhang HL, Li ZL, Du T, Chen YH, Wang Y, et al. FUT8-mediated aberrant N-glycosylation of B7-H3 suppresses the immune response in triple-negative breast cancer. Nat Commun. 2021;12:2672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Nishimura CD, Pulanco MC, Cui W, Lu L, Zang X. PD-L1 and B7-1 cis-interaction: New mechanisms in immune checkpoints and immunotherapies. Trends Mol Med. 2021;27:207–19.

    Article  CAS  PubMed  Google Scholar 

  119. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27:111–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Butte MJ, Pena-Cruz V, Kim MJ, Freeman GJ, Sharpe AH. Interaction of human PD-L1 and B7-1. Mol Immunol. 2008;45:3567–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Chaudhri A, Xiao Y, Klee AN, Wang X, Zhu B, Freeman GJ. PD-L1 binds to B7-1 only in cis on the same cell surface. Cancer Immunol Res. 2018;6:921–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Zhao Y, Lee CK, Lin CH, Gassen RB, Xu X, Huang Z, et al. PD-L1:CD80 cis-Heterodimer triggers the co-stimulatory receptor CD28 while repressing the inhibitory PD-1 and CTLA-4 pathways. Immunity. 2019;51:1059–73 e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Sugiura D, Maruhashi T, Okazaki IM, Shimizu K, Maeda TK, Takemoto T, et al. Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses. Science. 2019;364:558–66.

    Article  CAS  PubMed  Google Scholar 

  124. Garrett-Thomson SC, Massimi A, Fedorov EV, Bonanno JB, Scandiuzzi L, Hillerich B, et al. Mechanistic dissection of the PD-L1:B7-1 co-inhibitory immune complex. PLoS One. 2020;15:e0233578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Mayoux M, Roller A, Pulko V, Sammicheli S, Chen S, Sum E, et al. Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy. Sci Transl Med. 2020;12:eaav7431.

    Article  CAS  PubMed  Google Scholar 

  126. Paterson AM, Brown KE, Keir ME, Vanguri VK, Riella LV, Chandraker A, et al. The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo. J Immunol. 2011;187:1097–105.

    Article  CAS  PubMed  Google Scholar 

  127. Oh SA, Wu D-C, Cheung J, Navarro A, Xiong H, Cubas R, et al. PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer. Nat Cancer. 2020;1:681–91.

    Article  CAS  PubMed  Google Scholar 

  128. Wang J, Yoshida T, Nakaki F, Hiai H, Okazaki T, Honjo T. Establishment of NOD-Pdcd1−/− mice as an efficient animal model of type I diabetes. Proc Natl Acad Sci USA. 2005;102:11823–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203:883–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515:558–62.

    Article  CAS  PubMed  Google Scholar 

  132. Fares CM, Van Allen EM, Drake CG, Allison JP, Hu-Lieskovan S. Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients? Am Soc Clin Oncol Educ Book. 2019;39:147–64.

    Article  PubMed  Google Scholar 

  133. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl J Med. 2014;371:2189–99.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2016;352:207–12.

    Google Scholar 

  136. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N. Engl J Med. 2017;377:2500–1.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Chowell D, Morris LGT, Grigg CM, Weber JK, Samstein RM, Makarov V, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science. 2018;359:582–7.

    Article  CAS  PubMed  Google Scholar 

  138. Rizvi H, Sanchez-Vega F, La K, Chatila W, Jonsson P, Halpenny D, et al. Molecular determinants of response to anti–programmed cell death (PD)-1 and anti–programmed death-ligand 1 (PD-L1) blockade in patients with non–small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol. 2018;36:633–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J, et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science. 2018;362:eaar3593.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl J Med. 2016;375:819–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Sade-Feldman M, Jiao YJ, Chen JH, Rooney MS, Barzily-Rokni M, Eliane JP, et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat Commun. 2017;8:1136.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Gurjao C, Liu D, Hofree M, AlDubayan SH, Wakiro I, Su M-J, et al. Intrinsic resistance to immune checkpoint blockade in a mismatch repair–deficient colorectal cancer. Cancer Immunol Res. 2019;7:1230–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Johnson DB, Estrada VM, Salgado R, Sanchez V, Doxie DB, Opalenik SR, et al. Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy. Nat Commun. 2016;7:10582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Rodig SJ, Gusenleitner D, Jackson DG, Gjini E, Giobbie-Hurder A, Jin C, et al. MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. Sci Transl Med. 2018;10:eaar3342.

    Article  PubMed  Google Scholar 

  145. Liu D, Schilling B, Liu D, Sucker A, Livingstone E, Jerby-Arnon L, et al. Integrative molecular and clinical modeling of clinical outcomes to PD-1 blockade in patients with metastatic melanoma. Nat Med. 2019;25:1916–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Gettinger S, Choi J, Hastings K, Truini A, Datar I, Sowell R, et al. Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Disco. 2017;7:1420–35.

    Article  CAS  Google Scholar 

  147. Jorgovanovic D, Song M, Wang L, Zhang Y. Roles of IFN-γ in tumor progression and regression: a review. Biomark Res. 2020;8:1–16.

    Article  Google Scholar 

  148. Chen PL, Roh W, Reuben A, Cooper ZA, Spencer CN, Prieto PA, et al. Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Disco. 2016;6:827–37.

    Article  Google Scholar 

  149. Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127:2930–40.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Higgs BW, Morehouse CA, Streicher K, Brohawn PZ, Pilataxi F, Gupta A, et al. Interferon gamma messenger RNA-signature in tumor biopsies predicts outcomes in patients with non–small cell lung carcinoma or urothelial cancer treated with durvalumab. Clin Cancer Res. 2018;24:3857–66.

    Article  CAS  PubMed  Google Scholar 

  151. Gide TN, Wilmott JS, Scolyer RA, Long VG. Primary and acquired resistance to immune checkpoint inhibitors in metastatic melanoma. Clin Cancer Res. 2018;24:1260–70.

    Article  CAS  PubMed  Google Scholar 

  152. Shin DS, Zaretsky JM, Escuin-Ordinas H, Garcia-Diaz A, Hu-Lieskovan S, Kalbasi A, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Disco. 2017;7:188–201.

    Article  CAS  Google Scholar 

  153. Gao J, Shi LZ, Zhao H, Chen J, Xiong L, He Q, et al. Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell. 2016;167:397–404.e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJM, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Lopez de Rodas M, Nagineni V, Ravi A, Datar IJ, Mino-Kenudson M, Corredor G, et al. Role of tumor infiltrating lymphocytes and spatial immune heterogeneity in sensitivity to PD-1 axis blockers in non-small cell lung cancer. J Immunother Cancer. 2022;10:e004440.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, Gainor JF, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Disco. 2018;8:822–35.

    Article  CAS  Google Scholar 

  157. Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, et al. Loss of PTEN promotes resistance to T cell–mediated immunotherapy. Cancer Disco. 2016;6:202–16.

    Article  CAS  Google Scholar 

  158. George S, Miao D, Demetri GD, Adeegbe D, Rodig SJ, Shukla S, et al. Loss of PTEN is associated with resistance to anti-PD-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma. Immunity. 2017;46:197–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Kakavand H, Jackett LA, Menzies AM, Gide TN, Carlino MS, Saw RPM, et al. Negative immune checkpoint regulation by VISTA: A mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients. Mod Pathol. 2017;30:1666–76.

    Article  CAS  PubMed  Google Scholar 

  160. Ott PA, Stephen Hodi F, Buchbinder EI. Inhibition of immune checkpoints and vascular endothelial growth factor as combination therapy for metastatic melanoma: An overview of rationale, preclinical evidence, and initial clinical data. Front Oncol. 2015;5:1–7.

    Article  Google Scholar 

  161. Hodi FS, Lawrence D, Lezcano C, Wu X, Zhou J, Sasada T, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res. 2014;2:632–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016;7:1–8.

    Article  Google Scholar 

  163. Zhou J, Mahoney KM, Giobbie-Hurder A, Zhao F, Lee S, Liao X, et al. Soluble PD-L1 as a biomarker in malignant melanoma treated with checkpoint blockade. Cancer Immunol Res. 2017;5:480–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Oh SY, Kim S, Keam B, Kim TM, Kim DW, Heo DS. Soluble PD-L1 is a predictive and prognostic biomarker in advanced cancer patients who receive immune checkpoint blockade treatment. Sci Rep. 2021;11:19712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Mahoney KM, Ross-Macdonald P, Yuan L, Song L, Veras E, Wind-Rotolo M, et al. Soluble PD-L1 as an early marker of progressive disease on nivolumab. J Immunother Cancer. 2022;10:e003527.

    Article  PubMed  PubMed Central  Google Scholar 

  166. Gong B, Kiyotani K, Sakata S, Nagano S, Kumehara S, Baba S, et al. Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non–small cell lung cancer. J Exp Med. 2019;216:982–1000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Sagawa R, Sakata S, Gong B, Seto Y, Takemoto A, Takagi S, et al. Soluble PD-L1 works as a decoy in lung cancer immunotherapy via alternative polyadenylation. JCI Insight. 2022;7:e153323.

    Article  PubMed  PubMed Central  Google Scholar 

  168. Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018;560:382–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Del ReM, Marconcini R, Pasquini G, Rofi E, Vivaldi C, Bloise F, et al. PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC. Br J Cancer. 2018;118:820–4.

    Article  Google Scholar 

  170. Cordonnier M, Nardin C, Chanteloup G, Derangere V, Algros MP, Arnould L, et al. Tracking the evolution of circulating exosomal-PD-L1 to monitor melanoma patients. J Extracell Vesicles. 2020;9:1–11.

    Article  Google Scholar 

  171. Zhang C, Fan Y, Che X, Zhang M, Li Z, Li C, et al. Anti-PD-1 therapy response predicted by the combination of exosomal PD-L1 and CD28. Front Oncol. 2020;10:760.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell. 2016;165:35–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Reinhardt J, Landsberg J, Schmid-Burgk JL, Ramis BB, Bald T, Glodde N, et al. MAPK signaling and inflammation link melanoma phenotype switching to induction of CD73 during immunotherapy. Cancer Res. 2017;77:4697–709.

    Article  CAS  PubMed  Google Scholar 

  174. Wang L, Saci A, Szabo PM, Chasalow SD, Castillo-Martin M, Domingo-Domenech J, et al. EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer. Nat Commun. 2018;9:3503.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Lee JH, Shklovskaya E, Lim SY, Carlino MS, Menzies AM, Stewart A, et al. Transcriptional downregulation of MHC class I and melanoma de-differentiation in resistance to PD-1 inhibition. Nat Commun. 2020;11:1897.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Bagaev A, Kotlov N, Nomie K, Svekolkin V, Gafurov A, Isaeva O, et al. Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell. 2021;39:845–65.e7.

    Article  CAS  PubMed  Google Scholar 

  177. Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554:544–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Jiang P, Gu S, Pan D, Fu J, Sahu A, Hu X, et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med. 2018;24:1550–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Highfill SL, Cui Y, Giles AJ, Smith JP, Zhang H, Morse E, et al. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD-1 efficacy. Sci Transl Med. 2014;6:237ra67.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74:5057–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. John P, Pulanco MC, Galbo PM Jr, Wei Y, Ohaegbulam KC, Zheng D, et al. The immune checkpoint B7x expands tumor-infiltrating Tregs and promotes resistance to anti-CTLA-4 therapy. Nat Commun. 2022;13:2506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Hamid O, Schmidt H, Nissan A, Ridolfi L, Aamdal S, Hansson J, et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med. 2011;9:204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Ribas A, Shin DS, Zaretsky J, Frederiksen J, Cornish A, Avramis E, et al. PD-1 blockade expands intratumoral memory T cells. Cancer Immunol Res. 2016;4:194–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Daud AI, Loo K, Pauli ML, Sanchez-Rodriguez R, Sandoval PM, Taravati K, et al. Tumor immune profiling predicts response to anti–PD-1 therapy in human melanoma. J Clin Invest. 2016;126:3447–52.

    Article  PubMed  PubMed Central  Google Scholar 

  185. Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013;31:4311–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Simeone E, Gentilcore G, Giannarelli D, Grimaldi AM, Caracò C, Curvietto M, et al. Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol Immunother. 2014;63:675–83.

    Article  CAS  PubMed  Google Scholar 

  187. Martens A, Wistuba-Hamprecht K, Foppen MG, Yuan J, Postow MA, Wong P, et al. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res. 2016;22:2908–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Meyer C, Cagnon L, Costa-Nunes CM, Baumgaertner P, Montandon N, Leyvraz L, et al. Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol Immunother. 2014;63:247–57.

    Article  CAS  PubMed  Google Scholar 

  189. Gebhardt C, Sevko A, Jiang H, Lichtenberger R, Reith M, Tarnanidis K, et al. Myeloid cells and related chronic inflammatory factors as novel predictive markers in melanoma treatment with ipilimumab. Clin Cancer Res. 2015;21:5453–9.

    Article  CAS  PubMed  Google Scholar 

  190. Sade-Feldman M, Kanterman J, Klieger Y, Ish-Shalom E, Olga M, Saragovi A, et al. Clinical significance of circulating CD33+ CD11b+ HLA-DR- myeloid cells in patients with stage IV melanoma treated with ipilimumab. Clin Cancer Res. 2016;22:5661–72.

    Article  CAS  PubMed  Google Scholar 

  191. Li L, Lu G, Liu Y, Gong L, Zheng X, Zheng H, et al. Low infiltration of CD8 PD-L1+ T cells and M2 macrophages predicts improved clinical outcomes after immune checkpoint inhibitor therapy in non-small cell lung carcinoma. Front Oncol. 2021;11:658690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Toulmonde M, Penel N, Adam J, Chevreau C, Blay JY, Le Cesne A, et al. Use of PD-1 targeting, macrophage infiltration, and IDO pathway activation in sarcomas a phase 2 clinical trial. JAMA Oncol. 2018;4:93–7.

    Article  PubMed  Google Scholar 

  193. McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol. 2015;37:457–95.

    Article  Google Scholar 

  194. Thommen DS, Schreiner J, Müller P, Herzig P, Roller A, Belousov A, et al. Progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors. Cancer Immunol Res. 2015;3:1344–54.

    Article  CAS  PubMed  Google Scholar 

  195. Shayan G, Srivastava R, Li J, Schmitt N, Kane LP, Ferris RL. Adaptive resistance to anti-PD-1 therapy by TIM-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer. Oncoimmunology. 2017;6:e1261779.

    Article  PubMed  Google Scholar 

  196. Gao J, Ward JF, Pettaway CA, Shi LZ, Subudhi SK, Vence LM, et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med. 2017;23:551–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Datar I, Sanmamed MF, Wang J, Henick BS, Choi J, Badri T, et al. Expression analysis and significance of PD-1, LAG-3, and TIM-3 in human non–small cell lung cancer using spatially resolved and multiparametric single-cell analysis. Clin Cancer Res. 2019;25:4663–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016;7:1–9.

    Article  Google Scholar 

  199. Caushi JX, Zhang J, Ji Z, Vaghasia A, Zhang B, Hsiue EHC, et al. Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers. Nature. 2021;596:126–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91–7.

    Article  CAS  PubMed  Google Scholar 

  201. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets VT, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359:97–103.

    Article  CAS  PubMed  Google Scholar 

  202. Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 2017;28:1368–79.

    Article  CAS  PubMed  Google Scholar 

  203. Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, Rizvi H, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol. 2018;29:1437–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359:104–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Li X, Zhang S, Guo G, Han J, Yu J. Gut microbiome in modulating immune checkpoint inhibitors. EBioMedicine. 2022;82:104163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Xiong D, Wang Y, You M. A gene expression signature of TREM2hi macrophages and γδ T cells predicts immunotherapy response. Nat Commun. 2020;11:1–12.

    Article  Google Scholar 

  207. Du K, Wei S, Wei Z, Frederick DT, Miao B, Moll T, et al. Pathway signatures derived from on-treatment tumor specimens predict response to anti-PD-1 blockade in metastatic melanoma. Nat Commun. 2021;12:1–16.

    Article  Google Scholar 

  208. Riaz N, Havel JJ, Makarov V, Desrichard A, Urba WJ, Sims JS, et al. Tumor and microenvironment evolution during immunotherapy with Nivolumab. Cell. 2017;171:934–49.e15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Ock CY, Hwang JE, Keam B, Kim SB, Shim JJ, Jang HJ, et al. Genomic landscape associated with potential response to anti-CTLA-4 treatment in cancers. Nat Commun. 2017;8:1–12.

    Article  CAS  Google Scholar 

  210. Roh W, Chen PL, Reuben A, Spencer CN, Prieto PA, Miller JP, et al. Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci Transl Med. 2017;9:eaah3560.

    Article  PubMed  PubMed Central  Google Scholar 

  211. Jerby-Arnon L, Shah P, Cuoco MS, Rodman C, Su MJ, Melms JC, et al. A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell. 2018;175:984–97.e24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Auslander N, Zhang G, Lee JS, Frederick DT, Miao B, Moll T, et al. Robust prediction of response to immune checkpoint blockade therapy in metastatic melanoma. Nat Med. 2018;24:1545–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Carter JA, Gilbo P, Atwal GS. IMPRES does not reproducibly predict response to immune checkpoint blockade therapy in metastatic melanoma. Nat Med. 2019;25:1833–5.

    Article  CAS  PubMed  Google Scholar 

  214. Xiao X, Xu C, Yang W, Yu R. Inconsistent prediction capability of ImmuneCells.Sig across different RNA-seq datasets. Nat Commun. 2021;12:4167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Loo D, Alderson RF, Chen FZ, Huang L, Zhang W, Gorlatov S, et al. Development of an Fc-enhanced anti–B7-H3 monoclonal antibody with potent antitumor activity. Clin Cancer Res. 2012;18:3834–45.

    Article  CAS  PubMed  Google Scholar 

  216. Powderly J, Cote G, Flaherty K, Szmulewitz RZ, Ribas A, Weber J, et al. Interim results of an ongoing Phase I, dose escalation study of MGA271 (Fc-optimized humanized anti-B7-H3 monoclonal antibody) in patients with refractory B7-H3-expressing neoplasms or neoplasms whose vasculature expresses B7-H3. J Immunother Cancer. 2015;3:O8.

    Article  PubMed Central  Google Scholar 

  217. Shenderov E, Marzo AMD, Lotan TL, Wang H, Lim SJ, Allaf ME, et al. Targeting B7-H3 in prostate cancer: Phase 2 trial in localized prostate cancer using the anti-B7-H3 antibody enoblituzumab, with biomarker correlatives. J Clin Oncol. 2022;40:5015.

    Article  Google Scholar 

  218. Aggarwal C, Prawira A, Antonia S, Rahma O, Tolcher A, Cohen RB, et al. Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: Interim results from a multicenter phase I/II trial. J Immunother Cancer. 2022;10:e004424.

    Article  PubMed  PubMed Central  Google Scholar 

  219. Kramer K, Kushner BH, Modak S, Pandit-Taskar N, Tomlinson U, Wolden SL, et al. A curative approach to central nervous system metastases of neuroblastoma. J Clin Oncol. 2017;35:10545.

    Article  Google Scholar 

  220. Kramer K, Kushner BH, Modak S, Pandit-Taskar N, Smith-Jones P, Zanzonico P, et al. Compartmental intrathecal radioimmunotherapy: Results for treatment for metastatic CNS neuroblastoma. J Neurooncol. 2010;97:409–18.

    Article  PubMed  Google Scholar 

  221. Kramer K, Pandit-Taskar N, Zanzonico P, Wolden SL, Humm JL, DeSelm C, et al. Low incidence of radionecrosis in children treated with conventional radiation therapy and intrathecal radioimmunotherapy. J Neurooncol. 2015;123:245–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. De B, Kinnaman MD, Wexler LH, Kramer K, Wolden SL. Central nervous system relapse of rhabdomyosarcoma. Pediatr Blood Cancer. 2018;65. https://doi.org/10.1002/pbc.26710.

  223. Modak S, Zanzonico P, Grkovski M, Slotkin EK, Carrasquillo JA, Lyashchenko SK, et al. B7-H3-directed intraperitoneal radioimmunotherapy with radioiodinated omburtamab for desmoplastic small round cell tumor and other peritoneal tumors: Results of a phase I study. J Clin Oncol. 2020;38:4283–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Souweidane MM, Kramer K, Pandit-Taskar N, Haque S, Zanzonico P, Carrasquillo JA, et al. Phase 1 dose-escalation trial using convection-enhanced delivery of radiolabeled monoclonal antibody for diffuse intrinsic pontine glioma following external radiation therapy. J Clin Oncol. 2021;39:2010.

    Article  Google Scholar 

  225. Souweidane MM, Kramer K, Pandit-Taskar N, Zhou Z, Haque S, Zanzonico P, et al. Convection-enhanced delivery for diffuse intrinsic pontine glioma: A single-centre, dose-escalation, phase 1 trial. Lancet Oncol. 2018;19:1040–50.

    Article  PubMed  PubMed Central  Google Scholar 

  226. Patel MR, Johnson ML, Falchook GS, Doi T, Friedman CF, Piha-Paul SA, et al. DS-7300 (B7-H3 DXd-ADC) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): A subgroup analysis of a phase 1/2 multicenter study. J Clin Oncol. 2022;40:87.

    Article  Google Scholar 

  227. Jang S, Powderly JD, Spira AI, Bakkacha O, Loo D, Bohac GC, et al. Phase 1 dose escalation study of MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors. J Clin Oncol. 2021;39:2631.

    Article  Google Scholar 

  228. Shenderov E, Mallesara GHG, Wysocki PJ, Xu W, Ramlau R, Weickhardt AJ, et al. MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors: Preliminary results of phase I cohort expansion. Ann Oncol. 2021;32:S657–9.

    Article  Google Scholar 

  229. You G, Lee Y, Kang Y-W, Park HW, Park K, Kim H, et al. B7-H3 × 4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8 tumor-infiltrating lymphocytes. Sci Adv. 2021;7:eaax3160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Xu Y, Xiao Y, Luo C, Liu Q, Wei A, Yang Y, et al. Blocking PD-1/PD-L1 by an ADCC enhanced anti-B7-H3/PD-1 fusion protein engages immune activation and cytotoxicity. Int Immunopharmacol. 2020;84:106584.

    Article  CAS  PubMed  Google Scholar 

  231. Liu J, Yang S, Cao B, Zhou G, Zhang F, Wang Y, et al. Targeting B7-H3 via chimeric antigen receptor T cells and bispecific killer cell engagers augments antitumor response of cytotoxic lymphocytes. J Hematol Oncol. 2021;14:21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Feng Y, Xie K, Yin Y, Li B, Pi C, Xu X, et al. A novel anti-B7-H3 × anti-CD3 bispecific antibody with potent antitumor activity. Life. 2022;12:157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Vallera DA, Ferrone S, Kodal B, Hinderlie P, Bendzick L, Ettestad B, et al. NK cell-mediated targeting of various solid tumors using a B7-H3 tri-specific killer engager in vitro and in vivo. Cancers. 2020;12:2659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Tang X, Liu F, Liu Z, Cao Y, Zhang Z, Wang Y, et al. Bioactivity and safety of B7-H3-targeted chimeric antigen receptor T cells against anaplastic meningioma. Clin Transl Immunol. 2020;9:e1137.

    Article  CAS  Google Scholar 

  235. Tang X, Wang Y, Huang J, Zhang Z, Liu F, Xu J, et al. Administration of B7-H3 targeted chimeric antigen receptor-T cells induce regression of glioblastoma. Signal Transduct Target Ther. 2021;6:125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Hu G, Liang Y, Li G, Ding W. luo m. B7-H3 CAR-T therapy in relation to tumor growth in skin tumor. J Clin Oncol 2022;40:e21502-e.

    Article  Google Scholar 

  237. Pinto NR, Albert CM, Taylor M, Wilson A, Rawlings-Rhea S, Huang W, et al. STRIVE-02: A first-in-human phase 1 trial of systemic B7-H3 CAR T cells for children and young adults with relapsed/refractory solid tumors. J Clin Oncol. 2022;40:10011.

    Article  Google Scholar 

  238. Sachdev JC, Bauer TM, Chawla SP, Pant S, Patnaik A, Wainberg ZA, et al. Phase 1a/1b study of first-in-class B7-H4 antibody, FPA150, as monotherapy in patients with advanced solid tumors. J Clin Oncol. 2019;37:2529.

    Article  Google Scholar 

  239. Hellmann MD, Bivi N, Calderon B, Shimizu T, Delafontaine B, Liu ZT, et al. Safety and immunogenicity of LY3415244, a bispecific antibody against TIM-3 and PD-L1, in patients with advanced solid tumors. Clin Cancer Res. 2021;27:2773–81.

    Article  CAS  PubMed  Google Scholar 

  240. Guo Y, Liu B, Lv D, Cheng Y, Zhou T, Zhong Y, et al. Phase I/IIa study of PM8001, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with advanced tumors. J Clin Oncol. 2022;40:2512.

    Article  Google Scholar 

  241. Yap T, Wong D, Hu-Lieskovan S, Papadopoulos K, Morrow M, Grabowska U, et al. A first-in-human study of FS118, a tetravalent bispecific antibody targeting LAG-3 and PD-L1, in patients with advanced cancer and resistance to PD-L1 therapy. J Immunother Cancer. 2020;8:A240–A.

    Google Scholar 

  242. Gong J, Shen L, Hou J, Chen X, Yu Q, Zheng Y, et al. Safety results of Q-1802, a Claudin18.2/PD-L1 bsABs, in patients with relapsed or refractory solid tumors in a phase 1 study. J Clin Oncol. 2022;40:2568.

    Article  Google Scholar 

  243. Wang J, Sun Y, Chu Q, Duan J, Wan R, Wang Z, et al. Phase I study of IBI322 (anti-CD47/PD-L1 bispecific antibody) monotherapy therapy in patients with advanced solid tumors in China. Cancer Res. 2022;82:CT513.

    Article  Google Scholar 

  244. Sanborn RE, Bordoni RE, Fleming GF, Khasraw M, Hawthorne T, Thomas LJ, et al. A phase 1 dose-escalation study of a PD-L1 x CD27 bispecific antibody CDX-527 in patients with advanced malignancies. J Clin Oncol. 2021;39:2585.

    Article  Google Scholar 

  245. Prenen H, Kyi C, Van Lancker G, Patel SP, Mittag D, Weaver A, et al. Phase I dose escalation study of MCLA-145, a bispecific antibody targeting CD137 and PD-L1 in solid tumors. Ann Oncol. 2021;32:S1436.

    Article  Google Scholar 

  246. Garralda E, Geva R, Ben-Ami E, Maurice-Dror C, Calvo E, LoRusso P, et al. First-in-human phase I/IIa trial to evaluate the safety and initial clinical activity of DuoBody®-PD-L1×4–1BB (GEN1046) in patients with advanced solid tumors. J Immunother Cancer. 2020;8:A250–A1.

    Google Scholar 

  247. Xu R-H, Zhao H, Wei X-L, Zhang Y, Wang F, Wang Z, et al. Phase Ia dose escalation of IBI318, a first-in-class bispecific anti-PD-1/PD-L1, in patients with advanced tumors. J Clin Oncol. 2020;38:3062.

    Article  Google Scholar 

  248. Coward J, Frentzas S, Mislang A, Gao B, Lemech C, Jin X, et al. Efficacy and safety of AK112, an anti-PD-1/VEGF-A bispecific antibody, in patients with platinum-resistant/refractory epithelial ovarian cancer in a Phase 1 study. J Immunother Cancer. 2021;9:A457–A.

    Article  Google Scholar 

  249. Zhao Y, Fang W, Yang Y, Chen J, Zhuang L, Du Y, et al. A phase II study of AK112 (PD-1/VEGF bispecific) in combination with chemotherapy in patients with advanced non-small cell lung cancer. J Clin Oncol. 2022;40:9019.

    Article  Google Scholar 

  250. Wu X, Ji J, Lou H, Li Y, Feng M, Xu N, et al. Efficacy and safety of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, in previously treated recurrent or metastatic (R/M) cervical cancer: A multicenter, open-label, single-arm, phase II trial. Gynecologic Oncol. 2022;166:S47–S8.

    Article  Google Scholar 

  251. Wang J, Lou H, Cai H-B, Huang X, Li G, Wang L, et al. A study of AK104 (an anti-PD-1 and anti-CTLA-4 bispecific antibody) combined with standard therapy for the first-line treatment of persistent, recurrent, or metastatic cervical cancer (R/M CC). J Clin Oncol 2022;40:106.

    Article  Google Scholar 

  252. Millward M, Frentzas S, Gan HK, Prawira A, Tran B, Coward J, et al. Safety and antitumor activity of AK104, a bispecific antibody targeting PD-1 and CTLA-4, in patients with mesothelioma which is relapsed or refractory to standard therapies. Ann Oncol. 2020;31:S705–S6.

    Article  Google Scholar 

  253. Mai H, Lin S, Chen D, Chen X, Qu S, Lin Q, et al. A phase II study of AK104, a bispecific antibody targeting PD-1 and CTLA-4, in patients with metastatic nasopharyngeal carcinoma (NPC) who had progressed after two or more lines of chemotherapy. J Immunother Cancer. 2021;9:A466–A.

    Article  Google Scholar 

  254. Ji J, Shen L, Li Z, Xu N, Liu T, Chen Y, et al. AK104 (PD-1/CTLA-4 bispecific) combined with chemotherapy as first-line therapy for advanced gastric (G) or gastroesophageal junction (GEJ) cancer: Updated results from a phase Ib study. J Clin Oncol. 2021;39:232.

    Article  Google Scholar 

  255. Shum E, Reilley M, Najjar Y, Daud A, Thompson J, Baranda J, et al. Preliminary clinical experience with XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors. J Immunother Cancer. 2021;9:A553–A.

    Article  Google Scholar 

  256. Hickingbottom B, Clynes R, Desjarlais J, Li C, Ding Y. Preliminary safety and pharmacodynamic (PD) activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in a phase I dose escalation study of patients with selected advanced solid tumors. J Clin Oncol. 2020;38:e15001-e.

    Article  Google Scholar 

  257. Albiges L, Rodriguez LM, Kim S-W, Im S-A, Carcereny E, Rha SY, et al. Safety and clinical activity of MEDI5752, a PD-1/CTLA-4 bispecific checkpoint inhibitor, as monotherapy in patients (pts) with advanced renal cell carcinoma (RCC): Preliminary results from an FTIH trial. J Clin Oncol. 2022;40:107.

    Article  Google Scholar 

  258. Gong J, Shen L, Dong Z, Liu D, Xu J, Yang J, et al. Preliminary safety, tolerability and efficacy results of KN026 in combination with KN046 in patients with HER2 aberrated solid tumors. J Immunother Cancer. 2020;8:A485–A6.

    Google Scholar 

  259. Gong J, Dong Z, Liu D, Xu J, Yang J, Yang Y, et al. Preliminary safety, tolerability and efficacy results of KN026 (a HER2-targeted Bispecific Antibody) in combination with KN046 (an anti-PD-L1/CTLA-4 Bispecific Antibody) in patients (pts) with HER2 aberrated solid tumors. J Immunother Cancer. 2020;8:A207–A.

    Google Scholar 

  260. Xing B, Da X, Zhang Y, Ma Y. A phase II study combining KN046 (an anti-PD-L1/CTLA-4 bispecific antibody) and lenvatinib in the treatment for advanced unresectable or metastatic hepatocellular carcinoma (HCC): updated efficacy and safety results. J Clin Oncol. 2022;40:4115.

    Article  Google Scholar 

  261. Yachnin J, Ullenhag GJ, Carneiro A, Nielsen D, Rohrberg KS, Kvarnhammar AM, et al. A first-in-human phase I study in patients with advanced and/or refractory solid malignancies to evaluate the safety of ATOR-1015, a CTLA-4 x OX40 bispecific antibody. J Clin Oncol. 2020;38:3061.

    Article  Google Scholar 

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Funding

Research in the Zang lab is supported by NIH R01CA175495 and R01CA262132, the Department of Defense (PC210331 and BC190403), and the Price Family Foundation. M.C.P. is supported by NIH 5TL1TR002557. A.T.M. is supported by Scandinavia/Borge.

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  1. Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY, 10461, USA

    Marc C. Pulanco, Anne T. Madsen, Ankit Tanwar, Devin T. Corrigan & Xingxing Zang

  2. Department of Urology, Albert Einstein College of Medicine, New York, NY, 10461, USA

    Anne T. Madsen & Xingxing Zang

  3. Department of Oncology, Albert Einstein College of Medicine, New York, NY, 10461, USA

    Ankit Tanwar & Xingxing Zang

  4. Department of Medicine, Albert Einstein College of Medicine, New York, NY, 10461, USA

    Xingxing Zang

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Correspondence to Xingxing Zang.

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XZ is the scientific co-founder of NextPoint Therapeutics. The other authors declare no competing interests.

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Pulanco, M.C., Madsen, A.T., Tanwar, A. et al. Recent advancements in the B7/CD28 immune checkpoint families: new biology and clinical therapeutic strategies. Cell Mol Immunol 20, 694–713 (2023). https://doi.org/10.1038/s41423-023-01019-8

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