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Dendritic cells in cancer immunology and immunotherapy

Abstract

Dendritic cells (DCs) are a diverse group of specialized antigen-presenting cells with key roles in the initiation and regulation of innate and adaptive immune responses. As such, there is currently much interest in modulating DC function to improve cancer immunotherapy. Many strategies have been developed to target DCs in cancer, such as the administration of antigens with immunomodulators that mobilize and activate endogenous DCs, as well as the generation of DC-based vaccines. A better understanding of the diversity and functions of DC subsets and of how these are shaped by the tumour microenvironment could lead to improved therapies for cancer. Here we will outline how different DC subsets influence immunity and tolerance in cancer settings and discuss the implications for both established cancer treatments and novel immunotherapy strategies.

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Fig. 1: Induction of T cell-mediated immunity or tolerance by DCs.
Fig. 2: Regulation of DC function by tumours.
Fig. 3: DCs in the context of cancer therapy.
Fig. 4: Exploiting DCs for cancer immunotherapy.

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References

  1. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Mittal, D., Gubin, M. M., Schreiber, R. D. & Smyth, M. J. New insights into cancer immunoediting and its three component phases-elimination, equilibrium and escape. Curr. Opin. Immunol. 27, 16–25 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Broz, M. L. et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26, 638–652 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ruffell, B. et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26, 623–637 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Böttcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1028.e14 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Barry, K. C. et al. A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments. Nat. Med. 24, 1–14 (2018).

    Article  CAS  Google Scholar 

  8. Steinman, R. M. Decisions about dendritic cells: past, present, and future. Annu. Rev. Immunol. 30, 1–22 (2011).

    Article  PubMed  CAS  Google Scholar 

  9. Collin, M. & Bigley, V. Human dendritic cell subsets: an update. Immunology 154, 3–20 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev Immunol 31, 563–604 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Schlitzer, A., McGovern, N. & Ginhoux, F. Dendritic cells and monocyte-derived cells: two complementary and integrated functional systems. Semin. Cell Dev. Biol. 41, 9–22 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Böttcher, J. P. & Reis e Sousa, C. The role of type 1 conventional dendritic cells in cancer immunity. Trends Cancer 4, 784–792 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Demoulin, S., Herfs, M., Delvenne, P. & Hubert, P. Tumor microenvironment converts plasmacytoid dendritic cells into immunosuppressive/tolerogenic cells: insight into the molecular mechanisms. J. Leukoc. Biol. 93, 343–352 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Mildner, A. & Jung, S. Development and function of dendritic cell subsets. Immunity 40, 642–656 (2014).

    Article  CAS  PubMed  Google Scholar 

  15. Rodrigues, P. F. et al. Distinct progenitor lineages contribute to the heterogeneity of plasmacytoid dendritic cells. Nat. Immunol. 19, 711–722 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Roberts, E. W. et al. Critical role for CD103+/CD141+ dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell 30, 324–336 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Binnewies, M. et al. Unleashing type-2 dendritic cells to drive protective antitumor CD4+ T cell immunity. Cell 177, 556–571.e16 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Villani, A. C. et al. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science 356, eaah4573 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Salio, M., Palmowski, M. J., Atzberger, A., Hermans, I. F. & Cerundolo, V. CpG-matured murine plasmacytoid dendritic cells are capable of in vivo priming of functional CD8 T cell responses to endogenous but not exogenous antigens. J. Exp. Med. 199, 567–579 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tel, J. et al. Natural human plasmacytoid dendritic cells induce antigen-specific T-cell responses in melanoma patients. Cancer Res. 73, 1063–1075 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Chiang, M.-C. et al. Differential uptake and cross-presentation of soluble and necrotic cell antigen by human DC subsets. Eur. J. Immunol. 46, 329–339 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Sittig, S. P. et al. A comparative study of the T cell stimulatory and polarizing capacity of human primary blood dendritic cell subsets. Mediators Inflamm. 2016, 3605643 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Segura, E., Durand, M. & Amigorena, S. Similar antigen cross-presentation capacity and phagocytic functions in all freshly isolated human lymphoid organ-resident dendritic cells. J. Exp. Med. 210, 1035–1047 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schlitzer, A. et al. IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 38, 970–983 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Williams, J. W. et al. Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation. Nat. Commun. 4, 2990 (2013).

    Article  PubMed  CAS  Google Scholar 

  26. Yin, X. et al. Human blood CD1c+ dendritic cells encompass CD5high and CD5low subsets that differ significantly in phenotype, gene expression, and functions. J. Immunol. 198, 1553–1564 (2017).

    Article  CAS  PubMed  Google Scholar 

  27. Segura, E. et al. Human inflammatory dendritic cells induce Th17 cell differentiation. Immunity 38, 336–348 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8 + dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jongbloed, S. L. et al. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J. Exp. Med. 207, 1247–1260 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Salmon, H. et al. Expansion and activation of CD103+ dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity 44, 924–938 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sanchez-Paulete, A. R. et al. Cancer immunotherapy with immunomodulatory anti-CD137 and anti–PD-1 monoclonal antibodies requires BATF3-dependent dendritic cells. Cancer Discov. 6, 71–79 (2016).

    Article  CAS  PubMed  Google Scholar 

  32. Wculek, S. K. et al. Effective cancer immunotherapy by natural mouse conventional type-1 dendritic cells bearing dead tumor antigen. J. Immunother. Cancer 7, 100 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Theisen, D. J. et al. WDFY4 is required for cross-presentation in response to viral and tumor antigens. Science 362, 694–699 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Alloatti, A. et al. Critical role for Sec22b-dependent antigen cross-presentation in antitumor immunity. J. Exp. Med. 214, 2231–2241 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ma, Y. et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38, 729–741 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Casares, N. et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Apetoh, L. et al. Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050–1059 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Sánchez-Paulete, A. R. A. R. R. et al. Antigen cross-presentation and T-cell cross-priming in cancer immunology and immunotherapy. Ann. Oncol. 28, xii44–xii55 (2017).

    Article  PubMed  Google Scholar 

  39. Novak, L., Igoucheva, O., Cho, S. & Alexeev, V. Characterization of the CCL21-mediated melanoma-specific immune responses and in situ melanoma eradication. Mol. Cancer Ther. 6, 1755–1764 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Shields, J. D., Kourtis, I. C., Tomei, A. A., Roberts, J. M. & Swartz, M. A. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science 328, 749–752 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Villablanca, E. J. et al. Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses. Nat. Med. 16, 98–105 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Rowshanravan, B., Halliday, N. & Sansom, D. M. CTLA-4: a moving target in immunotherapy. Blood 131, 58–67 (2018).

    Article  CAS  PubMed  Google Scholar 

  43. Saoulli, K. et al. CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand. J. Exp. Med. 187, 1849–1862 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dannull, J. et al. Enhancing the immunostimulatory function of dendritic cells by transfection with mRNA encoding OX40 ligand. Blood 105, 3206–3213 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Cohen, A. D. et al. Agonist anti-GITR antibody enhances vaccine-induced CD8+ T-cell responses and tumor immunity. Cancer Res. 66, 4904–4912 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Buchan, S. L. et al. PD-1 blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8 + T-cell–driven antitumor immunity. Clin. Cancer Res. 24, 2383–2394 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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 

  48. León, B., López-Bravo, M. & Ardavín, C. Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania. Immunity 26, 519–531 (2007).

    Article  PubMed  CAS  Google Scholar 

  49. Martínez-López, M., Iborra, S., Conde-Garrosa, R. & Sancho, D. Batf3-dependent CD103 + dendritic cells are major producers of IL-12 that drive local Th1 immunity against Leishmania major infection in mice. Eur. J. Immunol. 45, 119–129 (2015).

    Article  PubMed  CAS  Google Scholar 

  50. Nizzoli, G. et al. Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T-cell responses. Blood 122, 932–942 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Parker, B. S., Rautela, J. & Hertzog, P. J. Antitumour actions of interferons: implications for cancer therapy. Nat. Rev. Cancer 16, 131–144 (2016).

    Article  PubMed  CAS  Google Scholar 

  52. Woo, S.-R. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41, 830–842 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Spranger, S., Dai, D., Horton, B. & Gajewski, T. F. Tumor-residing Batf3 dendritic cells are required for effector t cell trafficking and adoptive T cell therapy. Cancer Cell 31, 711–723.e4 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Enamorado, M. et al. Enhanced anti-tumour immunity requires the interplay between resident and circulating memory CD8+ T cells. Nat. Commun. 8, 16073 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Chow, M. T. et al. Intratumoral activity of the CXCR3 chemokine system is required for the efficacy of anti-PD-1 therapy. Immunity 50, 1498–1512.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chemnitz, J. M., Parry, R. V., Nichols, K. E., June, C. H. & Riley, J. L. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J. Immunol. 173, 945–954 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Flies, D. B. et al. Coinhibitory receptor PD-1H preferentially suppresses CD4+ T cell–mediated immunity. J. Clin. Invest. 124, 1966–1975 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Clement, M. et al. CD31 is a key coinhibitory receptor in the development of immunogenic dendritic cells. Proc. Natl Acad. Sci. USA 111, E1101–E1110 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Fallarino, F. et al. Modulation of tryptophan catabolism by regulatory T cells. Nat. Immunol. 4, 1206–1212 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Munn, D. H. & Mellor, A. L. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol. 37, 193–207 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ohm, J. E. et al. Effect of vascular endothelial growth factor and FLT3 ligand on dendritic cell generation in vivo. J. Immunol. 163, 3260–3268 (1999).

    CAS  PubMed  Google Scholar 

  63. Tang, M. et al. Toll-like receptor 2 activation promotes tumor dendritic cell dysfunction by regulating IL-6 and IL-10 receptor signaling. Cell Rep. 13, 2851–2864 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Zong, J., Keskinov, A. A., Shurin, G. V. & Shurin, M. R. Tumor-derived factors modulating dendritic cell function. Cancer Immunol. Immunother. 65, 821–833 (2016).

    Article  CAS  PubMed  Google Scholar 

  65. Johnson, D. E., O’Keefe, R. A. & Grandis, J. R. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol. 15, 234–248 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Diao, J., Zhao, J., Winter, E. & Cattral, M. S. Recruitment and differentiation of conventional dendritic cell precursors in tumors. J. Immunol. 184, 1261–1267 (2010).

    Article  CAS  PubMed  Google Scholar 

  67. Yanai, H. et al. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature 462, 99–103 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Chiba, S. et al. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat. Immunol. 13, 832–842 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Xu, M. M. et al. Dendritic cells but not macrophages sense tumor mitochondrial DNA for cross-priming through signal regulatory protein α signaling. Immunity 47, 363–373.e5 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Cubillos-Ruiz, J. R. et al. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell 161, 1527–1538 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Cao, W. et al. Oxidized lipids block antigen cross-presentation by dendritic cells in cancer. J. Immunol. 192, 2920–2931 (2014).

    Article  CAS  Google Scholar 

  73. Veglia, F. et al. Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer. Nat. Commun. 8, 2122 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Gottfried, E. et al. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 107, 2013–2021 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Aspord, C., Leccia, M.-T., Charles, J. & Plumas, J. Plasmacytoid dendritic cells support melanoma progression by promoting Th2 and regulatory immunity through OX40L and ICOSL. Cancer Immunol. Res. 1, 402–415 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Combes, A. et al. BAD-LAMP controls TLR9 trafficking and signalling in human plasmacytoid dendritic cells. Nat. Commun. 8, 913 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Humbert, M., Guery, L., Brighouse, D., Lemeille, S. & Hugues, S. Intratumoral CpG-B promotes anti-tumoral neutrophil, cDC, and T cell cooperation without reprograming tolerogenic pDC. Cancer Res. 78, 3280–3292 (2018).

  78. Galluzzi, L., Buqué, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97–111 (2017).

    Article  CAS  PubMed  Google Scholar 

  79. Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1Β-dependent adaptive immunity against tumors. Nat. Med. 15, 1170–1178 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Vacchelli, E. et al. Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1. Science. 350, 972–978 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Lesterhuis, W. J. et al. Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. J. Clin. Invest. 121, 3100–3108 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Rodriguez-Ruiz, M. E. et al. Abscopal effects of radiotherapy are enhanced by combined immunostimulatory mAbs and are dependent on CD8 T cells and crosspriming. Cancer Res. 76, 5994–6005 (2016).

    Article  CAS  PubMed  Google Scholar 

  84. 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 

  85. Vanpouille-Box, C. et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8, 15618 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Hou, Y. et al. Non-canonical NF-κB antagonizes STING sensor-mediated DNA sensing in radiotherapy. Immunity 49, 490–503 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ott, P. A. & Adams, S. Small-molecule protein kinase inhibitors and their effects on the immune system: Implications for cancer treatment. Immunotherapy 3, 213–227 (2011).

    Article  CAS  PubMed  Google Scholar 

  88. Nefedova, Y. et al. Activation of dendritic cells via inhibition of Jak2/STAT3 signaling. J. Immunol. 175, 4338–4346 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Oosterhoff, D. et al. Tumor-mediated inhibition of human dendritic cell differentiation and function is consistently counteracted by combined p38 MAPK and STAT3 inhibition. Oncoimmunology 1, 649–658 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Nefedova, Y. et al. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J. Immunol. 172, 464–474 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Li, H. S. et al. Bypassing STAT3-mediated inhibition of the transcriptional regulator ID2 improves the antitumor efficacy of dendritic cells. Sci. Signal. 9, ra94 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Zhao, F. et al. Activation of p38 mitogen-activated protein kinase drives dendritic cells to become tolerogenic in ret transgenic mice spontaneously developing melanoma. Clin. Cancer Res. 15, 4382–4390 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Liang, X. et al. β-Catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8+ T cells. J. Leukoc. Biol. 95, 179–190 (2014).

    Article  PubMed  CAS  Google Scholar 

  94. Fu, C. et al. β-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10. Proc. Natl Acad. Sci. USA 112, 2823–2828 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Wang, Y., Wang, X. Y., Subjeck, J. R., Shrikant, P. A. & Kim, H. L. Temsirolimus, an mTOR inhibitor, enhances anti-tumour effects of heat shock protein cancer vaccines. Br. J. Cancer 104, 643–652 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Wang, H. et al. cGAS is essential for the antitumor effect of immune checkpoint blockade. Proc. Natl Acad. Sci. USA 114, 1637–1642 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Cauwels, A. et al. Delivering type I interferon to dendritic cells empowers tumor eradication and immune combination treatments. Cancer Res. 78, 463–474 (2018).

    Article  CAS  PubMed  Google Scholar 

  98. Ribas, A. et al. SD-101 in combination with pembrolizumab in advanced melanoma: results of a phase Ib, multicenter study. Cancer Discov. 8, 1250–1257 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Rapp, M. et al. C-C chemokine receptor type-4 transduction of T cells enhances interaction with dendritic cells, tumor infiltration and therapeutic efficacy of adoptive T cell transfer. Oncoimmunology 5, e1105428 (2016).

    Article  PubMed  CAS  Google Scholar 

  100. Marigo, I. et al. T cell cancer therapy requires CD40-CD40L activation of tumor necrosis factor and inducible nitric-oxide-synthase-producing dendritic cells. Cancer Cell 30, 377–390 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).

    Article  CAS  PubMed  Google Scholar 

  102. Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 359, 104–108 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Zitvogel, L. et al. Cancer and the gut microbiota: an unexpected link. Sci. Transl Med. 7, 271ps1 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Uribe-Herranz, M. et al. Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12. JCI Insight 3, 94952 (2018).

    Article  PubMed  Google Scholar 

  105. Saxena, M. & Bhardwaj, N. Turbocharging vaccines: emerging adjuvants for dendritic cell based therapeutic cancer vaccines. Curr. Opin. Immunol. 47, 35–43 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Bommareddy, P. K., Patel, A., Hossain, S. & Kaufman, H. L. Talimogene laherparepvec (T-VEC) and other oncolytic viruses for the treatment of melanoma. Am. J. Clin. Dermatol. 18, 1–15 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Yan, W.-L., Shen, K.-Y., Tien, C.-Y., Chen, Y.-A. & Liu, S.-J. Recent progress in GM-CSF-based cancer immunotherapy. Immunotherapy 9, 347–360 (2017).

    Article  CAS  PubMed  Google Scholar 

  108. Saito, T. et al. Combined mobilization and stimulation of tumor-infiltrating dendritic cells and natural killer cells with Flt3 ligand and IL-18 in vivo induces systemic antitumor immunity. Cancer Sci. 99, 2028–2036 (2008).

    CAS  PubMed  Google Scholar 

  109. Chi, H. et al. Anti-tumor activity of Toll-like receptor 7 agonists. Front. Pharmacol. 8, 304 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Jiang, L. et al. The combination of MBP and BCG-induced dendritic cell maturation through TLR2/TLR4 promotes Th1 activation in vitro and vivo. Mediators Inflamm. 2017, 1953680 (2017).

    PubMed  PubMed Central  Google Scholar 

  111. Salmon, H. et al. Expansion and activation of CD103+ dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immun. 44, 924–938 (2016).

    Article  CAS  Google Scholar 

  112. Martins, K. A. O., Bavari, S. & Salazar, A. M. Vaccine adjuvant uses of poly-IC and derivatives. Expert. Rev. Vaccines 14, 447–459 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. Aznar, M. A. et al. Immunotherapeutic effects of intratumoral nanoplexed poly I:C. J. Immunother. Cancer 7, 116 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Kyi, C. et al. Therapeutic immune modulation against solid cancers with intratumoral poly-ICLC: a pilot trial. Clin. Cancer Res. 24, 4937–4948 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Drobits, B. et al. Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. J. Clin. Invest. 122, 575–585 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Molenkamp, B. G. et al. Local administration of PF-3512676 CpG-B instigates tumor-specific CD8+T-cell reactivity in melanoma patients. Clin. Cancer Res. 14, 4532–4542 (2008).

    Article  CAS  PubMed  Google Scholar 

  117. Moon, Y. W., Hajjar, J., Hwu, P. & Naing, A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J. Immunother. Cancer 3, 1–10 (2015).

    Article  Google Scholar 

  118. Finn, O. J. Human tumor antigens yesterday, today, and tomorrow. Cancer Immunol. Res. 5, 347–354 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Sahin, U. & Türeci, Ö. Personalized vaccines for cancer immunotherapy. Science 359, 1355–1360 (2018).

    Article  CAS  Google Scholar 

  120. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Balachandran, V. P. et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551, 512–516 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Garg, A. D. et al. Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell-driven rejection of high-grade glioma. Sci. Transl Med. 8, 328ra27 (2016).

    Article  PubMed  CAS  Google Scholar 

  124. Chiang, C., Coukos, G. & Kandalaft, L. Whole tumor antigen vaccines: where are we? Vaccines 3, 344–372 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Goyvaerts, C. & Breckpot, K. The journey of in vivo virus engineered dendritic cells from bench to bedside: a bumpy road. Front. Immunol. 9, 2052 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Moyer, T. J., Zmolek, A. C. & Irvine, D. J. Beyond antigens and adjuvants: formulating future vaccines. J. Clin. Invest. 126, 799–808 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Chesson, C. B. & Zloza, A. Nanoparticles: augmenting tumor antigen presentation for vaccine and immunotherapy treatments of cancer. Nanomedicine 12, 2693–2706 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Kreutz, M., Tacken, P. J. & Figdor, C. G. Targeting dendritic cells-why bother? Blood 121, 2836–2844 (2013).

    Article  CAS  PubMed  Google Scholar 

  129. Bonifaz, L. C. et al. In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination. J. Exp. Med. 199, 815–824 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Idoyaga, J. et al. Comparable T helper 1 (Th1) and CD8 T-cell immunity by targeting HIV gag p24 to CD8 dendritic cells within antibodies to Langerin, DEC205, and Clec9A. Proc. Natl Acad. Sci. USA. 108, 2384–2389 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Sancho, D. et al. Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin. J. Clin. Invest. 118, 2098–2110 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Birkholz, K. et al. Targeting of DEC-205 on human dendritic cells results in efficient MHC class II-restricted antigen presentation. Blood 116, 2277–2285 (2010).

    Article  CAS  PubMed  Google Scholar 

  133. Tsuji, T. et al. Antibody-targeted NY-ESO-1 to mannose receptor or DEC-205 in vitro elicits dual human CD8+ and CD4+ T cell responses with broad antigen specificity. J. Immunol. 186, 1218–1227 (2011).

    Article  CAS  PubMed  Google Scholar 

  134. Dhodapkar, M. V. et al. Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the dendritic cell receptor DEC-205. Sci. Transl Med. 6, 1–10 (2014).

    Article  CAS  Google Scholar 

  135. Tacken, P. J. et al. Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti-DC-SIGN antibody. Blood 106, 1278–1285 (2005).

    Article  CAS  PubMed  Google Scholar 

  136. Hutten, T. J. A. et al. CLEC12A-mediated antigen uptake and cross-presentation by human dendritic cell subsets efficiently boost tumor-reactive t cell responses. J. Immunol. 197, 2715–2725 (2016).

    Article  CAS  PubMed  Google Scholar 

  137. Chatterjee, B. et al. Internalization and endosomal degradation of receptor-bound antigens regulate the efficiency of cross presentation by human dendritic cells. Blood 120, 2011–2020 (2012).

    Article  CAS  PubMed  Google Scholar 

  138. Apostolopoulos, V. et al. Dendritic cell immunotherapy: clinical outcomes. Clin. Transl Immunol. 3, e21 (2014).

    Article  CAS  Google Scholar 

  139. Yin, W. et al. Functional specialty of CD40 and dendritic cell surface lectins for exogenous antigen presentation to CD8+ and CD4+ T cells. EBioMedicine 5, 46–58 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Yin, W. et al. Therapeutic HPV cancer vaccine targeted to CD40 elicits effective CD8+ T-cell immunity. Cancer Immunol. Res. 4, 823–834 (2016).

    Article  CAS  PubMed  Google Scholar 

  141. Hangalapura, B. N. et al. CD40-targeted adenoviral cancer vaccines: the long and winding road to the clinic. J. Gene Med. 14, 416–427 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Saluja, S. S. et al. Targeting human dendritic cells via DEC-205 using PLGA nanoparticles leads to enhanced cross-presentation of a melanoma-associated antigen. Int. J. Nanomed. 9, 5231–5246 (2014).

    Google Scholar 

  143. Schreibelt, G. et al. The C-type lectin receptor CLEC9A mediates antigen uptake and (cross-)presentation by human blood BDCA3+ myeloid dendritic cells. Blood 119, 2284–2292 (2012).

    Article  CAS  PubMed  Google Scholar 

  144. Bol, K. F., Schreibelt, G., Gerritsen, W. R., De Vries, I. J. M. & Figdor, C. G. Dendritic cell-based immunotherapy: state of the art and beyond. Clin. Cancer Res. 22, 1897–1906 (2016).

    Article  CAS  PubMed  Google Scholar 

  145. Garg, A. D., Coulie, P. G., Van den Eynde, B. J. & Agostinis, P. Integrating next-generation dendritic cell vaccines into the current cancer immunotherapy landscape. Trends Immunol. 38, 577–593 (2017).

    Article  CAS  PubMed  Google Scholar 

  146. Melero, I. et al. Therapeutic vaccines for cancer: an overview of clinical trials. Nat. Rev. Clin. Oncol. 11, 509–524 (2014).

    Article  CAS  PubMed  Google Scholar 

  147. Saxena, M. & Bhardwaj, N. Re-emergence of dendritic cell vaccines for cancer treatment. Trends Cancer 4, 119–137 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Cheever, M. A. & Higano, C. S. PROVENGE (sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin. Cancer Res. 17, 3520–3526 (2011).

    Article  PubMed  Google Scholar 

  149. Liau, L. M. et al. First results on survival from a large phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J. Transl Med. 16, 1 (2018).

    Google Scholar 

  150. Dey, M. et al. Dendritic cell–based vaccines that utilize myeloid rather than plasmacytoid cells offer a superior survival advantage in malignant glioma. J. Immunol. 195, 367–376 (2015).

    Article  CAS  PubMed  Google Scholar 

  151. Laoui, D. et al. The tumour microenvironment harbours ontogenically distinct dendritic cell populations with opposing effects on tumour immunity. Nat. Commun. 7, 13720 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Davis, I. D. et al. Blood dendritic cells generated with Flt3 ligand and CD40 ligand prime CD8+ T cells efficiently in cancer patients. J. Immunother. 29, 499–511 (2006).

    Article  PubMed  Google Scholar 

  153. Prue, R. L. et al. A phase I clinical trial of CD1c (BDCA-1)+ dendritic cells pulsed with HLA-A0201 peptides for immunotherapy of metastatic hormone refractory prostate cancer. J. Immunother. 38, 71–76 (2015).

    Article  CAS  PubMed  Google Scholar 

  154. Schreibelt, G. et al. Effective clinical responses in metastatic melanoma patients after vaccination with primary myeloid dendritic cells. Clin. Cancer Res. 22, 2155–2166 (2016).

    Article  CAS  PubMed  Google Scholar 

  155. Verronèse, E. et al. Immune cell dysfunctions in breast cancer patients detected through whole blood multi-parametric flow cytometry assay. Oncoimmunology 5, 1–15 (2016).

    Article  CAS  Google Scholar 

  156. Kirkling, M. E. et al. Notch signaling facilitates in vitro generation of cross-presenting classical dendritic cells. Cell Rep. 23, 3658–3672 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Balan, S. et al. Large-scale human dendritic cell differentiation revealing notch-dependent lineage bifurcation and heterogeneity. Cell Rep. 24, 1902–1915 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Moeller, I., Spagnoli, G. C., Finke, J., Veelken, H. & Houet, L. Uptake routes of tumor-antigen MAGE-A3 by dendritic cells determine priming of naïve T-cell subtypes. Cancer Immunol. Immunother. 61, 2079–2090 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Pinho, M. P. et al. Dendritic-tumor cell hybrids induce tumor-specific immune responses more effectively than the simple mixture of dendritic and tumor cells. Cytotherapy 18, 570–580 (2016).

    Article  CAS  PubMed  Google Scholar 

  161. Geskin, L. J. et al. Three antigen-loading methods in dendritic cell vaccines for metastatic melanoma. Melanoma Res. 28, 211–221 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Radomski, M. et al. Prolonged intralymphatic delivery of dendritic cells through implantable lymphatic ports in patients with advanced cancer. J. Immunother. Cancer 4, 1–9 (2016).

    Article  Google Scholar 

  163. Seyfizadeh, N., Muthuswamy, R., Mitchell, D. A., Nierkens, S. & Seyfizadeh, N. Migration of dendritic cells to the lymph nodes and its enhancement to drive anti-tumor responses. Crit. Rev. Oncol. Hematol. 107, 100–110 (2016).

    Article  PubMed  Google Scholar 

  164. Sandoval, F. et al. Mucosal imprinting of vaccine-induced CD8+ T cells is crucial to inhibit the growth of mucosal tumors. Sci. Transl Med. 5, 172ra20 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Aarntzen, E. H. J. G. et al. Targeting of 111In-labeled dendritic cell human vaccines improved by reducing number of cells. Clin. Cancer Res. 19, 1525–1533 (2013).

    Article  CAS  PubMed  Google Scholar 

  166. Butterfield, L. H. Dendritic cells in cancer immunotherapy clinical trials: are we making progress? Front. Immunol. 4, 3–9 (2013).

    Article  CAS  Google Scholar 

  167. Van Willigen, W. W. et al. Dendritic cell cancer therapy: vaccinating the right patient at the right time. Front. Immunol. 9, 2265 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

The authors thank all members of the D.S. laboratory at Centro Nacional de Investigaciones Cardiovasculares (CNIC) for scientific discussions. S.K.W. is supported by a European Molecular Biology Organization Long-Term Fellowship (grant ALTF 438–2016) and a CNIC–International Postdoctoral Program Fellowship (grant 17230–2016). F.J.C. is the recipient of a PhD ‘La Caixa’ fellowship. Work in the D.S. laboratory is funded by the CNIC, by the European Research Council (ERC Consolidator Grant 2016 725091), by the European Commission (635122-PROCROP H2020), by the Ministerio de Ciencia, Innovación e Universidades (MCNU), Agencia Estatal de Investigación and Fondo Europeo de Desarrollo Regional (FEDER) (SAF2016-79040-R), by the Comunidad de Madrid (B2017/BMD-3733 Immunothercan-CM), by FIS-Instituto de Salud Carlos III, MCNU and FEDER (RD16/0015/0018-REEM), by Acteria Foundation, by Atresmedia (Constantes y Vitales prize) and by Fundació La Marató de TV3 (201723). The CNIC is supported by the Instituto de Salud Carlos III, the MCNU and the Pro CNIC Foundation, and is a Severo Ochoa Centre of Excellence (SEV-2015-0505).

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Nature Reviews Immunology thanks V. Bigley, T. de Gruijl and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Contributions

F.J.C. and S.K.W. contributed equally to this work and share first authorship. S.K.W. and F.J.C. prepared tables and figures and conceptualized and wrote the manuscript. A.M.M. and M.F.K. conceptualized and wrote part of the manuscript. I.M. helped with conceptualization and edited the manuscript. D.S. conceptualized and wrote the manuscript. All authors contributed to manuscript editing, and read and approved the final version.

Corresponding author

Correspondence to David Sancho.

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Competing interests

I.M. reports receiving commercial research grants from Bristol-Myers Squibb and Roche and serves as a consultant/advisory board member for Bristol-Myers Squibb, Merck Serono, Roche-Genentech, Genmab, Incyte, Bioncotech, Tusk, Molecular Partners, F-STAR, Alligator and AstraZeneca. The other authors declare no competing interests.

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Glossary

Pathogen-associated molecular patterns

(PAMPs). Conserved molecules expressed by microorganisms that activate host pattern recognition receptors to alert the immune system to the presence of infection.

Damage-associated molecular patterns

(DAMPs). Endogenous molecular motifs associated with host cell death and tissue damage that can activate the immune system via pattern recognition receptors.

Pattern recognition receptors

(PRRs). Germ line-encoded host sensors that detect pathogen-associated molecular patterns, although many of them have also been described to sense damage-associated molecular patterns. This interaction triggers signalling in the host cell.

Tumour microenvironment

(TME). Usually refers to the non-tumoural cells that surround tumour cells, including fibroblasts, blood vessels and immune cells as well as the milieu of extracellular factors such as cytokines, soluble molecules and extracellular matrix.

Tumour-associated antigens

(TAAs). Autologous cellular antigens generated in tumour cells. They can be the product of mutated genes, antigens produced by oncogenic viruses, oncofetal antigens, altered glycolipids and glycoproteins, differentiation antigens specific for a cell type and overexpressed or aberrantly expressed cellular proteins.

Cross-presentation

The presentation of exogenous antigens (which are typically presented on MHC class II antigens) on MHC class I molecules. It can occur through the vacuolar pathway, leading to loading of peptides onto MHC class I molecules in the phagosome. Alternatively, cross-presentation can involve the transfer of exogenously acquired antigens to the cytosol, where they are processed by the proteasome and degraded to peptides that are transported to the endoplasmic reticulum for loading on MHC class I molecules. The stimulation of naive cytotoxic CD8+ T cells following cross-presentation is known as ‘cross-priming’ and is needed for antitumour immunity.

Immunogenic cell death

A form of cell death that induces an effective immune response through activation of dendritic cells. Hallmarks include the exposure of calreticulin on the cell surface and the active release of high mobility group protein B1 (HMGB1). This is in contrast to silent apoptosis, which is not immunogenic.

Out-of-field or abscopal effects

The ability of localized irradiation or treatment of a tumour to trigger a systemic antitumour effect that can lead to rejection of distant tumours or metastases.

Immune checkpoint blockade

(ICB). Blockade of specific interactions between immune cells and cancer cells or other immune cells by targeting inhibitory molecules such as CTLA4, PD1 and PDL1 that dampen immune cell activation. Inhibiting these interactions releases the ‘brakes’ on the immune system and promotes immune cell activation.

Adjuvants

Charles Janeway described adjuvants as the ‘immunologist’s dirty little secret’, as they were substances added to antigens to make vaccines effective, but their mode of action was not known at that time. Adjuvants contain compounds that stimulate the immune system, frequently pathogen-associated molecular patterns acting on pattern recognition receptors.

Neoantigens

Antigens formed by peptides that are absent from the normal human genome. These neoepitopes can be derived from tumour-specific DNA mutations or from viral sequences in the case of virus-associated tumours.

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Wculek, S.K., Cueto, F.J., Mujal, A.M. et al. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol 20, 7–24 (2020). https://doi.org/10.1038/s41577-019-0210-z

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