Review Article | Published:

CD4+ T cell help in cancer immunology and immunotherapy

Nature Reviews Immunology (2018) | Download Citation

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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References

  1. 1.

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

  2. 2.

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

  3. 3.

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

  4. 4.

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

  5. 5.

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

  6. 6.

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

  7. 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).

  8. 8.

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

  9. 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.

  10. 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).

  11. 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).

  12. 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.

  13. 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).

  14. 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).

  15. 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).

  16. 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).

  17. 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).

  18. 18.

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

  19. 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).

  20. 20.

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

  21. 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.

  22. 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).

  23. 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.

  24. 24.

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

  25. 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).

  26. 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).

  27. 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).

  28. 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).

  29. 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).

  30. 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).

  31. 31.

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

  32. 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.

  33. 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).

  34. 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).

  35. 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).

  36. 36.

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

  37. 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).

  38. 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).

  39. 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).

  40. 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).

  41. 41.

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

  42. 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).

  43. 43.

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

  44. 44.

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

  45. 45.

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

  46. 46.

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

  47. 47.

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

  48. 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).

  49. 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).

  50. 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).

  51. 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).

  52. 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).

  53. 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).

  54. 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).

  55. 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).

  56. 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).

  57. 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).

  58. 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).

  59. 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).

  60. 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).

  61. 61.

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

  62. 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).

  63. 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).

  64. 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).

  65. 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).

  66. 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).

  67. 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).

  68. 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).

  69. 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).

  70. 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).

  71. 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).

  72. 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).

  73. 73.

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

  74. 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).

  75. 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).

  76. 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).

  77. 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).

  78. 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).

  79. 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).

  80. 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).

  81. 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).

  82. 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).

  83. 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).

  84. 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).

  85. 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.

  86. 86.

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

  87. 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).

  88. 88.

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

  89. 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).

  90. 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).

  91. 91.

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

  92. 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).

  93. 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).

  94. 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).

  95. 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).

  96. 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.

  97. 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).

  98. 98.

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

  99. 99.

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

  100. 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).

  101. 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).

  102. 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).

  103. 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.

  104. 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).

  105. 105.

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

  106. 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.

  107. 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).

  108. 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).

  109. 109.

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

  110. 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).

  111. 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).

  112. 112.

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

  113. 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).

  114. 114.

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

  115. 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).

  116. 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).

  117. 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).

  118. 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).

  119. 119.

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

  120. 120.

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

  121. 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).

  122. 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).

  123. 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).

  124. 124.

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

  125. 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).

  126. 126.

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

  127. 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).

  128. 128.

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

  129. 129.

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

  130. 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).

  131. 131.

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

  132. 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).

  133. 133.

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

  134. 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. 135.

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

  136. 136.

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

  137. 137.

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

  138. 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).

  139. 139.

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

  140. 140.

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

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Acknowledgements

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

Reviewer information

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

Author information

Affiliations

  1. Division of Tumour Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, Netherlands

    • Jannie Borst
    • , Tomasz Ahrends
    •  & Nikolina Bąbała
  2. Leiden University Medical Center and ISA Pharmaceuticals, Leiden, Netherlands

    • Cornelis J. M. Melief
  3. Institute for Systems Immunology, Würzburg, Germany

    • Wolfgang Kastenmüller

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Contributions

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.

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.

Corresponding author

Correspondence to Jannie Borst.

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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DOI

https://doi.org/10.1038/s41577-018-0044-0