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CD4+ T cells in cancer

Abstract

Cancer immunology and immunotherapy are driving forces of research and development in oncology, mostly focusing on CD8+ T cells and the tumor microenvironment. Recent progress highlights the importance of CD4+ T cells, corresponding to the long-known fact that CD4+ T cells are central players and coordinators of innate and antigen-specific immune responses. Moreover, they have now been recognized as anti-tumor effector cells in their own right. Here we review the current status of CD4+ T cells in cancer, which hold great promise for improving knowledge and therapies in cancer.

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Fig. 1: Roles of CD4+ T cells in cancer: pro- and anti-tumor effects.
Fig. 2: CD4+ T cell functions in immunotherapy.

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References

  1. Ruterbusch, M., Pruner, K. B., Shehata, L. & Pepper, M. In vivo CD4+ T cell differentiation and function: revisiting the TH1/TH2 paradigm. Annu. Rev. Immunol. 38, 705–725 (2020).

    Article  CAS  PubMed  Google Scholar 

  2. Kiner, E. et al. Gut CD4+ T cell phenotypes are a continuum molded by microbes, not by TH archetypes. Nat. Immunol. 22, 216–228 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhou, L., Chong, M. M. & Littman, D. R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Greenberg, P. D., Cheever, M. A. & Fefer, A. Eradication of disseminated murine leukemia by chemoimmunotherapy with cyclophosphamide and adoptively transferred immune syngeneic Lyt-1+2 lymphocytes. J. Exp. Med. 154, 952–963 (1981).

    Article  CAS  PubMed  Google Scholar 

  5. Bos, R. & Sherman, L. A. CD4+ T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8+ T lymphocytes. Cancer Res. 70, 8368–8377 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Quezada, S. A. et al. Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J. Exp. Med. 207, 637–650 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Poncette, L., Chen, X., Lorenz, F. K. & Blankenstein, T. Effective NY-ESO-1-specific MHC II-restricted T cell receptors from antigen-negative hosts enhance tumor regression. J. Clin. Invest. 129, 324–335 (2019).

    Article  PubMed  Google Scholar 

  8. Corthay, A. et al. Primary antitumor immune response mediated by CD4+ T cells. Immunity 22, 371–383 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Ferris, S. T. et al. cDC1 prime and are licensed by CD4+ T cells to induce anti-tumour immunity. Nature 584, 624–629 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Schoenberger, S. P., Toes, R. E., van der Voort, E. I., Offringa, R. & Melief, C. J. T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 393, 480–483 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Sun, J. C. & Bevan, M. J. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300, 339–342 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Eickhoff, S. et al. Robust anti-viral immunity requires multiple distinct T cell–dendritic cell interactions. Cell 162, 1322–1337 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Soares, H. et al. A subset of dendritic cells induces CD4+ T cells to produce IFN-γ by an IL-12-independent but CD70-dependent mechanism in vivo. J. Exp. Med. 204, 1095–1106 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schulz, O. et al. CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal. Immunity 13, 453–462 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Agarwal, P. et al. Gene regulation and chromatin remodeling by IL-12 and type I IFN in programming for CD8 T cell effector function and memory. J. Immunol. 183, 1695–1704 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Victora, G. D. & Nussenzweig, M. C. Germinal centers. Annu. Rev. Immunol. 30, 429–457 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Münz, C. Latency and lytic replication in Epstein–Barr virus-associated oncogenesis. Nat. Rev. Microbiol. 17, 691–700 (2019).

    Article  PubMed  Google Scholar 

  18. Wong, Y., Meehan, M. T., Burrows, S. R., Doolan, D. L. & Miles, J. J. Estimating the global burden of Epstein–Barr virus-related cancers. J. Cancer Res. Clin. Oncol. 148, 31–46 (2022).

    Article  PubMed  Google Scholar 

  19. Kieser, A. & Sterz, K. R. The latent membrane protein 1 (LMP1). Curr. Top. Microbiol. Immunol. 391, 119–149 (2015).

    CAS  PubMed  Google Scholar 

  20. Choi, I. K. et al. Mechanism of EBV inducing anti-tumour immunity and its therapeutic use. Nature 590, 157–162 (2021).

    Article  CAS  PubMed  Google Scholar 

  21. Zhang, B. et al. Immune surveillance and therapy of lymphomas driven by Epstein–Barr virus protein LMP1 in a mouse model. Cell 148, 739–751 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. van Zyl, D. G. et al. Immunogenic particles with a broad antigenic spectrum stimulate cytolytic T cells and offer increased protection against EBV infection ex vivo and in mice. PLoS Pathog. 14, e1007464 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Posch, F. et al. Maturation of tertiary lymphoid structures and recurrence of stage II and III colorectal cancer. OncoImmunology 7, e1378844 (2018).

    Article  PubMed  Google Scholar 

  24. Gunderson, A. J. et al. Germinal center reactions in tertiary lymphoid structures associate with neoantigen burden, humoral immunity and long-term survivorship in pancreatic cancer. OncoImmunology 10, 1900635 (2021).

    Article  PubMed Central  Google Scholar 

  25. Noel, G. et al. Functional TH1-oriented T follicular helper cells that infiltrate human breast cancer promote effective adaptive immunity. J. Clin. Invest. 131, e139905 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sackstein, R., Schatton, T. & Barthel, S. R. T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy. Lab. Invest. 97, 669–697 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lanitis, E., Dangaj, D., Irving, M. & Coukos, G. Mechanisms regulating T-cell infiltration and activity in solid tumors. Ann. Oncol. 28, xii18–xii32 (2017).

    Article  CAS  PubMed  Google Scholar 

  28. Haabeth, O. A. W. et al. CD4+ T-cell-mediated rejection of MHC class II-positive tumor cells is dependent on antigen secretion and indirect presentation on host APCs. Cancer Res. 78, 4573–4585 (2018).

    Article  CAS  PubMed  Google Scholar 

  29. Seliger, B., Kloor, M. & Ferrone, S. HLA class II antigen-processing pathway in tumors: molecular defects and clinical relevance. OncoImmunology 6, e1171447 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Accolla, R. S., Ramia, E., Tedeschi, A. & Forlani, G. CIITA-driven MHC class II expressing tumor cells as antigen presenting cell performers: toward the construction of an optimal anti-tumor vaccine. Front. Immunol. 10, 1806 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Axelrod, M. L., Cook, R. S., Johnson, D. B. & Balko, J. M. Biological consequences of MHC-II expression by tumor cells in cancer. Clin. Cancer Res. 25, 2392–2402 (2019).

    Article  CAS  PubMed  Google Scholar 

  32. Oliveira, G. et al. Landscape of helper and regulatory antitumour CD4+ T cells in melanoma. Nature 605, 532–538 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Harle, G. et al. Macroautophagy in lymphatic endothelial cells inhibits T cell-mediated autoimmunity. J. Exp. Med. 218, e20201776 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jiang, W., Adler, L. N., Macmillan, H. & Mellins, E. D. Synergy between B cell receptor/antigen uptake and MHCII peptide editing relies on HLA-DO tuning. Sci. Rep. 9, 13877 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  35. McDaniel, J. R. et al. Identification of tumor-reactive B cells and systemic IgG in breast cancer based on clonal frequency in the sentinel lymph node. Cancer Immunol. Immunother. 67, 729–738 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Poncette, L., Bluhm, J. & Blankenstein, T. The role of CD4 T cells in rejection of solid tumors. Curr. Opin. Immunol. 74, 18–24 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Borst, J., Ahrends, T., Babala, N., Melief, C. J. M. & Kastenmuller, W. CD4+ T cell help in cancer immunology and immunotherapy. Nat. Rev. Immunol. 18, 635–647 (2018).

    Article  CAS  PubMed  Google Scholar 

  38. Richardson, J. R., Schollhorn, A., Gouttefangeas, C. & Schuhmacher, J. CD4+ T cells: multitasking cells in the duty of cancer immunotherapy. Cancers 13, 596 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ni, J. et al. Adoptively transferred natural killer cells maintain long-term antitumor activity by epigenetic imprinting and CD4+ T cell help. OncoImmunology 5, e1219009 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Horowitz, A., Behrens, R. H., Okell, L., Fooks, A. R. & Riley, E. M. NK cells as effectors of acquired immune responses: effector CD4+ T cell-dependent activation of NK cells following vaccination. J. Immunol. 185, 2808–2818 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Huntington, N. D., Cursons, J. & Rautela, J. The cancer–natural killer cell immunity cycle. Nat. Rev. Cancer 20, 437–454 (2020).

    Article  CAS  PubMed  Google Scholar 

  42. Ruggeri, L. et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295, 2097–2100 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Wang, Z., Chimenti, M. S., Strouse, C. & Weiner, G. J. T cells, particularly activated CD4+ cells, maintain anti-CD20-mediated NK cell viability and antibody dependent cellular cytotoxicity. Cancer Immunol. Immunother. 71, 237–249 (2021).

  44. Bogen, B., Fauskanger, M., Haabeth, O. A. & Tveita, A. CD4+ T cells indirectly kill tumor cells via induction of cytotoxic macrophages in mouse models. Cancer Immunol. Immunother. 68, 1865–1873 (2019).

    Article  CAS  PubMed  Google Scholar 

  45. Corthay, A., Lundin, K. U., Lorvik, K. B., Hofgaard, P. O. & Bogen, B. Secretion of tumor-specific antigen by myeloma cells is required for cancer immunosurveillance by CD4+ T cells. Cancer Res. 69, 5901–5907 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Ahrends, T. et al. CD4+ T cell help confers a cytotoxic T cell effector program including coinhibitory receptor downregulation and increased tissue invasiveness. Immunity 47, 848–861 (2017).

    Article  CAS  PubMed  Google Scholar 

  47. Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer–immune set point. Nature 541, 321–330 (2017).

    Article  CAS  PubMed  Google Scholar 

  48. Williams, M. A., Tyznik, A. J. & Bevan, M. J. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature 441, 890–893 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zander, R. et al. CD4+ T cell help is required for the formation of a cytolytic CD8+ T cell subset that protects against chronic infection and cancer. Immunity 51, 1028–1042 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Oh, S. et al. IL-15 as a mediator of CD4+ help for CD8+ T cell longevity and avoidance of TRAIL-mediated apoptosis. Proc. Natl Acad. Sci. USA 105, 5201–5206 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mumberg, D. et al. CD4+ T cells eliminate MHC class II-negative cancer cells in vivo by indirect effects of IFN-γ. Proc. Natl Acad. Sci. USA 96, 8633–8638 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hoekstra, M. E. et al. Long-distance modulation of bystander tumor cells by CD8+ T cell-secreted IFNγ. Nat Cancer 1, 291–301 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Huse, M., Lillemeier, B. F., Kuhns, M. S., Chen, D. S. & Davis, M. M. T cells use two directionally distinct pathways for cytokine secretion. Nat. Immunol. 7, 247–255 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Müller, A. J. et al. CD4+ T cells rely on a cytokine gradient to control intracellular pathogens beyond sites of antigen presentation. Immunity 37, 147–157 (2012).

    Article  PubMed  Google Scholar 

  55. Boulch, M. et al. A cross-talk between CAR T cell subsets and the tumor microenvironment is essential for sustained cytotoxic activity. Sci. Immunol. 6, eabd4344 (2021).

    Article  CAS  PubMed  Google Scholar 

  56. Tate, D. J. Jr. et al. Interferon-γ-induced nitric oxide inhibits the proliferation of murine renal cell carcinoma cells. Int. J. Biol. Sci. 8, 1109–1120 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Rakshit, S. et al. Interferon-γ induced cell death: regulation and contributions of nitric oxide, cJun N-terminal kinase, reactive oxygen species and peroxynitrite. Biochim. Biophys. Acta 1843, 2645–2661 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Gocher, A. M., Workman, C. J. & Vignali, D. A. A. Interferon-γ: teammate or opponent in the tumour microenvironment? Nat. Rev. Immunol. 22, 158–172 (2022).

    Article  CAS  PubMed  Google Scholar 

  59. Freeman, A. J. et al. HOIP limits anti-tumor immunity by protecting against combined TNF and IFN-γ-induced apoptosis. EMBO Rep. 22, e53391 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Neubert, N. J. et al. Broad and conserved immune regulation by genetically heterogeneous melanoma cells. Cancer Res. 77, 1623–1636 (2017).

    Article  CAS  PubMed  Google Scholar 

  61. Brenner, E. et al. Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours. Nat. Commun. 11, 1335 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Deng, J. et al. IFNγ-responsiveness of endothelial cells leads to efficient angiostasis in tumours involving down-regulation of Dll4. J. Pathol. 233, 170–182 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Kammertoens, T. et al. Tumour ischaemia by interferon-γ resembles physiological blood vessel regression. Nature 545, 98–102 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Muller-Hermelink, N. et al. TNFR1 signaling and IFN-γ signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell 13, 507–518 (2008).

    Article  PubMed  Google Scholar 

  65. Kataru, R. P. et al. T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity 34, 96–107 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. Tian, L. et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544, 250–254 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Asrir, A. et al. Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy. Cancer Cell 40, 318–334 (2022).

    Article  CAS  PubMed  Google Scholar 

  68. Kerdidani, D. et al. Lung tumor MHCII immunity depends on in situ antigen presentation by fibroblasts. J. Exp. Med. 219, e20210815 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102–1123 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Xie, Y. et al. Naive tumor-specific CD4+ T cells differentiated in vivo eradicate established melanoma. J. Exp. Med. 207, 651–667 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Cachot, A. et al. Tumor-specific cytolytic CD4 T cells mediate immunity against human cancer. Sci. Adv. 7, eabe3348 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Heller, K. N., Gurer, C. & Münz, C. Virus-specific CD4+ T cells: ready for direct attack. J. Exp. Med. 203, 805–808 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Takeuchi, A. & Saito, T. CD4 CTL, a cytotoxic subset of CD4+ T cells, their differentiation and function. Front. Immunol. 8, 194 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Donnarumma, T. et al. Opposing development of cytotoxic and follicular helper CD4 T cells controlled by the TCF-1–Bcl6 nexus. Cell Rep. 17, 1571–1583 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Alspach, E. et al. MHC-II neoantigens shape tumour immunity and response to immunotherapy. Nature 574, 696–701 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Sledzinska, A. et al. Regulatory T cells restrain interleukin-2- and Blimp-1-dependent acquisition of cytotoxic function by CD4+ T cells. Immunity 52, 151–166 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hirschhorn-Cymerman, D. et al. Induction of tumoricidal function in CD4+ T cells is associated with concomitant memory and terminally differentiated phenotype. J. Exp. Med. 209, 2113–2126 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kitano, S. et al. Enhancement of tumor-reactive cytotoxic CD4+ T cell responses after ipilimumab treatment in four advanced melanoma patients. Cancer Immunol. Res. 1, 235–244 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Mucida, D. et al. Transcriptional reprogramming of mature CD4+ helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes. Nat. Immunol. 14, 281–289 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Takeuchi, A. et al. CRTAM determines the CD4+ cytotoxic T lymphocyte lineage. J. Exp. Med. 213, 123–138 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Oh, D. Y. & Fong, L. Cytotoxic CD4+ T cells in cancer: expanding the immune effector toolbox. Immunity 54, 2701–2711 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Oh, D. Y. et al. Intratumoral CD4+ T cells mediate anti-tumor cytotoxicity in human bladder cancer. Cell 181, 1612–1625 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhang, Z. et al. RNF2 ablation reprograms the tumor-immune microenvironment and stimulates durable NK and CD4+ T-cell-dependent antitumor immunity. Nat. Cancer 2, 1018–1038 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wiedemann, A., Depoil, D., Faroudi, M. & Valitutti, S. Cytotoxic T lymphocytes kill multiple targets simultaneously via spatiotemporal uncoupling of lytic and stimulatory synapses. Proc. Natl Acad. Sci. USA 103, 10985–10990 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Breart, B., Lemaitre, F., Celli, S. & Bousso, P. Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice. J. Clin. Invest. 118, 1390–1397 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Weigelin, B. et al. Cytotoxic T cells are able to efficiently eliminate cancer cells by additive cytotoxicity. Nat. Commun. 12, 5217 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Obst, R., van Santen, H. M., Mathis, D. & Benoist, C. Antigen persistence is required throughout the expansion phase of a CD4+ T cell response. J. Exp. Med. 201, 1555–1565 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Helft, J. et al. Antigen-specific T–T interactions regulate CD4 T-cell expansion. Blood 112, 1249–1258 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Trefzer, A. et al. Dynamic adoption of anergy by antigen-exhausted CD4+ T cells. Cell Rep. 34, 108748 (2021).

    Article  CAS  PubMed  Google Scholar 

  92. Poppema, S., Potters, M., Visser, L. & van den Berg, A. M. Immune escape mechanisms in Hodgkin’s disease. Ann. Oncol. 9, S21–S24 (1998).

    Article  PubMed  Google Scholar 

  93. Aoki, T. et al. Single-cell profiling reveals the importance of CXCL13/CXCR5 axis biology in lymphocyte-rich classic Hodgkin lymphoma. Proc. Natl Acad. Sci. USA 118, e2105822118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Van de Velde, L.-A. et al. Neuroblastoma formation requires unconventional CD4 T cells and arginase-1-dependent myeloid cells. Cancer Res. 81, 5047–5059 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Sakaguchi, S. et al. Regulatory T cells and human disease. Annu. Rev. Immunol. 38, 541–566 (2020).

    Article  CAS  PubMed  Google Scholar 

  96. Kos, K. & de Visser, K. E. The multifaceted role of regulatory T cells in breast cancer. Annu. Rev. Cancer Biol. 5, 291–310 (2021).

    Article  PubMed  Google Scholar 

  97. Sugiyama, D. et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc. Natl Acad. Sci. USA 110, 17945–17950 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. De Simone, M. et al. Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells. Immunity 45, 1135–1147 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Saito, T. et al. Two FOXP3+CD4+ T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat. Med. 22, 679–684 (2016).

    Article  CAS  PubMed  Google Scholar 

  100. Núñez, N. G. et al. Tumor invasion in draining lymph nodes is associated with Treg accumulation in breast cancer patients. Nat. Commun. 11, 3272 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Malek, T. R. & Castro, I. Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity 33, 153–165 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Walker, L. S. & Sansom, D. M. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat. Rev. Immunol. 11, 852–863 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Zhang, Y. et al. Regulatory T-cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis. Cancer Discov. 10, 422–439 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Hughes, E. et al. Primary breast tumours but not lung metastases induce protective anti-tumour immune responses after Treg-depletion. Cancer Immunol. Immunother. 69, 2063–2073 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Halvorsen, E. C. et al. IL-33 increases ST2+ Tregs and promotes metastatic tumour growth in the lungs in an amphiregulin-dependent manner. OncoImmunology 8, e1527497 (2019).

    Article  CAS  PubMed  Google Scholar 

  108. Malchow, S. et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339, 1219–1224 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Alonso, R. et al. Induction of anergic or regulatory tumor-specific CD4+ T cells in the tumor-draining lymph node. Nat. Commun. 9, 2113 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Staveley-O’Carroll, K. et al. Induction of antigen-specific T cell anergy: an early event in the course of tumor progression. Proc. Natl Acad. Sci. USA 95, 1178–1183 (1998).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Kalekar, L. A. et al. CD4+ T cell anergy prevents autoimmunity and generates regulatory T cell precursors. Nat. Immunol. 17, 304–314 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Reticker-Flynn, N. E. et al. Lymph node colonization induces tumor-immune tolerance to promote distant metastasis. Cell 185, 1924–1942 (2022).

    Article  CAS  PubMed  Google Scholar 

  113. Ling, A. et al. The infiltration, and prognostic importance, of TH1 lymphocytes vary in molecular subgroups of colorectal cancer. J. Pathol. Clin. Res. 2, 21–31 (2016).

    Article  CAS  PubMed  Google Scholar 

  114. Laheurte, C. et al. Distinct prognostic value of circulating anti-telomerase CD4+ TH1 immunity and exhausted PD-1+/TIM-3+ T cells in lung cancer. Br. J. Cancer 121, 405–416 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Svennevig, J. L., Lunde, O. C., Holter, J. & Bjørgsvik, D. Lymphoid infiltration and prognosis in colorectal carcinoma. Br. J. Cancer 49, 375–377 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 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 

  117. Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Bruni, D., Angell, H. K. & Galon, J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat. Rev. Cancer 20, 662–680 (2020).

    Article  CAS  PubMed  Google Scholar 

  120. Jordanova, E. S. et al. Human leukocyte antigen class I, MHC class I chain-related molecule A, and CD8+/regulatory T-cell ratio: which variable determines survival of cervical cancer patients? Clin. Cancer Res. 14, 2028–2035 (2008).

    Article  CAS  PubMed  Google Scholar 

  121. Maier, B. et al. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature 580, 257–262 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Pfirschke, C. et al. Macrophage-targeted therapy unlocks antitumoral cross-talk between IFNγ-secreting lymphocytes and IL12-producing dendritic cells. Cancer Immunol. Res. 10, 40–55 (2022).

    Article  CAS  PubMed  Google Scholar 

  123. Cohen, M. et al. The interaction of CD4+ helper T cells with dendritic cells shapes the tumor microenvironment and immune checkpoint blockade response. Nat. Cancer 3, 303–317 (2022).

    Article  CAS  PubMed  Google Scholar 

  124. Dieu-Nosjean, M. C. et al. Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers. Immunol. Rev. 271, 260–275 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  126. Datar, I. 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. 25, 4663–4673 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kagamu, H. et al. CD4+ T-cell immunity in the peripheral blood correlates with response to anti-PD-1 therapy. Cancer Immunol. Res. 8, 334–344 (2020).

    Article  CAS  PubMed  Google Scholar 

  128. Martens, A. et al. Increases in absolute lymphocytes and circulating CD4+ and CD8+ T cells are associated with positive clinical outcome of melanoma patients treated with ipilimumab. Clin. Cancer Res. 22, 4848–4858 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Wei, S. C. et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170, 1120–1133 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Simpson, T. R. et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695–1710 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 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 

  132. 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 

  133. 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 

  134. Abelin, J. G. et al. Defining HLA-II ligand processing and binding rules with mass spectrometry enhances cancer epitope prediction. Immunity 51, 766–779 (2019).

    Article  CAS  PubMed  Google Scholar 

  135. Haabeth, O. A. et al. Idiotype-specific CD4+ T cells eradicate disseminated myeloma. Leukemia 30, 1216–1220 (2016).

    Article  CAS  PubMed  Google Scholar 

  136. Snell, L. M. et al. Dynamic CD4+ T cell heterogeneity defines subset-specific suppression and PD-L1-blockade-driven functional restoration in chronic infection. Nat. Immunol. 22, 1524–1537 (2021).

    Article  CAS  PubMed  Google Scholar 

  137. 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 

  138. 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 

  139. 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 

  140. 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 

  141. Satpathy, A. T. et al. Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion. Nat. Biotechnol. 37, 925–936 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 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 

  143. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Baumgaertner, P. et al. Vaccination of stage III/IV melanoma patients with long NY-ESO-1 peptide and CpG-B elicits robust CD8+ and CD4+ T-cell responses with multiple specificities including a novel DR7-restricted epitope. OncoImmunology 5, e1216290 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. van der Burg, S. H., Arens, R., Ossendorp, F., van Hall, T. & Melief, C. J. Vaccines for established cancer: overcoming the challenges posed by immune evasion. Nat. Rev. Cancer 16, 219–233 (2016).

    Article  PubMed  Google Scholar 

  146. Melssen, M. & Slingluff, C. L. Jr. Vaccines targeting helper T cells for cancer immunotherapy. Curr. Opin. Immunol. 47, 85–92 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Saillard, M., Cenerenti, M., Romero, P. & Jandus, C. Impact of immunotherapy on CD4 T cell phenotypes and function in cancer. Vaccines 9, 454 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Kenter, G. G. et al. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N. Engl. J. Med. 361, 1838–1847 (2009).

    Article  CAS  PubMed  Google Scholar 

  149. Sharma, A. et al. HER-2 pulsed dendritic cell vaccine can eliminate HER-2 expression and impact ductal carcinoma in situ. Cancer 118, 4354–4362 (2012).

    Article  CAS  PubMed  Google Scholar 

  150. Lowenfeld, L. et al. Dendritic cell vaccination enhances immune responses and induces regression of HER2pos DCIS independent of route: results of randomized selection design trial. Clin. Cancer Res. 23, 2961–2971 (2017).

    Article  CAS  PubMed  Google Scholar 

  151. Koski, G. K. et al. A novel dendritic cell-based immunization approach for the induction of durable TH1-polarized anti-HER-2/neu responses in women with early breast cancer. J. Immunother. 35, 54–65 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. van Poelgeest, M. I. et al. Vaccination against oncoproteins of HPV16 for noninvasive vulvar/vaginal lesions: lesion clearance is related to the strength of the T-cell response. Clin. Cancer Res. 22, 2342–2350 (2016).

    Article  PubMed  Google Scholar 

  153. 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 

  154. 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 

  155. Hu, Z. et al. Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma. Nat. Med. 27, 515–525 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Hunder, N. N. et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N. Engl. J. Med. 358, 2698–2703 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Veatch, J. R. et al. Tumor-infiltrating BRAFV600E-specific CD4+ T cells correlated with complete clinical response in melanoma. J. Clin. Invest. 128, 1563–1568 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Westin, J. R. et al. Efficacy and safety of CD19-directed CAR-T cell therapies in patients with relapsed/refractory aggressive B-cell lymphomas: observations from the JULIET, ZUMA-1, and TRANSCEND trials. Am. J. Hematol. 96, 1295–1312 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Garfall, A. L. et al. T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma. Blood Adv. 3, 2812–2815 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Abramson, J. S. et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 396, 839–852 (2020).

    Article  PubMed  Google Scholar 

  161. Cohen, A. D. et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J. Clin. Invest. 129, 2210–2221 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Nagarsheth, N. B. et al. TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat. Med. 27, 419–425 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Rapoport, A. P. et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat. Med. 21, 914–921 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 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 

  165. Ellyard, J. I., Simson, L. & Parish, C. R. TH2-mediated anti-tumour immunity: friend or foe? Tissue Antigens 70, 1–11 (2007).

    Article  CAS  PubMed  Google Scholar 

  166. Lorvik, K. B. et al. Adoptive transfer of tumor-specific TH2 cells eradicates tumors by triggering an in situ inflammatory immune response. Cancer Res. 76, 6864–6876 (2016).

    Article  CAS  PubMed  Google Scholar 

  167. Purwar, R. et al. Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat. Med. 18, 1248–1253 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Vegran, F. et al. The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH9 cells. Nat. Immunol. 15, 758–766 (2014).

    Article  CAS  PubMed  Google Scholar 

  169. Benchetrit, F. et al. Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood 99, 2114–2121 (2002).

    Article  CAS  PubMed  Google Scholar 

  170. Numasaki, M. et al. IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. J. Immunol. 175, 6177–6189 (2005).

    Article  CAS  PubMed  Google Scholar 

  171. Vitiello, G. A. & Miller, G. Targeting the interleukin-17 immune axis for cancer immunotherapy. J. Exp. Med. 217, e20190456 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Raffin, C., Vo, L. T. & Bluestone, J. A. Treg cell-based therapies: challenges and perspectives. Nat. Rev. Immunol. 20, 158–172 (2020).

    Article  CAS  PubMed  Google Scholar 

  173. Crotty, S. T follicular helper cell biology: a decade of discovery and diseases. Immunity 50, 1132–1148 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Jurtz, V. et al. NetMHCpan-4.0: improved peptide–MHC class I interaction predictions integrating eluted ligand and peptide binding affinity data. J. Immunol. 199, 3360–3368 (2017).

    Article  CAS  PubMed  Google Scholar 

  175. Schmidt, J. et al. Prediction of neo-epitope immunogenicity reveals TCR recognition determinants and provides insight into immunoediting. Cell Rep. Med. 2, 100194 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Galon, J. & Bruni, D. Tumor immunology and tumor evolution: intertwined histories. Immunity 52, 55–81 (2020).

    Article  CAS  PubMed  Google Scholar 

  177. Zhang, A. W. et al. Interfaces of malignant and immunologic clonal dynamics in ovarian cancer. Cell 173, 1755–1769 (2018).

    Article  CAS  PubMed  Google Scholar 

  178. Mohan, J. F. & Unanue, E. R. Unconventional recognition of peptides by T cells and the implications for autoimmunity. Nat. Rev. Immunol. 12, 721–728 (2012).

    Article  CAS  PubMed  Google Scholar 

  179. Luca, B. A. et al. Atlas of clinically distinct cell states and ecosystems across human solid tumors. Cell 184, 5482–5496 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to our colleagues for their dedicated collaboration and support. We apologize for not mentioning and citing numerous interesting studies due to space limitations. D.E.S. is supported by the Cancer Research Institute (USA), Ludwig Cancer Research (USA), the Wilhelm Sander Foundation (Germany) and grants from Swiss Cancer Research (3971-08-2016, 5246-02-2021) and the Swiss National Science Foundation (310030_179459). O.C. is supported by Cancer Research Switzerland (KFS-4371-02-2018, KFS-5292-02-2021), the CRPP ImmunoCure of the University of Zürich and HMZ ImmunoTargET of the University of Zürich. C.M. is supported by Cancer Research Switzerland (KFS-4962-02-2020), the Sobek Foundation, the Swiss Vaccine Research Institute, the Swiss MS Society (2021-09), Roche, Novartis, the Vontobel Foundation and the Swiss National Science Foundation (310030_204470/1, 310030L_197952/1 and CRSII5_180323).

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Speiser, D.E., Chijioke, O., Schaeuble, K. et al. CD4+ T cells in cancer. Nat Cancer 4, 317–329 (2023). https://doi.org/10.1038/s43018-023-00521-2

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