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A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance

Nature Immunology volume 23, pages 660–670 (2022)Cite this article

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Abstract

Ten years since the immune checkpoint inhibitor ipilimumab was approved for advanced melanoma, it is time to reflect on the lessons learned regarding modulation of the immune system to treat cancer and on novel approaches to further extend the efficacy of current and emerging immunotherapies. Here, we review the studies that led to our current understanding of the melanoma immune microenvironment in humans and the mechanistic work supporting these observations. We discuss how this information is guiding more precise analyses of the mechanisms of action of immune checkpoint blockade and novel immunotherapeutic approaches. Lastly, we review emerging evidence supporting the negative impact of melanoma metabolic adaptation on anti-tumor immunity and discuss how to counteract such mechanisms for more successful use of immunotherapy.

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Fig. 1: The immune microenvironment of melanoma.
Fig. 2: Main cellular targets of ICB in humans.
Fig. 3: Impact of melanoma metabolism on the immune microenvironment and response to ICB.

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References

  1. Jakob, J. A. et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 118, 4014–4023 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Cohen, B. E., Manga, P., Lin, K. & Elbuluk, N. Vitiligo and melanoma-associated vitiligo: understanding their similarities and differences. Am. J. Clin. Dermatol. 21, 669–680 (2020).

    Article  PubMed  Google Scholar 

  3. Clark, W. H. Jr, From, L., Bernardino, E. A. & Mihm, M. C. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res. 29, 705–727 (1969).

    PubMed  Google Scholar 

  4. Clark, W. H. Jr. et al. Model predicting survival in stage I melanoma based on tumor progression. J. Natl Cancer Inst. 81, 1893–1904 (1989).

    Article  PubMed  Google Scholar 

  5. Clemente, C. G. et al. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77, 1303–1310 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Azimi, F. et al. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J. Clin. Oncol. 30, 2678–2683 (2012).

    Article  PubMed  Google Scholar 

  7. Thomas, N. E. et al. Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study. J. Clin. Oncol. 31, 4252–4259 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Pauken, K. E., Torchia, J. A., Chaudhri, A., Sharpe, A. H. & Freeman, G. J. Emerging concepts in PD-1 checkpoint biology. Semin. Immunol. 52, 101480 (2021).

  12. Strome, S. E. et al. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 63, 6501–6505 (2003).

    CAS  PubMed  Google Scholar 

  13. Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl Acad. Sci. USA 99, 12293–12297 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 20, 1239–1251 (2019).

    Article  CAS  PubMed  Google Scholar 

  17. Ascierto, P. A. et al. Survival outcomes in patients with previously untreated BRAF wild-type advanced melanoma treated with nivolumab therapy: three-year follow-up of a randomized phase 3 trial. JAMA Oncol. 5, 187–194 (2019).

    Article  PubMed  Google Scholar 

  18. Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. Brahmer, J. R. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wolchok, J. D. et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. J. Clin. Oncol. 40, 127–137 (2021)

  21. Zappasodi, R., Wolchok, J. D. & Merghoub, T. Strategies for predicting response to checkpoint inhibitors. Curr. Hematol. Malig. Rep. 13, 383–395 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ruscetti, F. W., Morgan, D. A. & Gallo, R. C. Functional and morphologic characterization of human T cells continuously grown in vitro. J. Immunol. 119, 131–138 (1977).

    CAS  PubMed  Google Scholar 

  23. Kvistborg, P. et al. TIL therapy broadens the tumor-reactive CD8+ T cell compartment in melanoma patients. Oncoimmunology 1, 409–418 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Andersen, R. S. et al. Dissection of T-cell antigen specificity in human melanoma. Cancer Res. 72, 1642–1650 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Tran, E., Robbins, P. F. & Rosenberg, S. A. ‘Final common pathway’ of human cancer immunotherapy: targeting random somatic mutations. Nat. Immunol. 18, 255–262 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Van den Eynde, B. J. & van der Bruggen, P. T cell defined tumor antigens. Curr. Opin. Immunol. 9, 684–693 (1997).

    Article  PubMed  Google Scholar 

  28. Lennerz, V. et al. The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc. Natl Acad. Sci. USA 102, 16013–16018 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Oliveira, G. et al. Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma. Nature 596, 119–125 (2021).

    Article  CAS  PubMed  Google Scholar 

  30. Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).

    Article  CAS  PubMed  Google Scholar 

  32. Carreno, B. M. et al. Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348, 803–808 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Itzhaki, O. et al. Establishment and large-scale expansion of minimally cultured “young” tumor infiltrating lymphocytes for adoptive transfer therapy. J. Immunother. 34, 212–220 (2011).

    Article  PubMed  Google Scholar 

  34. Radvanyi, L. G. et al. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin. Cancer Res. 18, 6758–6770 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rosenberg, S. A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Goff, S. L. et al. Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J. Clin. Oncol. 34, 2389–2397 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Linnemann, C. et al. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat. Med. 21, 81–85 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Lu, Y. C. et al. Mutated PPP1R3B is recognized by T cells used to treat a melanoma patient who experienced a durable complete tumor regression. J. Immunol. 190, 6034–6042 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Prickett, T. D. et al. Durable complete response from metastatic melanoma after transfer of autologous T cells recognizing 10 mutated tumor antigens. Cancer Immunol. Res. 4, 669–678 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Robbins, P. F. et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 19, 747–752 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tran, E. et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 350, 1387–1390 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Krishna, S. et al. Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer. Science 370, 1328–1334 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gilbert, A. E. et al. Monitoring the systemic human memory B cell compartment of melanoma patients for anti-tumor IgG antibodies. PLoS ONE 6, e19330 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pfreundschuh, M. The genealogy of SEREX. Cancer Immun. 12, 7 (2012).

    PubMed  PubMed Central  Google Scholar 

  45. Sahin, U. et al. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc. Natl Acad. Sci. USA 92, 11810–11813 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Vijayasaradhi, S., Bouchard, B. & Houghton, A. N. The melanoma antigen gp75 is the human homologue of the mouse b (brown) locus gene product. J. Exp. Med. 171, 1375–1380 (1990).

    Article  CAS  PubMed  Google Scholar 

  47. Wang, R. F., Robbins, P. F., Kawakami, Y., Kang, X. Q. & Rosenberg, S. A. Identification of a gene encoding a melanoma tumor antigen recognized by HLA-A31-restricted tumor-infiltrating lymphocytes. J. Exp. Med. 181, 799–804 (1995).

    Article  CAS  PubMed  Google Scholar 

  48. Livingston, P. O. et al. Improved survival in stage III melanoma patients with GM2 antibodies: a randomized trial of adjuvant vaccination with GM2 ganglioside. J. Clin. Oncol. 12, 1036–1044 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Cipponi, A. et al. Neogenesis of lymphoid structures and antibody responses occur in human melanoma metastases. Cancer Res. 72, 3997–4007 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. Ladanyi, A. et al. Prognostic impact of B-cell density in cutaneous melanoma. Cancer Immunol. Immunother. 60, 1729–1738 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Sautes-Fridman, C., Petitprez, F., Calderaro, J. & Fridman, W. H. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat. Rev. Cancer 19, 307–325 (2019).

    Article  CAS  PubMed  Google Scholar 

  52. Liu, W., Peng, Y. & Tobin, D. J. A new 12-gene diagnostic biomarker signature of melanoma revealed by integrated microarray analysis. PeerJ 1, e49 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Mortarini, R. et al. Constitutive expression and costimulatory function of LIGHT/TNFSF14 on human melanoma cells and melanoma-derived microvesicles. Cancer Res. 65, 3428–3436 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Erdag, G. et al. Immunotype and immunohistologic characteristics of tumor-infiltrating immune cells are associated with clinical outcome in metastatic melanoma. Cancer Res. 72, 1070–1080 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Garg, K. et al. Tumor-associated B cells in cutaneous primary melanoma and improved clinical outcome. Hum. Pathol. 54, 157–164 (2016).

    Article  CAS  PubMed  Google Scholar 

  56. Martinez-Rodriguez, M., Thompson, A. K. & Monteagudo, C. A significant percentage of CD20-positive TILs correlates with poor prognosis in patients with primary cutaneous malignant melanoma. Histopathology 65, 726–728 (2014).

    Article  PubMed  Google Scholar 

  57. Eschweiler, S. et al. Intratumoral follicular regulatory T cells curtail anti-PD-1 treatment efficacy. Nat. Immunol. 22, 1052–1063 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Joshi, N. S. et al. Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses. Immunity 43, 579–590 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zlotnik, A., Burkhardt, A. M. & Homey, B. Homeostatic chemokine receptors and organ-specific metastasis. Nat. Rev. Immunol. 11, 597–606 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Crawford, A. et al. Molecular and transcriptional basis of CD4+ T cell dysfunction during chronic infection. Immunity 40, 289–302 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zappasodi, R. et al. Non-conventional inhibitory CD4+Foxp3–PD-1hi T cells as a biomarker of immune checkpoint blockade activity. Cancer Cell 33, 1017–1032 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Cabrita, R. et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577, 561–565 (2020).

    Article  CAS  PubMed  Google Scholar 

  63. Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577, 556–560 (2020).

    Article  CAS  PubMed  Google Scholar 

  65. Spranger, S. et al. Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci. Transl. Med. 5, 200ra116 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Taube, J. M. et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl. Med. 4, 127ra137 (2012).

    Article  CAS  Google Scholar 

  67. Zippelius, A. et al. Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res. 64, 2865–2873 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Ahmadzadeh, M. et al. FOXP3 expression accurately defines the population of intratumoral regulatory T cells that selectively accumulate in metastatic melanoma lesions. Blood 112, 4953–4960 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Viguier, M. et al. Foxp3 expressing CD4+CD25high regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J. Immunol. 173, 1444–1453 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Mukherji, B. et al. Clonal analysis of cytotoxic and regulatory T cell responses against human melanoma. J. Exp. Med. 169, 1961–1976 (1989).

    Article  CAS  PubMed  Google Scholar 

  71. Wang, H. Y., Peng, G., Guo, Z., Shevach, E. M. & Wang, R. F. Recognition of a new ARTC1 peptide ligand uniquely expressed in tumor cells by antigen-specific CD4+ regulatory T cells. J. Immunol. 174, 2661–2670 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Oliveira, G. et al. 655 Landscape of helper and regulatory CD4+ T cells in melanoma. J. Immunother. Cancer 9, A684 (2021).

    Article  Google Scholar 

  73. Enninga, E. A., Nevala, W. K., Holtan, S. G., Leontovich, A. A. & Markovic, S. N. Galectin-9 modulates immunity by promoting Th2/M2 differentiation and impacts survival in patients with metastatic melanoma. Melanoma Res. 26, 429–441 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lauerova, L. et al. Malignant melanoma associates with TH1/TH2 imbalance that coincides with disease progression and immunotherapy response. Neoplasma 49, 159–166 (2002).

    CAS  PubMed  Google Scholar 

  75. Nevala, W. K. et al. Evidence of systemic TH2-driven chronic inflammation in patients with metastatic melanoma. Clin. Cancer Res. 15, 1931–1939 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Klarquist, J. S. & Janssen, E. M. Melanoma-infiltrating dendritic cells: limitations and opportunities of mouse models. Oncoimmunology 1, 1584–1593 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Marzagalli, M., Ebelt, N. D. & Manuel, E. R. Unraveling the crosstalk between melanoma and immune cells in the tumor microenvironment. Semin Cancer Biol. 59, 236–250 (2019).

    Article  CAS  PubMed  Google Scholar 

  78. Pieniazek, M., Matkowski, R. & Donizy, P. Macrophages in skin melanoma-the key element in melanomagenesis. Oncol. Lett. 15, 5399–5404 (2018).

    PubMed  PubMed Central  Google Scholar 

  79. Tucci, M. et al. Immune system evasion as hallmark of melanoma progression: the role of dendritic cells. Front Oncol. 9, 1148 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. Spranger, S., Dai, D., Horton, B. & Gajewski, T. F. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31, 711–723 e714 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Böttcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Sun, X., Zhang, N., Yin, C., Zhu, B. & Li, X. Ultraviolet radiation and melanomagenesis: from mechanism to immunotherapy. Front Oncol. 10, 951 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Schwarz, A. et al. Langerhans cells are required for UVR-induced immunosuppression. J. Invest. Dermatol. 130, 1419–1427 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Wang, L., Jameson, S. C. & Hogquist, K. A. Epidermal Langerhans cells are not required for UV-induced immunosuppression. J. Immunol. 183, 5548–5553 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Nirschl, C. J. et al. IFNγ-dependent tissue-immune homeostasis is co-opted in the tumor microenvironment. Cell 170, 127–141.e115 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Khalil, D. N. et al. In situ vaccination with defined factors overcomes T cell exhaustion in distant tumors. J. Clin. Invest. 129, 3435–3447 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Esensten, J. H., Helou, Y. A., Chopra, G., Weiss, A. & Bluestone, J. A. CD28 costimulation: from mechanism to therapy. Immunity 44, 973–988 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).

    Article  CAS  PubMed  Google Scholar 

  90. Huang, A. C. et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat. Med. 25, 454–461 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Huang, A. C. et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545, 60–65 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kamphorst, A. O. et al. Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients. Proc. Natl Acad. Sci. USA 114, 4993–4998 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Curiel, T. J. et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat. Med. 9, 562–567 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Zappasodi, R., Merghoub, T. & Wolchok, J. D. Emerging concepts for immune checkpoint blockade-based combination therapies. Cancer Cell 33, 581–598 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Long, G. V. et al. Standard-dose pembrolizumab plus alternate-dose ipilimumab in advanced melanoma: KEYNOTE-029 cohort 1C, a phase 2 randomized study of two dosing schedules. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.Ccr-21-0793 (2021).

  96. Maruhashi, T., Sugiura, D., Okazaki, I. M. & Okazaki, T. LAG-3: from molecular functions to clinical applications. J. Immunother. Cancer 8, e001014 (2020).

  97. Tawbi, H. A. et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N. Engl. J. Med. 386, 24–34 (2022).

    Article  CAS  PubMed  Google Scholar 

  98. Shen, R. et al. LAG-3 expression on peripheral blood cells identifies patients with poorer outcomes after immune checkpoint blockade. Sci. Transl. Med. 13, eabf5107 (2021).

    Article  CAS  PubMed  Google Scholar 

  99. Andrews, L. P. et al. Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding. Sci. Immunol. 5, eabc2728 (2020).

  100. Eggermont, A. M. et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N. Engl. J. Med. 375, 1845–1855 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Eggermont, A. M. M. et al. Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial. Eur. J. Cancer 119, 1–10 (2019).

    Article  CAS  PubMed  Google Scholar 

  102. Curti, B. D. & Faries, M. B. Recent advances in the treatment of melanoma. N. Engl. J. Med. 384, 2229–2240 (2021).

    Article  CAS  PubMed  Google Scholar 

  103. Eggermont, A. M. M. et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 22, 643–654 (2021).

    Article  CAS  PubMed  Google Scholar 

  104. Luke, J. J. Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: efficacy and safety results from the KEYNOTE-716 double-blind phase III trial. Ann. Oncol. 32, S1283–S1346 (2021).

    Article  Google Scholar 

  105. Amaria, R. N. et al. Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium. Lancet Oncol. 20, e378–e389 (2019).

    Article  PubMed  Google Scholar 

  106. Tarhini, A. A. et al. Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS ONE 9, e87705 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Amaria, R. N. et al. Neoadjuvant and adjuvant nivolumab (nivo) with anti-LAG3 antibody relatlimab (rela) for patients (pts) with resectable clinical stage III melanoma. J. Clin. Oncol. 39, 9502–9502 (2021).

    Article  Google Scholar 

  108. Menzies, A. M. et al. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC). Nat. Med. 27, 301–309 (2021).

    Article  CAS  PubMed  Google Scholar 

  109. Rawson, R. V. et al. Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma. Ann. Oncol. 32, 766–777 (2021).

    Article  CAS  PubMed  Google Scholar 

  110. Rozeman, E. A. et al. Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma. Nat. Med. 27, 256–263 (2021).

    Article  CAS  PubMed  Google Scholar 

  111. Blank, C. U. et al. First safety and efficacy results of PRADO: a phase II study of personalized response-driven surgery and adjuvant therapy after neoadjuvant ipilimumab (IPI) and nivolumab (NIVO) in resectable stage III melanoma. J. Clin. Oncol. 38, 10002–10002 (2020).

    Article  Google Scholar 

  112. Moschos, S. J. et al. Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. J. Clin. Oncol. 24, 3164–3171 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Carthon, B. C. et al. Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin. Cancer Res. 16, 2861–2871 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ng Tang, D. et al. Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy. Cancer Immunol. Res. 1, 229–234 (2013).

    Article  PubMed  CAS  Google Scholar 

  115. Wei, S. C., Duffy, C. R. & Allison, J. P. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Disco. 8, 1069–1086 (2018).

    Article  Google Scholar 

  116. Arce Vargas, F. et al. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell 33, 649–663 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Romano, E. et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc. Natl Acad. Sci. USA 112, 6140–6145 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Sharma, A. et al. Anti-CTLA-4 immunotherapy does not deplete FOXP3+ regulatory T cells (Tregs) in human cancers. Clin. Cancer Res. 25, 1233–1238 (2019).

    Article  CAS  PubMed  Google Scholar 

  119. Kavanagh, B. et al. CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion. Blood 112, 1175–1183 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Selby, M. J. et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol. Res. 1, 32–42 (2013).

    Article  CAS  PubMed  Google Scholar 

  121. Wing, J. B., Ise, W., Kurosaki, T. & Sakaguchi, S. Regulatory T cells control antigen-specific expansion of TFH cell number and humoral immune responses via the coreceptor CTLA-4. Immunity 41, 1013–1025 (2014).

    Article  CAS  PubMed  Google Scholar 

  122. Zappasodi, R. et al. CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours. Nature 591, 652–658 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Korman, A. J. et al. Abstract SY09-01: next-generation anti-CTLA-4 antibodies. Cancer Res. 77, SY09-01 (2017).

    Article  Google Scholar 

  124. Hashimoto, M. et al. CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions. Annu Rev. Med 69, 301–318 (2018).

    Article  CAS  PubMed  Google Scholar 

  125. Valpione, S. et al. Immune-awakening revealed by peripheral T cell dynamics after one cycle of immunotherapy. Nat. Cancer 1, 210–221 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Kamada, T. et al. PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc. Natl Acad. Sci. USA 116, 9999–10008 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kumagai, S. et al. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat. Immunol. 21, 1346–1358 (2020).

    Article  CAS  PubMed  Google Scholar 

  128. Sage, P. T., Paterson, A. M., Lovitch, S. B. & Sharpe, A. H. The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity 41, 1026–1039 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. van der Leun, A. M., Thommen, D. S. & Schumacher, T. N. CD8+ T cell states in human cancer: insights from single-cell analysis. Nat. Rev. Cancer 20, 218–232 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Li, H. et al. Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma. Cell 176, 775–789 (2019).

    Article  CAS  PubMed  Google Scholar 

  131. Falck Miniotis, M. et al. MEK1/2 inhibition decreases lactate in BRAF-driven human cancer cells. Cancer Res. 73, 4039 (2013).

    Article  CAS  PubMed  Google Scholar 

  132. Hall, A. et al. Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the V600EBRAF oncogene. Oncotarget 4, 584–599 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Haq, R. et al. Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. Cancer Cell 23, 302–315 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Cascone, T. et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 27, 977–987 e974 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Peng, W. et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6, 202–216 (2016).

    Article  CAS  PubMed  Google Scholar 

  136. Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24, 657–671 (2016).

    Article  CAS  PubMed  Google Scholar 

  137. Hugo, W. et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165, 35–44 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Fischer, G. M. et al. Molecular profiling reveals unique immune and metabolic features of melanoma brain metastases. Cancer Discov. 9, 628–645 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Jaiswal, A. R. et al. Melanoma evolves complete immunotherapy resistance through the acquisition of a hypermetabolic phenotype. Cancer Immunol. Res. 8, 1365–1380 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Najjar, Y. G. et al. Tumor cell oxidative metabolism as a barrier to PD-1 blockade immunotherapy in melanoma. JCI Insight 4, e124989 (2019).

  141. Kim, S. H. et al. Phenformin inhibits myeloid-derived suppressor cells and enhances the anti-tumor activity of PD-1 blockade in melanoma. J. Invest. Dermatol. 137, 1740–1748 (2017).

    Article  CAS  PubMed  Google Scholar 

  142. Afzal, M. Z., Mercado, R. R. & Shirai, K. Efficacy of metformin in combination with immune checkpoint inhibitors (anti-PD-1/anti-CTLA-4) in metastatic malignant melanoma. J. Immunother. Cancer 6, 64 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Scharping, N. E. et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat. Immunol. 22, 205–215 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Watson, M. J. et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 591, 645–651 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Wang, H. et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat. Immunol. 21, 298–308 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Brahmer, J. R. et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J. Immunother. Cancer 9, e002435 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Leko, V. & Rosenberg, S. A. Identifying and targeting human tumor antigens for T cell-based immunotherapy of solid tumors. Cancer Cell 38, 454–472 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Coulie, P. G., Van den Eynde, B. J., van der Bruggen, P. & Boon, T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat. Rev. Cancer 14, 135–146 (2014).

    Article  CAS  PubMed  Google Scholar 

  149. Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Turajlic, S. et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 18, 1009–1021 (2017).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank G. Linette, B. Carreno, R. Amaravadi, T. Mitchell, and J. D. Wolchok for their insightful feedback on this manuscript. A. C. H. is funded by grant K08 CA230157 from the NIH, the Doris Duke CSDA, Damon Runyon CIA, and funding from the Tara Miller Melanoma Foundation. R. Z. was supported by the Parker Institute for Cancer Immunotherapy Bridge Fellows Award. R. Z . acknowledges funding from the NCI SPORE (P50-CA192937).

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Alexander C. Huang

  2. Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Alexander C. Huang

  3. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    Alexander C. Huang

  4. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Alexander C. Huang

  5. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA

    Alexander C. Huang & Roberta Zappasodi

  6. Division of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    Roberta Zappasodi

  7. Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA

    Roberta Zappasodi

  8. Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Roberta Zappasodi

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  1. Alexander C. Huang
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Correspondence to Alexander C. Huang or Roberta Zappasodi.

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Competing interests

A. C. H. is a consultant for Immunai and receives research support from Bristol Myers Squibb. R. Z. is inventor on patent applications related to work on GITR, PD-1, and CTLA-4. R. Z. is a scientific advisory board member of iTEOS Therapeutics and receives grant support from AstraZeneca and Bristol Myers Squibb.

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Nature Immunology thanks the anonymous reviewer(s) for their contribution to the peer review of this work. Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Huang, A.C., Zappasodi, R. A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance. Nat Immunol 23, 660–670 (2022). https://doi.org/10.1038/s41590-022-01141-1

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