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  • Review Article
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CD4+ T cell help in cancer immunology and immunotherapy

Abstract

Cancer immunotherapy aims to promote the activity of cytotoxic T lymphocytes (CTLs) within a tumour, assist the priming of tumour-specific CTLs in lymphoid organs and establish efficient and durable antitumour immunity. During priming, help signals are relayed from CD4+ T cells to CD8+ T cells by specific dendritic cells to optimize the magnitude and quality of the CTL response. In this Review, we highlight the cellular dynamics and membrane receptors that mediate CD4+ T cell help and the molecular mechanisms of the enhanced antitumour activity of CTLs. We outline how deficient CD4+ T cell help reduces the response of CTLs and how maximizing CD4+ T cell help can improve outcomes in cancer immunotherapy strategies.

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Fig. 1: Models of the contribution of CD4+ T cell help and innate signals to DC functions and CD8+ T cell priming.
Fig. 2: Cellular interactions in the priming of CTLs.
Fig. 3: Key cell surface receptor–ligand interactions during the second step of T cell priming.
Fig. 4: Molecular mechanisms of CD4+ T cell help.
Fig. 5: CD4+ T cell help in cancer immunotherapy.

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References

  1. Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Spitzer, M. H. et al. Systemic immunity is required for effective cancer immunotherapy. Cell 168, 487–502 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kennedy, R. & Celis, E. Multiple roles for CD4+ T cells in anti-tumor immune responses. Immunol. Rev. 222, 129–144 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Bevan, M. J. Helping the CD8+ T cell response. Nat. Rev. Immunol. 4, 595–602 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Castellino, F. & Germain, R. N. Cooperation between CD4+ and CD8+ T cells: when, where, and how. Annu. Rev. Immunol. 24, 519–540 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Bedoui, S., Heath, W. R. & Mueller, S. N. CD4+ T cell help amplifies innate signals for primary CD8+ T cell immunity. Immunol. Rev. 272, 52–64 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. 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 

  9. Hor, J. L. et al. Spatiotemporally distinct interactions with dendritic cell subsets facilitates CD4+ and CD8+ T cell activation to localized viral infection. Immunity 43, 554–565 (2015). References 8 and 9 establish that lymph node-resident cDC1s are crucial for the transfer of help signals from CD4 + T cells to CD8 + T cells.

    Article  CAS  PubMed  Google Scholar 

  10. Kitano, M. et al. Imaging of the cross-presenting dendritic cell subsets in the skin-draining lymph node. Proc. Natl Acad. Sci. USA 113, 1044–1049 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Laidlaw, B. J., Craft, J. E. & Kaech, S. M. The multifaceted role of CD4+ T cells in CD8+ T cell memory. Nat. Rev. Immunol. 16, 102–111 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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). This study identifies multiple molecular mechanisms by which CD4 + T cell help increases CTL effectiveness in finding and eliminating their target cells.

    Article  CAS  PubMed  Google Scholar 

  13. Keene, J.-A. & Forman, J. Helper activity is required for the in vivo generation of cytotoxic T lymphocytes. J. Exp. Med. 155, 768–782 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mizuochi, T. et al. Both L3T4+ and Lyt-2+ helper T cells initiate cytotoxic T lymphocyte responses against allogenic major histocompatibility antigens but not against trinitrophenyl-modified self. J. Exp. Med. 162, 427–443 (1985).

    Article  CAS  PubMed  Google Scholar 

  15. Cassell, D. & Forman, J. Linked recognition of helper and cytotoxic antigenic determinants for the generation of cytotoxic T lymphocytes. Ann. NY Acad. Sci. 532, 51–60 (1988).

    Article  CAS  PubMed  Google Scholar 

  16. Husmann, L. A. & Bevan, M. J. Cooperation between helper T cells and cytotoxic T lymphocyte precursors. Ann. NY Acad. Sci. 532, 158–169 (1988).

    Article  CAS  PubMed  Google Scholar 

  17. Mitchison, N. A. & O’Malley, C. Three-cell-type clusters of T cells with antigen-presenting cells best explain the epitope linkage and noncognate requirements of the in vivo cytolytic response. Eur. J. Immunol. 17, 1579–1583 (1987).

    Article  CAS  PubMed  Google Scholar 

  18. Joffre, O. P., Segura, E., Savina, A. & Amigorena, S. Cross-presentation by dendritic cells. Nat. Rev. Immunol. 12, 557–569 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Bennett, S. R. M., Carbone, F. R., Karamalis, F., Miller, J. F. A. P. & Heath, W. R. Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help. J. Exp. Med. 186, 65–70 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bennett, S. R. M. et al. Help for cytotoxic-T cell responses is mediated by CD40 signalling. Nature 393, 478 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. 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 (1998). Together with reference 20, this study shows that CD4 + T cell help during the primary response is mediated by CD40 signalling in DCs.

    Article  CAS  PubMed  Google Scholar 

  22. Ossendorp, F., Mengedé, E., Camps, M., Filius, R. & Melief, C. J. Specific T helper cell requirement for optimal induction of cytotoxic T lymphocytes against major histocompatibility complex class II negative tumors. J. Exp. Med. 187, 693–702 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ridge, J. P., Di Rosa, F. & Matzinger, P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393, 474–478 (1998). This study reveals that DCs deliver CD4 + T cell help to CD8 + T cells.

    Article  CAS  PubMed  Google Scholar 

  24. Grewal, I. S. & Flavell, R. A. The role of CD40 ligand in costimulation and T cell activation. Immunol. Rev. 153, 85–106 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Diehl, L. et al. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat. Med 5, 774–779 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Schuurhuis, D. H. et al. Immature dendritic cells acquire CD8+ cytotoxic T lymphocyte priming capacity upon activation by T helper cell–independent or–dependent stimuli. J. Exp. Med. 192, 145–150 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bijker, M. S. et al. CD8+ CTL priming by exact peptide epitopes in incomplete Freund’s adjuvant induces a vanishing CTL response, whereas long peptides induce sustained CTL reactivity. J. Immunol. 179, 5033–5040 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Zwaveling, S. et al. Established human papillomavirus type 16-expressing tumors are effectively eradicated following vaccination with long peptides. J. Immunol. 169, 350–358 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Wang, J.-C. E. & Livingstone, A. M. Cutting edge: CD4+ T cell help can be essential for primary CD8+ T cell responses in vivo. J. Immunol. 171, 6339–6343 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Janssen, E. M. et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852–856 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Shedlock, D. J. & Shen, H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300, 337–339 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Sun, J. C. & Bevan, M. J. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300, 339–342 (2003). References 30–32 are the first reports to show the importance of CD4+ T cell help for the generation of optimal memory CD8+ T cell responses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wiesel, M. & Oxenius, A. From crucial to negligible: functional CD8+ T cell responses and their dependence on CD4+ T cell help. Eur. J. Immunol. 42, 1080–1088 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Kaech, S. M. & Ahmed, R. Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naïve cells. Nat. Immunol. 2, 415–422 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. van Stipdonk, M. J., Lemmens, E. E. & Schoenberger, S. P. Naïve CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nat. Immunol. 2, 423–429 (2001).

    Article  PubMed  Google Scholar 

  36. Calabro, S. et al. Differential intrasplenic migration of dendritic cell subsets tailors adaptive immunity. Cell Rep. 16, 2472–2485 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gerner, M. Y., Casey, K. A., Kastenmuller, W. & Germain, R. N. Dendritic cell and antigen dispersal landscapes regulate T cell immunity. J. Exp. Med. 214, 3105–3122 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bachem, A. et al. Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells. J. Exp. Med. 207, 1273–1281 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Brewitz, A. et al. CD8+ T cells orchestrate pDC-XCR1+ dendritic cell spatial and functional cooperativity to optimize priming. Immunity 46, 205–219 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Groom, J. R. et al. CXCR3 chemokine receptor-ligand interactions in the lymph node optimize CD4+ T helper 1 cell differentiation. Immunity 37, 1091–1103 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Iannacone, M. et al. Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus. Nature 465, 1079–1083 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kastenmuller, W., Torabi-Parizi, P., Subramanian, N., Lammermann, T. & Germain, R. N. A spatially-organized multicellular innate immune response in lymph nodes limits systemic pathogen spread. Cell 150, 1235–1248 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kaech, S. M. & Cui, W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat. Rev. Immunol. 12, 749 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Acuto, O. & Michel, F. CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat. Rev. Immunol. 3, 939–951 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Watts, T. H. TNF/TNFR family members in costimulation of T cell responses. Annu. Rev. Immunol. 23, 23–68 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Curtsinger, J. M. & Mescher, M. F. Inflammatory cytokines as a third signal for T cell activation. Curr. Opin. Immunol. 22, 333–340 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wiesel, M., Kratky, W. & Oxenius, A. Type I IFN substitutes for T cell help during viral infections. J. Immunol. 186, 754–763 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. 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 

  49. Curtsinger, J. M., Johnson, C. M. & Mescher, M. F. CD8 T cell clonal expansion and development of effector function require prolonged exposure to antigen, costimulation, and signal 3 cytokine. J. Immunol. 171, 5165–5171 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. 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. xImmunol. 183, 1695–1704 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Schluns, K. S., Williams, K., Ma, A., Zheng, X. X. & Lefrançois, L. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J. Immunol. 168, 4827–4831 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. 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 

  53. Greyer, M. et al. T cell help amplifies innate signals in CD8+ DCs for optimal CD8+ T cell priming. Cell Rep. 14, 586–597 (2016).

    Article  CAS  PubMed  Google Scholar 

  54. Curtsinger, J. M., Agarwal, P., Lins, D. C. & Mescher, M. F. Autocrine IFN-γ promotes naive CD8 T cell differentiation and synergizes with IFN-α to stimulate strong function. J. Immunol. 189, 659–668 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Cook, K. D., Waggoner, S. N. & Whitmire, J. K. NK cells and their ability to modulate T cells during virus infections. Crit. Rev. Immunol. 34, 359–388 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Pipkin, M. E. et al. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32, 79–90 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. D’Souza, W. N. & Lefrançois, L. IL-2 is not required for the initiation of CD8 T cell cycling but sustains expansion. J. Immunol. 171, 5727–5735 (2003).

    Article  PubMed  Google Scholar 

  58. D’Souza, W. N. & Lefrançois, L. Frontline: an in-depth evaluation of the production of IL-2 by antigen-specific CD8 T cells in vivo. Eur. J. Immunol. 34, 2977–2985 (2004).

    Article  PubMed  CAS  Google Scholar 

  59. Obar, J. J. et al. CD4+ T cell regulation of CD25 expression controls development of short-lived effector CD8+ T cells in primary and secondary responses. Proc. Natl Acad. Sci. USA 107, 193–198 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Wilson, E. B. & Livingstone, A. M. Cutting edge: CD4+ T cell-derived IL-2 is essential for help-dependent primary CD8+ T cell responses. J. Immunol. 181, 7445–7448 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Elsaesser, H., Sauer, K. & Brooks, D. G. IL-21 is required to control chronic viral infection. Science 324, 1569–1572 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bachmann, M. F. et al. Cutting edge: distinct roles for T help and CD40/CD40 ligand in regulating differentiation of proliferation-competent memory CD8+ T cells. J. Immunol. 173, 2217–2221 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Prilliman, K. R. et al. Cutting edge: a crucial role for B7-CD28 in transmitting T help from APC to CTL. J. Immunol. 169, 4094–4097 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Bullock, T. N. J. & Yagita, H. Induction of CD70 on dendritic cells through CD40 or TLR stimulation contributes to the development of CD8+ T cell responses in the absence of CD4+ T cells. J. Immunol. 174, 710–717 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. van de Ven, K. & Borst, J. Targeting the T cell co-stimulatory CD27/CD70 pathway in cancer immunotherapy: rationale and potential. Immunotherapy 7, 655–667 (2015).

    Article  PubMed  CAS  Google Scholar 

  66. Sanchez, P. J., McWilliams, J. A., Haluszczak, C., Yagita, H. & Kedl, R. M. Combined TLR/CD40 stimulation mediates potent cellular immunity by regulating dendritic cell expression of CD70 in vivo. J. Immunol. 178, 1564–1572 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Taraban, V. Y., Rowley, T. F. & Al-Shamkhani, A. Cutting edge: a critical role for CD70 in CD8 T cell priming by CD40-Licensed APCs. J. Immunol. 173, 6542–6546 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Peperzak, V. et al. CD8+ T cells produce the chemokine CXCL10 in response to CD27/CD70 costimulation to promote generation of the CD8+ effector T cell pool. J. Immunol. 191, 3025–3036 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Ramakrishna, V. et al. Characterization of the human T cell response to in vitro CD27 costimulation with varlilumab. J. Immunother. Cancer 3, 37 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Feau, S. et al. The CD4+ T cell help signal is transmitted from APC to CD8+ T cells via CD27–CD70 interactions. Nat. Commun. 3, 948 (2012).

    Article  PubMed  CAS  Google Scholar 

  71. Keller, A. M., Schildknecht, A., Xiao, Y., van den Broek, M. & Borst, J. Expression of costimulatory ligand CD70 on steady-state dendritic cells breaks CD8+ T cell tolerance and permits effective immunity. Immunity 29, 934–946 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Ahrends, T. et al. CD27 agonism plus PD-1 blockade recapitulates CD4+ T cell help in therapeutic anticancer vaccination. Cancer Res. 76, 2921–2931 (2016).

    Article  CAS  PubMed  Google Scholar 

  73. Hui, E. et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355, 1428–1433 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hendriks, J. et al. During viral infection of the respiratory tract, CD27, 4-1BB, and OX40 collectively determine formation of CD8+ memory T cells and their capacity for secondary expansion. J. Immunol. 175, 1665–1676 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Kumamoto, Y., Mattei, L. M., Sellers, S., Payne, G. W. & Iwasaki, A. CD4+ T cells support cytotoxic T lymphocyte priming by controlling lymph node input. Proc. Natl Acad. Sci. USA 108, 8749–8754 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hendriks, J., Xiao, Y. & Borst, J. CD27 promotes survival of activated T cells and complements CD28 in generation and establishment of the effector T cell pool. J. Exp. Med. 198, 1369–1380 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Colombetti, S., Basso, V., Mueller, D. L. & Mondino, A. Prolonged TCR/CD28 engagement drives IL-2-independent T cell clonal expansion through signaling mediated by the mammalian target of rapamycin. J. Immunol. 176, 2730–2738 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Peperzak, V., Veraar, E. A. M., Keller, A. M., Xiao, Y. & Borst, J. The Pim kinase pathway contributes to survival signaling in primed CD8+ T cells upon CD27 costimulation. J. Immunol. 185, 6670–6678 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. van Gisbergen, K. P. J. M. et al. The costimulatory molecule CD27 maintains clonally diverse CD8+ T cell responses of low antigen affinity to protect against viral variants. Immunity 35, 97–108 (2011).

    Article  PubMed  CAS  Google Scholar 

  80. Peperzak, V., Xiao, Y., Veraar, E. A. M. & Borst, J. CD27 sustains survival of CTLs in virus-infected nonlymphoid tissue in mice by inducing autocrine IL-2 production. J. Clin. Invest. 120, 168–178 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. 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 

  82. Gray, S. M., Kaech, S. M. & Staron, M. M. The interface between transcriptional and epigenetic control of effector and memory CD8+ T cell differentiation. Immunol. Rev. 261, 157–168 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Weng, N., Araki, Y. & Subedi, K. The molecular basis of the memory T cell response: differential gene expression and its epigenetic regulation. Nat. Rev. Immunol. 12, 306–315 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Oosterhuis, K., Aleyd, E., Vrijland, K., Schumacher, T. N. & Haanen, J. B. Rational design of DNA vaccines for the induction of human papillomavirus type 16 E6− and E7-specific cytotoxic T cell responses. Hum. Gene Ther. 23, 1301–1312 (2012).

    Article  CAS  PubMed  Google Scholar 

  85. Provine, N. M. et al. Immediate dysfunction of vaccine-elicited CD8+ T cells primed in the absence of CD4+ T cells. J. Immunol. 197, 1809–1822 (2016). This study reveals that the gene expression profile of helpless CTLs resembles that of exhausted CTLs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. West, E. E. et al. Tight regulation of memory CD8+ T cells limits their effectiveness during sustained high viral load. Immunity 35, 285–298 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Shin, H. M. et al. Epigenetic modifications induced by Blimp-1 regulate CD8+ T cell memory progression during acute virus infection. Immunity 39, 661–675 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Northrop, J. K., Thomas, R. M., Wells, A. D. & Shen, H. Epigenetic remodeling of the IL-2 and IFN-gamma loci in memory CD8 T cells is influenced by CD4 T cells. J. Immunol. 177, 1062–1069 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Wolkers, M. C. et al. Nab2 regulates secondary CD8+ T cell responses through control of TRAIL expression. Blood 119, 798–804 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Janssen, E. M. et al. CD4+ T cell help controls CD8+ T cell memory via TRAIL-mediated activation-induced cell death. Nature 434, 88–93 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Badovinac, V. P., Messingham, K. A. N., Griffith, T. S. & Harty, J. T. TRAIL deficiency delays, but does not prevent, erosion in the quality of ‘helpless’ memory CD8 T cells. J. Immunol. 177, 999–1006 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Sacks, J. A. & Bevan, M. J. TRAIL deficiency does not rescue impaired CD8+ T cell memory generated in the absence of CD4+ T cell help. J. Immunol. 180, 4570–4576 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Northrop, J. K., Wells, A. D. & Shen, H. Cutting edge: chromatin remodeling as a molecular basis for the enhanced functionality of memory CD8 T cells. J. Immunol. 181, 865–868 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Gros, A. et al. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat. Med. 22, 433–438 (2016). This study reveals that tumour-specific CD8 + T cells in the blood of patients with cancer can be identified by their expression of PD1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Schietinger, A. et al. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45, 389–401 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 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 

  99. Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Mariathasan, S. et al. TGFβ attenuates tumor response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Deng, L. et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41, 843–852 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Fu, J. et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci. Transl Med. 7, 283ra52 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Kenter, G. G. et al. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N. Engl. J. Med. 361, 1838–1847 (2009). This study shows that the inclusion of helper epitopes in peptide vaccines results in a favourable clinical outcome in patients with pre-malignant lesions.

    Article  CAS  PubMed  Google Scholar 

  104. van Poelgeest, M. I. E. 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  CAS  Google Scholar 

  105. 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 

  106. Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222 (2017). Together with reference 105, this study shows that the generation of polyfunctional CD8 + T cell responses after therapeutic vaccination in patients with cancer correlates with the induction of CD4 + T cell responses.

    Article  CAS  PubMed  Google Scholar 

  107. Melief, C. J. M., Hall, T., van, Arens, R., Ossendorp, F. & van der Burg, S. H. Therapeutic cancer vaccines. J. Clin. Invest. 125, 3401–3412 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  109. Kroemer, G., Galluzzi, L., Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013).

    Article  CAS  PubMed  Google Scholar 

  110. van der Sluis, T. C. et al. Vaccine-induced tumor necrosis factor-producing T cells synergize with cisplatin to promote tumor cell death. Clin. Cancer Res. 21, 781–794 (2015).

    Article  PubMed  CAS  Google Scholar 

  111. Welters, M. J. et al. Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T cell responses. Sci. Transl Med. 8, 334ra52 (2016).

    Article  PubMed  CAS  Google Scholar 

  112. Zanetti, M. Tapping CD4 T cells for cancer immunotherapy: the choice of personalized genomics. J. Immunol. 194, 2049–2056 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. 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 

  114. 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 

  115. 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 

  116. Valzasina, B., Piconese, S., Guiducci, C. & Colombo, M. P. Tumor-induced expansion of regulatory T cells by conversion of CD4+CD25 lymphocytes is thymus and proliferation independent. Cancer Res. 66, 4488–4495 (2006).

    Article  CAS  PubMed  Google Scholar 

  117. Liu, V. C. et al. Tumor evasion of the immune system by converting CD4+CD25 T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-β. J. Immunol. 178, 2883–2892 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. 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. https://doi.org/10.1158/0008-5472.CAN-17-2426 (2018).

    Article  PubMed  Google Scholar 

  119. Kastenmüller, W., Kastenmüller, K., Kurts, C. & Seder, R. A. Dendritic cell-targeted vaccines — hope or hype? Nat. Rev. Immunol. 14, 705–711 (2014).

    Article  PubMed  CAS  Google Scholar 

  120. Rieckmann, J. C. et al. Social network architecture of human immune cells unveiled by quantitative proteomics. Nat. Immunol. 18, 583–593 (2017).

    Article  CAS  PubMed  Google Scholar 

  121. Crozat, K. et al. The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8α+ dendritic cells. J. Exp. Med. 207, 1283–1292 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Balan, S. et al. Human XCR1+ dendritic cells derived in vitro from CD34+ progenitors closely resemble blood dendritic cells, including their adjuvant responsiveness, contrary to monocyte-derived dendritic cells. J. Immunol. 193, 1622–1635 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Constantino, J., Gomes, C., Falcão, A., Cruz, M. T. & Neves, B. M. Antitumor dendritic cell-based vaccines: lessons from 20 years of clinical trials and future perspectives. Transl Res. 168, 74–95 (2016).

    Article  CAS  PubMed  Google Scholar 

  124. Guilliams, M. et al. Unsupervised high-dimensional analysis aligns dendritic cells across tissues and species. Immunity 45, 669–684 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Burris, H. A. et al. Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, in patients with advanced solid tumors. J. Clin. Oncol. 35, 2028–2036 (2017).

    Article  CAS  PubMed  Google Scholar 

  126. 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 

  127. 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 

  128. Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Sadelain, M. CAR therapy: the CD19 paradigm. J. Clin. Invest. 125, 3392–3400 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Linnemann, C., Schumacher, T. N. & Bendle, G. M. T cell receptor gene therapy: critical parameters for clinical success. J. Invest. Dermatol. 131, 1806–1816 (2011).

    Article  CAS  PubMed  Google Scholar 

  131. Hinrichs, C. S. & Rosenberg, S. A. Exploiting the curative potential of adoptive T cell therapy for cancer. Immunol. Rev. 257, 56–71 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Song, D.-G. et al. CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo. Blood 119, 696–706 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Mahoney, K. M., Rennert, P. D. & Freeman, G. J. Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug Discov. 14, 561 (2015).

    Article  CAS  PubMed  Google Scholar 

  134. Qureshi, O. S. et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332, 600–603 (2011).

  135. 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 

  136. Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Kvistborg, P. et al. Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response. Sci. Transl Med. 6, 254ra128 (2014).

    Article  PubMed  CAS  Google Scholar 

  138. Postow, M. A. et al. Peripheral T cell receptor diversity is associated with clinical outcomes following ipilimumab treatment in metastatic melanoma. J. Immunother. Cancer. 3, 23 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  139. 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 

  140. Murphy, T. L. et al. Transcriptional control of dendritic cell development. Annu. Rev. Immunol. 34, 93–119 (2016).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

J.B. received funding from the KWF Kankerbestrijding (Dutch Cancer Society; grant 11097).

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Nature Reviews Immunology thanks S. Mueller and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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All authors contributed to researching data for the article, discussion of content and reviewing and editing of the manuscript before submission. J.B. and W.K. wrote the article.

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Correspondence to Jannie Borst.

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Competing interests

J.B. is an inventor on a patent for CD27 agonist antibodies. C.J.M.M. is beneficiary of a management participation plan in ISA Pharmaceuticals, Leiden, Netherlands, is a named inventor on a patent for the use of synthetic long peptides as vaccines and is employed as Chief Scientific Officer by ISA Pharmaceuticals, which exploits this patent. The other authors declare no competing interests.

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Glossary

Effector functions

T cell functions that are required to eliminate infected cells or tumour cells, including the ability to infiltrate tissues and to produce specific cytokines, chemokines and cytotoxic molecules.

Memory functions

Functions that allow a previously activated T cell to maintain longevity and to more rapidly and effectively proliferate and exert effector functions after a second exposure to their cognate antigen.

Co-stimulatory signals

Signals in T cells that are induced upon initial, activating T cell receptor–CD3 support; these signals activate additional, so-called co-stimulatory signalling pathways, leading to proliferation, differentiation and survival of the T cells.

Antigen cross-presentation

The presentation of peptides derived from extracellular sources by antigen-presenting cells via MHC class I molecules.

Exhaustion

A dysfunctional state characterized by impaired cytotoxicity and cytokine production in effector T cells.

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Borst, J., Ahrends, T., Bąbała, N. et al. CD4+ T cell help in cancer immunology and immunotherapy. Nat Rev Immunol 18, 635–647 (2018). https://doi.org/10.1038/s41577-018-0044-0

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