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  • Review Article
  • Published:

Vaccines for established cancer: overcoming the challenges posed by immune evasion

Nature Reviews Cancer volume 16, pages 219–233 (2016)Cite this article

Subjects

Key Points

  • Therapeutic vaccines for the induction of tumour-specific T cell responses show high immunogenicity and clinical efficacy over different formulation platforms in pre-cancers but not in established cancers.

  • Cancer vaccines fail to treat established disease owing to a lack of appropriate co-treatment for the immune evasion mechanisms that are operational in the target group.

  • Recognition of escaped tumours with defective major histocompatibility complex (MHC) class I processing and presentation can, in most cases, be restored or induced by activation of CD8+ T cells specific for T cell epitopes associated with impaired peptide processing (TEIPP) antigens.

  • The potency of peptide-based vaccines to stimulate type 1 T helper (TH1) cells and CD8+ T cells will be improved by coupling them with pattern recognition receptor (PRR) agonists and by the formation of supramolecular peptide conjugates.

  • The combination of vaccines with therapies that target immune-suppressive myeloid cells, prevent immune checkpoint activation and stimulate local immune cell infiltration will maximize clinical benefit.

  • Future research will focus on methods to quickly assess the most important immunological hurdles present in a patient's tumour so that the best cancer vaccine combination therapy can be given.

Abstract

Therapeutic vaccines preferentially stimulate T cells against tumour-specific epitopes that are created by DNA mutations or oncogenic viruses. In the setting of premalignant disease, carcinoma in situ or minimal residual disease, therapeutic vaccination can be clinically successful as monotherapy; however, in established cancers, therapeutic vaccines will require co-treatments to overcome immune evasion and to become fully effective. In this Review, we discuss the progress that has been made in overcoming immune evasion controlled by tumour cell-intrinsic factors and the tumour microenvironment. We summarize how therapeutic benefit can be maximized in patients with established cancers by improving vaccine design and by using vaccines to increase the effects of standard chemotherapies, to establish and/or maintain tumour-specific T cells that are re-energized by checkpoint blockade and other therapies, and to sustain the antitumour response of adoptively transferred T cells.

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Figure 1: Tumour escape gives rise to alternative peptide antigens.
Figure 2: Vaccines require co-treatment for T cells to withstand the immune-suppressive microenvironment.

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References

  1. Melief, C. J. & van der Burg, S. H. Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines. Nat. Rev. Cancer 8, 351–360 (2008).

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  3. Talebian Yazdi, M., Keene, K. R., Hiemstra, P. S. & van der Burg, S. H. Recent progress in peptide vaccination in cancer with a focus on non-small-cell lung cancer. Expert Rev. Vaccines 13, 87–116 (2014).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. Kraynyak, K. A., Bodles-Brakhop, A. & Bagarazzi, M. Tapping the potential of DNA delivery with electroporation for cancer immunotherapy. Curr. Top. Microbiol. Immunol. http://dx.doi.org/10.1007/82_2015_431, (2015).

  6. Sahin, U., Kariko, K. & Tureci, O. mRNA-based therapeutics—developing a new class of drugs. Nat. Rev. Drug. Discov. 13, 759–780 (2014).

    CAS  PubMed  Google Scholar 

  7. Butterfield, L. H. Dendritic cells in cancer immunotherapy clinical trials: are we making progress? Front. Immunol. 4, 454 (2013).

    PubMed  PubMed Central  Google Scholar 

  8. Lichty, B. D., Breitbach, C. J., Stojdl, D. F. & Bell, J. C. Going viral with cancer immunotherapy. Nat. Rev. Cancer 14, 559–567 (2014).

    CAS  PubMed  Google Scholar 

  9. Sawada, Y. et al. Programmed death-1 blockade enhances the antitumor effects of peptide vaccine-induced peptide-specific cytotoxic T lymphocytes. Int. J. Oncol. 46, 28–36 (2015).

    CAS  PubMed  Google Scholar 

  10. Binder, D. C. et al. Antigen-specific bacterial vaccine combined with anti-PD-L1 rescues dysfunctional endogenous T cells to reject long-established cancer. Cancer Immunol. Res. 1, 123–133 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

    CAS  PubMed  Google Scholar 

  12. Finn, O. J. Vaccines for cancer prevention: a practical and feasible approach to the cancer epidemic. Cancer Immunol. Res. 2, 708–713 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Gubin, M. M. et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577–581 (2014). This article shows that SLP vaccination against two neo-epitopes in a chemically induced mouse tumour is as effective as treatment with a blocking monoclonal antibody against CTLA4 or PD1.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Engelhard, V. H., Bullock, T. N., Colella, T. A., Sheasley, S. L. & Mullins, D. W. Antigens derived from melanocyte differentiation proteins: self-tolerance, autoimmunity, and use for cancer immunotherapy. Immunol. Rev. 188, 136–146 (2002).

    CAS  PubMed  Google Scholar 

  15. Bos, R. et al. Expression of a natural tumor antigen by thymic epithelial cells impairs the tumor-protective CD4+ T-cell repertoire. Cancer Res. 65, 6443–6449 (2005).

    CAS  PubMed  Google Scholar 

  16. Pedersen, S. R., Sorensen, M. R., Buus, S., Christensen, J. P. & Thomsen, A. R. Comparison of vaccine-induced effector CD8 T cell responses directed against self- and non-self-tumor antigens: implications for cancer immunotherapy. J. Immunol. 191, 3955–3967 (2013). This article shows unequivocally how central thymic tolerance results in the selection of self-antigen-specific CD8+ T cells with low avidity for their cognate antigen and failure to control tumours in vivo in response to vaccination.

    CAS  PubMed  Google Scholar 

  17. Alvarez, I. et al. Central T cell tolerance: identification of tissue-restricted autoantigens in the thymus HLA-DR peptidome. J. Autoimmun. 60, 12–19 (2015).

    CAS  PubMed  Google Scholar 

  18. Yamano, T. et al. Thymic B cells are licensed to present self antigens for central T cell tolerance induction. Immunity 42, 1048–1061 (2015).

    CAS  PubMed  Google Scholar 

  19. Prehn, R. T. & Main, J. M. Immunity to methylcholanthrene-induced sarcomas. J. Natl Cancer Inst. 18, 769–778 (1957).

    CAS  PubMed  Google Scholar 

  20. Kripke, M. L. & Fisher, M. S. Immunologic parameters of ultraviolet carcinogenesis. J. Natl Cancer Inst. 57, 211–215 (1976).

    CAS  PubMed  Google Scholar 

  21. Klein, E. & Klein, G. Antigenic properties of lymphomas induced by the Moloney agent. J. Natl Cancer Inst. 32, 547–568 (1964).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  23. Donnem, T. et al. Stromal CD8+ T-cell density—a promising supplement to TNM staging in non-small cell lung cancer. Clin. Cancer Res. 21, 2635–2643 (2015).

    PubMed  Google Scholar 

  24. Ladanyi, A. Prognostic and predictive significance of immune cells infiltrating cutaneous melanoma. Pigment Cell Melanoma Res. 28, 490–500 (2015).

    PubMed  Google Scholar 

  25. Piersma, S. J. et al. High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer. Cancer Res. 67, 354–361 (2007).

    CAS  PubMed  Google Scholar 

  26. Cariani, E. et al. Immunological and molecular correlates of disease recurrence after liver resection for hepatocellular carcinoma. PLoS ONE 7, e32493 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Van der Burg, S. H., Arens, R. & Melief, C. J. Immunotherapy for persistent viral infections and associated disease. Trends Immunol. 32, 97–103 (2011).

    CAS  PubMed  Google Scholar 

  28. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  30. Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).

    PubMed  Google Scholar 

  31. Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    PubMed  PubMed Central  Google Scholar 

  32. Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015). References 28, 29 and 32 show a direct correlation between the number of mutations in individual tumours and the effectiveness of treatment by T cell checkpoint blockade, indicating that rescue of T cell responses against mutation-based neoantigens is likely to be a major mechanism of action of this treatment.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Van Rooij, N. et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J. Clin. Oncol. 31, e439–e442 (2013).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Ruiter, D. J., Bhan, A. K., Harrist, T. J., Sober, A. J. & Mihm, M. C. Jr. Major histocompatibility antigens and mononuclear inflammatory infiltrate in benign nevomelanocytic proliferations and malignant melanoma. J. Immunol. 129, 2808–2815 (1982).

    CAS  PubMed  Google Scholar 

  38. Natali, P. G. et al. Heterogeneity in the expression of HLA and tumor-associated antigens by surgically removed and cultured breast carcinoma cells. Cancer Res. 43, 660–668 (1983).

    CAS  PubMed  Google Scholar 

  39. Marincola, F. M., Jaffee, E. M., Hicklin, D. J. & Ferrone, S. Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv. Immunol. 74, 181–273 (2000).

    CAS  PubMed  Google Scholar 

  40. Garrido, F., Cabrera, T. & Aptsiauri, N. “Hard” and “soft” lesions underlying the HLA class I alterations in cancer cells: implications for immunotherapy. Int. J. Cancer 127, 249–256 (2010).

    CAS  PubMed  Google Scholar 

  41. Van Esch, E. M. et al. Alterations in classical and nonclassical HLA expression in recurrent and progressive HPV-induced usual vulvar intraepithelial neoplasia and implications for immunotherapy. Int. J. Cancer 135, 830–842 (2014).

    CAS  PubMed  Google Scholar 

  42. Vermeulen, C. F. et al. Frequent HLA class I loss is an early event in cervical carcinogenesis. Hum. Immunol. 66, 1167–1173 (2005).

    CAS  PubMed  Google Scholar 

  43. Seliger, B. et al. Down-regulation of the MHC class I antigen-processing machinery after oncogenic transformation of murine fibroblasts. Eur. J. Immunol. 28, 122–133 (1998).

    CAS  PubMed  Google Scholar 

  44. Vertuani, S. et al. HER-2/neu mediated down-regulation of MHC class I antigen processing prevents CTL-mediated tumor recognition upon DNA vaccination in HLA-A2 transgenic mice. Cancer Immunol. Immunother. 58, 653–664 (2009).

    CAS  PubMed  Google Scholar 

  45. Concha-Benavente, F., Srivastava, R. M., Ferrone, S. & Ferris, R. L. EGFR-mediated tumor immunoescape: the imbalance between phosphorylated STAT1 and phosphorylated STAT3. Oncoimmunology 2, e27215 (2013).

    PubMed  PubMed Central  Google Scholar 

  46. Georgopoulos, N. T., Proffitt, J. L. & Blair, G. E. Transcriptional regulation of the major histocompatibility complex (MHC) class I heavy chain, TAP1 and LMP2 genes by the human papillomavirus (HPV) type 6b, 16 and 18 E7 oncoproteins. Oncogene 19, 4930–4935 (2000).

    CAS  PubMed  Google Scholar 

  47. Charni, S. et al. Oxidative phosphorylation induces de novo expression of the MHC class I in tumor cells through the ERK5 pathway. J. Immunol. 185, 3498–3503 (2010).

    CAS  PubMed  Google Scholar 

  48. Bartoszewski, R. et al. The unfolded protein response (UPR)-activated transcription factor X-box-binding protein 1 (XBP1) induces microRNA-346 expression that targets the human antigen peptide transporter 1 (TAP1) mRNA and governs immune regulatory genes. J. Biol. Chem. 286, 41862–41870 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Setiadi, A. F. et al. Epigenetic enhancement of antigen processing and presentation promotes immune recognition of tumors. Cancer Res. 68, 9601–9607 (2008).

    CAS  PubMed  Google Scholar 

  50. Khan, A. N., Gregorie, C. J. & Tomasi, T. B. Histone deacetylase inhibitors induce TAP, LMP, Tapasin genes and MHC class I antigen presentation by melanoma cells. Cancer Immunol. Immunother. 57, 647–654 (2008).

    CAS  PubMed  Google Scholar 

  51. Fruci, D. et al. Altered expression of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in transformed non-lymphoid human tissues. J. Cell. Physiol. 216, 742–749 (2008).

    CAS  PubMed  Google Scholar 

  52. Koopman, L. A., Corver, W. E., van der Slik, A. R., Giphart, M. J. & Fleuren, G. J. Multiple genetic alterations cause frequent and heterogeneous human histocompatibility leukocyte antigen class I loss in cervical cancer. J. Exp. Med. 191, 961–976 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Del Campo, A. B. et al. Immune escape of cancer cells with beta2-microglobulin loss over the course of metastatic melanoma. Int. J. Cancer 134, 102–113 (2014).

    PubMed  Google Scholar 

  54. Cabrera, T. et al. HLA class I expression in metastatic melanoma correlates with tumor development during autologous vaccination. Cancer Immunol. Immunother. 56, 709–717 (2007).

    CAS  PubMed  Google Scholar 

  55. Carretero, R. et al. Analysis of HLA class I expression in progressing and regressing metastatic melanoma lesions after immunotherapy. Immunogenetics 60, 439–447 (2008).

    CAS  PubMed  Google Scholar 

  56. Seliger, B. Novel insights into the molecular mechanisms of HLA class I abnormalities. Cancer Immunol. Immunother. 61, 249–254 (2012).

    CAS  PubMed  Google Scholar 

  57. Saric, T. et al. An IFNγ-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides. Nat. Immunol. 3, 1169–1176 (2002).

    CAS  PubMed  Google Scholar 

  58. Lampen, M. H. & van Hall, T. Strategies to counteract MHC-I defects in tumors. Curr. Opin. Immunol. 23, 293–298 (2011).

    CAS  PubMed  Google Scholar 

  59. Van Hall, T. et al. Selective cytotoxic T-lymphocyte targeting of tumor immune escape variants. Nat. Med. 12, 417–424 (2006).

    CAS  PubMed  Google Scholar 

  60. Seidel, U. J., Oliveira, C. C., Lampen, M. H. & Hall, T. A novel category of antigens enabling CTL immunity to tumor escape variants: Cinderella antigens. Cancer Immunol. Immunother. 61, 119–125 (2012).

    CAS  PubMed  Google Scholar 

  61. Oliveira, C. C. et al. Peptide transporter TAP mediates between competing antigen sources generating distinct surface MHC class I peptide repertoires. Eur. J. Immunol. 41, 3114–3124 (2011).

    CAS  PubMed  Google Scholar 

  62. Shastri, N., Nagarajan, N., Lind, K. C. & Kanaseki, T. Monitoring peptide processing for MHC class I molecules in the endoplasmic reticulum. Curr. Opin. Immunol. 26, 123–127 (2014).

    CAS  PubMed  Google Scholar 

  63. Oliveira, C. C. et al. New role of signal peptide peptidase to liberate C-terminal peptides for MHC class I presentation. J. Immunol. 191, 4020–4028 (2013).

    CAS  PubMed  Google Scholar 

  64. Oliveira, C. C. et al. Dominant contribution of the proteasome and metalloproteinases to TAP-independent MHC-I peptide repertoire. Mol. Immunol. 62, 129–136 (2014). This study describes processing mechanisms by which TAP-independent non-tolerized epitopes are presented by MHC class I of TAP-deficient tumour cells.

    CAS  PubMed  Google Scholar 

  65. Nagarajan, N. A., Gonzalez, F. & Shastri, N. Nonclassical MHC class Ib-restricted cytotoxic T cells monitor antigen processing in the endoplasmic reticulum. Nat. Immunol. 13, 579–586 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Chambers, B. et al. Induction of protective CTL immunity against peptide transporter TAP-deficient tumors through dendritic cell vaccination. Cancer Res. 67, 8450–8455 (2007).

    CAS  PubMed  Google Scholar 

  67. Lampen, M. H. et al. CD8+ T cell responses against TAP-inhibited cells are readily detected in the human population. J. Immunol. 185, 6508–6517 (2010).

    CAS  PubMed  Google Scholar 

  68. Durgeau, A. et al. Different expression levels of the TAP peptide transporter lead to recognition of different antigenic peptides by tumor-specific CTL. J. Immunol. 187, 5532–5539 (2011).

    CAS  PubMed  Google Scholar 

  69. Noman, M. Z. et al. Hypoxia-inducible miR-210 regulates the susceptibility of tumor cells to lysis by cytotoxic T cells. Cancer Res. 72, 4629–4641 (2012).

    CAS  PubMed  Google Scholar 

  70. Noman, M. Z. et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 211, 781–790 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Voron, T. et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med. 212, 139–148 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Akalay, I. et al. EMT impairs breast carcinoma cell susceptibility to CTL-mediated lysis through autophagy induction. Autophagy 9, 1104–1106 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Demotte, N. et al. Restoring the association of the T cell receptor with CD8 reverses anergy in human tumor-infiltrating lymphocytes. Immunity 28, 414–424 (2008).

    CAS  PubMed  Google Scholar 

  74. Motz, G. T. & Coukos, G. Deciphering and reversing tumor immune suppression. Immunity 39, 61–73 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Biswas, S. K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889–896 (2010).

    CAS  PubMed  Google Scholar 

  76. Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. De Vos van Steenwijk, P. J. et al. Tumor-infiltrating CD14-positive myeloid cells and CD8-positive T-cells prolong survival in patients with cervical carcinoma. Int. J. Cancer 133, 2884–2894 (2013).

    CAS  PubMed  Google Scholar 

  78. Ma, J. et al. The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time. BMC Cancer 10, 112 (2010).

    PubMed  PubMed Central  Google Scholar 

  79. Heys, S. D. et al. Characterisation of tumour-infiltrating macrophages: impact on response and survival in patients receiving primary chemotherapy for breast cancer. Breast Cancer Res. Treat. 135, 539–548 (2012).

    CAS  PubMed  Google Scholar 

  80. Ohri, C. M., Shikotra, A., Green, R. H., Waller, D. A. & Bradding, P. Macrophages within NSCLC tumour islets are predominantly of a cytotoxic M1 phenotype associated with extended survival. Eur. Respir. J. 33, 118–126 (2009).

    CAS  PubMed  Google Scholar 

  81. Heusinkveld, M. et al. M2 macrophages induced by prostaglandin E2 and IL-6 from cervical carcinoma are switched to activated M1 macrophages by CD4+ Th1 cells. J. Immunol. 187, 1157–1165 (2011).

    CAS  PubMed  Google Scholar 

  82. Lewis, C. E. & Pollard, J. W. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 66, 605–612 (2006).

    CAS  PubMed  Google Scholar 

  83. Coward, J. et al. Interleukin-6 as a therapeutic target in human ovarian cancer. Clin. Cancer Res. 17, 6083–6096 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Wouters, M. C. A. et al. Interleukin-6 receptor and its ligand interleukin-6 are opposite markers for survival and infiltration with mature myeloid cells in ovarian cancer. Oncoimmunology 3, e962397 (2015).

    PubMed  PubMed Central  Google Scholar 

  85. Predina, J. et al. Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery. Proc. Natl Acad. Sci. USA 110, E415–E424 (2013).

    CAS  PubMed  Google Scholar 

  86. Mantovani, A. & Allavena, P. The interaction of anticancer therapies with tumor-associated macrophages. J. Exp. Med. 212, 435–445 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. van der Sluis, T. C. et al. Therapeutic peptide vaccine-induced CD8 T cells strongly modulate intratumoral macrophages required for tumor regression. Cancer Immunol. Res. 3, 1042–1051 (2015). This report shows that TAMs can be modulated by vaccine-induced T cells to start contributing to the antitumour effect of specific anticancer vaccination in a mouse tumour model.

    CAS  PubMed  Google Scholar 

  88. Hagemann, T. et al. “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J. Exp. Med. 205, 1261–1268 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Van den Boorn, J. G. & Hartmann, G. Turning tumors into vaccines: co-opting the innate immune system. Immunity 39, 27–37 (2013).

    CAS  PubMed  Google Scholar 

  90. Dijkgraaf, E. M. et al. Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment. Cancer Res. 73, 2480–2492 (2013).

    CAS  PubMed  Google Scholar 

  91. Dijkgraaf, E. M. et al. A phase I trial combining carboplatin/doxorubicin with tocilizumab, an anti-IL-6R monoclonal antibody, and interferon-α2b in patients with recurrent epithelial ovarian cancer. Ann. Oncol. 26, 2141–2149 (2015).

    CAS  PubMed  Google Scholar 

  92. Panni, R. Z., Linehan, D. C. & DeNardo, D. G. Targeting tumor-infiltrating macrophages to combat cancer. Immunotherapy 5, 1075–1087 (2013).

    CAS  PubMed  Google Scholar 

  93. Arina, A. & Bronte, V. Myeloid-derived suppressor cell impact on endogenous and adoptively transferred T cells. Curr. Opin. Immunol. 33, 120–125 (2015).

    CAS  PubMed  Google Scholar 

  94. Marigo, I. et al. Tumor-induced tolerance and immune suppression depend on the C/EBPβ transcription factor. Immunity 32, 790–802 (2010).

    CAS  PubMed  Google Scholar 

  95. Arina, A. et al. Adoptively transferred immune T cells eradicate established tumors despite cancer-induced immune suppression. J. Immunol. 192, 1286–1293 (2014).

    CAS  PubMed  Google Scholar 

  96. Walter, S. et al. Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat. Med. 18, 1254–1261 (2012).

    CAS  PubMed  Google Scholar 

  97. Meyer, C. et al. Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol. Immunother. 63, 247–257 (2014).

    CAS  PubMed  Google Scholar 

  98. Kimura, T. et al. MUC1 vaccine for individuals with advanced adenoma of the colon: a cancer immunoprevention feasibility study. Cancer Prev. Res. (Phila) 6, 18–26 (2013). This article shows that cancer of the colon may be prevented by vaccination of patients at the premalignant adenoma stage.

    CAS  Google Scholar 

  99. Antonia, S. J. et al. Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer. Clin. Cancer Res. 12, 878–887 (2006).

    CAS  PubMed  Google Scholar 

  100. Bronte, V. et al. Identification of a CD11b+/Gr-1+/CD31+ myeloid progenitor capable of activating or suppressing CD8+ T cells. Blood 96, 3838–3846 (2000).

    CAS  PubMed  Google Scholar 

  101. Kerkar, S. P. et al. IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. J. Clin. Invest. 121, 4746–4757 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Steding, C. E. et al. The role of interleukin-12 on modulating myeloid-derived suppressor cells, increasing overall survival and reducing metastasis. Immunology 133, 221–238 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Bonertz, A. et al. Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. J. Clin. Invest. 119, 3311–3321 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Van der Burg, S. H. et al. Association of cervical cancer with the presence of CD4+ regulatory T cells specific for human papillomavirus antigens. Proc. Natl Acad. Sci. USA 104, 12087–12092 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Piersma, S. J., Welters, M. J. & van der Burg, S. H. Tumor-specific regulatory T cells in cancer patients. Hum. Immunol. 69, 241–249 (2008).

    CAS  PubMed  Google Scholar 

  106. Welters, M. J. et al. Success or failure of vaccination for HPV16-positive vulvar lesions correlates with kinetics and phenotype of induced T-cell responses. Proc. Natl Acad. Sci. USA 107, 11895–11899 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Zhou, G., Drake, C. G. & Levitsky, H. I. Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines. Blood 107, 628–636 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. De Vries, I. J. et al. Immunomonitoring tumor-specific T cells in delayed-type hypersensitivity skin biopsies after dendritic cell vaccination correlates with clinical outcome. J. Clin. Oncol. 23, 5779–5787 (2005).

    CAS  PubMed  Google Scholar 

  109. Rech, A. J. et al. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci. Transl Med. 4, 134ra62 (2012).

    PubMed  PubMed Central  Google Scholar 

  110. Huss, D. J. et al. In vivo maintenance of human regulatory T cells during CD25 blockade. J. Immunol. 194, 84–92 (2015).

    CAS  PubMed  Google Scholar 

  111. Colombo, M. P. & Piconese, S. Regulatory-T-cell inhibition versus depletion: the right choice in cancer immunotherapy. Nat. Rev. Cancer 7, 880–887 (2007).

    CAS  PubMed  Google Scholar 

  112. Alizadeh, D. & Larmonier, N. Chemotherapeutic targeting of cancer-induced immunosuppressive cells. Cancer Res. 74, 2663–2668 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Mitchell, D. A. et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 519, 366–369 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Van Hall, T. & van der Burg, S. H. Mechanisms of peptide vaccination in mouse models: tolerance, immunity, and hyperreactivity. Adv. Immunol. 114, 51–76 (2012).

    CAS  PubMed  Google Scholar 

  115. Arens, R., van Hall, T., van der Burg, S. H., Ossendorp, F. & Melief, C. J. Prospects of combinatorial synthetic peptide vaccine-based immunotherapy against cancer. Semin. Immunol. 25, 182–190 (2013).

    CAS  PubMed  Google Scholar 

  116. Klebanoff, C. A., Gattinoni, L. & Restifo, N. P. CD8+ T-cell memory in tumor immunology and immunotherapy. Immunol. Rev. 211, 214–224 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Klebanoff, C. A. et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc. Natl Acad. Sci. USA 102, 9571–9576 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. De Vos van Steenwijk, P. J. et al. The long-term immune response after HPV16 peptide vaccination in women with low-grade pre-malignant disorders of the uterine cervix: a placebo-controlled phase II study. Cancer Immunol. Immunother. 63, 147–160 (2014).

    CAS  PubMed  Google Scholar 

  119. Karbach, J. et al. Efficient in vivo priming by vaccination with recombinant NY-ESO-1 protein and CpG in antigen naive prostate cancer patients. Clin. Cancer Res. 17, 861–870 (2011).

    CAS  PubMed  Google Scholar 

  120. Stebbing, J. et al. An intra-patient placebo-controlled phase I trial to evaluate the safety and tolerability of intradermal IMM-101 in melanoma. Ann. Oncol. 23, 1314–1319 (2012).

    CAS  PubMed  Google Scholar 

  121. Rittig, S. M. et al. Intradermal vaccinations with RNA coding for TAA generate CD8+ and CD4+ immune responses and induce clinical benefit in vaccinated patients. Mol. Ther. 19, 990–999 (2011).

    CAS  PubMed  Google Scholar 

  122. Sampson, J. H. et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J. Clin. Oncol. 28, 4722–4729 (2010).

    PubMed  PubMed Central  Google Scholar 

  123. Van den Hende, M. et al. Skin reactions to human papillomavirus (HPV) 16 specific antigens intradermally injected in healthy subjects and patients with cervical neoplasia. Int. J. Cancer 123, 146–152 (2008).

    CAS  PubMed  Google Scholar 

  124. Coffman, R. L., Sher, A. & Seder, R. A. Vaccine adjuvants: putting innate immunity to work. Immunity 33, 492–503 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Mellman, I. & Steinman, R. M. Dendritic cells: specialized and regulated antigen processing machines. Cell 106, 255–258 (2001).

    CAS  PubMed  Google Scholar 

  127. Gay, N. J. & Gangloff, M. Structure and function of Toll receptors and their ligands. Annu. Rev. Biochem. 76, 141–165 (2007).

    CAS  PubMed  Google Scholar 

  128. 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).

    CAS  PubMed  Google Scholar 

  129. Welters, M. J. et al. Multiple CD4 and CD8 T-cell activation parameters predict vaccine efficacy in vivo mediated by individual DC-activating agonists. Vaccine 25, 1379–1389 (2007).

    CAS  PubMed  Google Scholar 

  130. Fu, J. et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci. Transl Med. 7, 283ra52 (2015). This study demonstrates that it is important for cancer vaccines to contain a strong adjuvant such as a STING agonist.

    PubMed  PubMed Central  Google Scholar 

  131. Burdette, D. L. & Vance, R. E. STING and the innate immune response to nucleic acids in the cytosol. Nat. Immunol. 14, 19–26 (2013).

    CAS  PubMed  Google Scholar 

  132. Zom, G. G., Khan, S., Filippov, D. V. & Ossendorp, F. TLR ligand–peptide conjugate vaccines: toward clinical application. Adv. Immunol. 114, 177–201 (2012).

    CAS  PubMed  Google Scholar 

  133. Wen, Y. & Collier, J. H. Supramolecular peptide vaccines: tuning adaptive immunity. Curr. Opin. Immunol. 35, 73–79 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Khan, S. et al. Distinct uptake mechanisms but similar intracellular processing of two different toll-like receptor ligand–peptide conjugates in dendritic cells. J. Biol. Chem. 282, 21145–21159 (2007).

    CAS  PubMed  Google Scholar 

  135. Van der Burg, S. H., Bijker, M. S., Welters, M. J., Offringa, R. & Melief, C. J. Improved peptide vaccine strategies, creating synthetic artificial infections to maximize immune efficacy. Adv. Drug Deliv. Rev. 58, 916–930 (2006).

    CAS  PubMed  Google Scholar 

  136. Daftarian, P. et al. Novel conjugates of epitope fusion peptides with CpG-ODN display enhanced immunogenicity and HIV recognition. Vaccine 23, 3453–3468 (2005).

    CAS  PubMed  Google Scholar 

  137. Zhang, H. et al. Comparing pooled peptides with intact protein for accessing cross-presentation pathways for protective CD8+ and CD4+ T cells. J. Biol. Chem. 284, 9184–9191 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Vecchi, S. et al. Conjugation of a TLR7 agonist and antigen enhances protection in the S. pneumoniae murine infection model. Eur. J. Pharm. Biopharm. 87, 310–317 (2014).

    CAS  PubMed  Google Scholar 

  139. Zom, G. G. et al. Efficient induction of antitumor immunity by synthetic toll-like receptor ligand–peptide conjugates. Cancer Immunol. Res. 2, 756–764 (2014). References 138 and 139 indicate that conjugates of TLR ligands and antigen are very efficient therapeutic vaccines, because they achieve both targeting of antigen to DCs and DC activation.

    CAS  PubMed  Google Scholar 

  140. Deres, K., Schild, H., Wiesmuller, K. H., Jung, G. & Rammensee, H. G. In vivo priming of virus-specific cytotoxic T lymphocytes with synthetic lipopeptide vaccine. Nature 342, 561–564 (1989).

    CAS  PubMed  Google Scholar 

  141. Van Montfoort, N. et al. Antigen storage compartments in mature dendritic cells facilitate prolonged cytotoxic T lymphocyte cross-priming capacity. Proc. Natl Acad. Sci. USA 106, 6730–6735 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Willems, M. M. et al. N-tetradecylcarbamyl lipopeptides as novel agonists for Toll-like receptor 2. J. Med. Chem. 57, 6873–6878 (2014).

    CAS  PubMed  Google Scholar 

  143. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Royal, R. E. et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 33, 828–833 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Gooden, M. et al. HLA-E expression by gynecological cancers restrains tumor-infiltrating CD8+ T lymphocytes. Proc. Natl Acad. Sci. USA 108, 10656–10661 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Piersma, S. J. et al. Human papilloma virus specific T cells infiltrating cervical cancer and draining lymph nodes show remarkably frequent use of HLA-DQ and -DP as a restriction element. Int. J. Cancer 122, 486–494 (2008).

    CAS  PubMed  Google Scholar 

  149. De Vos van Steenwijk, P. J. et al. An unexpectedly large polyclonal repertoire of HPV-specific T cells is poised for action in patients with cervical cancer. Cancer Res. 70, 2707–2717 (2010).

    CAS  PubMed  Google Scholar 

  150. Koch, M. et al. Tumor infiltrating T lymphocytes in colorectal cancer: tumor-selective activation and cytotoxic activity in situ. Ann. Surg. 244, 986–992 (2006).

    PubMed  PubMed Central  Google Scholar 

  151. Fridman, W. H., Pages, F., Sautes-Fridman, C. & Galon, J. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer 12, 298–306 (2012).

    CAS  PubMed  Google Scholar 

  152. Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480–489 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Van Elsas, A. et al. Elucidating the autoimmune and antitumor effector mechanisms of a treatment based on cytotoxic T lymphocyte antigen-4 blockade in combination with a B16 melanoma vaccine: comparison of prophylaxis and therapy. J. Exp. Med. 194, 481–489 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Duraiswamy, J., Kaluza, K. M., Freeman, G. J. & Coukos, G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 73, 3591–3603 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Van den Eertwegh, A. J. et al. Combined immunotherapy with granulocyte–macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 13, 509–517 (2012).

    CAS  PubMed  Google Scholar 

  156. Le, D. T. & Jaffee, E. M. Next-generation cancer vaccine approaches: integrating lessons learned from current successes with promising biotechnologic advances. J. Natl Compr. Canc. Netw. 11, 766–772 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Melero, I. et al. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat. Rev. Cancer 15, 457–472 (2015).

    CAS  PubMed  Google Scholar 

  158. Boissonnas, A., Fetler, L., Zeelenberg, I. S., Hugues, S. & Amigorena, S. In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor. J. Exp. Med. 204, 345–356 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  162. Fourcade, J. et al. PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8+ T cells induced by melanoma vaccines. Cancer Res. 74, 1045–1055 (2014).

    CAS  PubMed  Google Scholar 

  163. Soares, K. C. et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J. Immunother. 38, 1–11 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Church, S. E., Jensen, S. M., Antony, P. A., Restifo, N. P. & Fox, B. A. Tumor-specific CD4+ T cells maintain effector and memory tumor-specific CD8+ T cells. Eur. J. Immunol. 44, 69–79 (2014).

    CAS  PubMed  Google Scholar 

  165. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    CAS  PubMed  Google Scholar 

  166. Zitvogel, L., Galluzzi, L., Smyth, M. J. & Kroemer, G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 39, 74–88 (2013).

    CAS  PubMed  Google Scholar 

  167. Kang, T. H. et al. Chemotherapy acts as an adjuvant to convert the tumor microenvironment into a highly permissive state for vaccination-induced antitumor immunity. Cancer Res. 73, 2493–2504 (2013). This article describes favourable sculpting of the tumour microenvironment by chemotherapy that promotes more efficient therapeutic vaccine action.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Ramakrishnan, R. et al. Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J. Clin. Invest. 120, 1111–1124 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Bae, S. H. et al. Therapeutic synergy of human papillomavirus E7 subunit vaccines plus cisplatin in an animal tumor model: causal involvement of increased sensitivity of cisplatin-treated tumors to CTL-mediated killing in therapeutic synergy. Clin. Cancer Res. 13, 341–349 (2007).

    CAS  PubMed  Google Scholar 

  170. Tseng, C. W. et al. Pretreatment with cisplatin enhances E7-specific CD8+ T-cell-mediated antitumor immunity induced by DNA vaccination. Clin. Cancer Res. 14, 3185–3192 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Sin, J. I. et al. Adoptive transfer of human papillomavirus E7-specific CTL enhances tumor chemoresponse through the perforin/granzyme-mediated pathway. Mol. Ther. 17, 906–913 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Van der Most, R. G. et al. Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth. PLoS ONE 4, e6982 (2009).

    PubMed  PubMed Central  Google Scholar 

  173. Huang, X., Huang, G., Song, H. & Chen, L. Preconditioning chemotherapy with paclitaxel and cisplatin enhances the antitumor activity of cytokine induced-killer cells in a murine lung carcinoma model. Int. J. Cancer 129, 648–658 (2011).

    CAS  PubMed  Google Scholar 

  174. Nowak, A. K. et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J. Immunol. 170, 4905–4913 (2003).

    CAS  PubMed  Google Scholar 

  175. Tang, C. et al. Combining radiation and immunotherapy: a new systemic therapy for solid tumors? Cancer Immunol. Res. 2, 831–838 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Kleinovink, J. W. et al. Combination of photodynamic therapy and specific immunotherapy efficiently eradicates established tumors. Clin. Cancer Res. http://dx.doi.org/10.1158/1078-0432.CCR-15-0515 (2015).

  177. Peng, S. et al. Low-dose cyclophosphamide administered as daily or single dose enhances the antitumor effects of a therapeutic HPV vaccine. Cancer Immunol. Immunother. 62, 171–182 (2013).

    CAS  PubMed  Google Scholar 

  178. Ghiringhelli, F. et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol. Immunother. 56, 641–648 (2007).

    CAS  PubMed  Google Scholar 

  179. Vermeij, R. et al. Potentiation of a p53-SLP vaccine by cyclophosphamide in ovarian cancer: a single-arm phase II study. Int. J. Cancer 131, E670–E680 (2012).

    CAS  PubMed  Google Scholar 

  180. Rettig, L. et al. Gemcitabine depletes regulatory T-cells in human and mice and enhances triggering of vaccine-specific cytotoxic T-cells. Int. J. Cancer 129, 832–838 (2011).

    CAS  PubMed  Google Scholar 

  181. Dijkgraaf, E. M. et al. A Phase 1/2 study combining gemcitabine, Pegintron and p53 SLP vaccine in patients with platinum-resistant ovarian cancer. Oncotarget 6, 32228–32243 (2015).

    PubMed  PubMed Central  Google Scholar 

  182. Srivastava, M. K., Sinha, P., Clements, V. K., Rodriguez, P. & Ostrand-Rosenberg, S. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res. 70, 68–77 (2010).

    CAS  PubMed  Google Scholar 

  183. Suzuki, E., Kapoor, V., Jassar, A. S., Kaiser, L. R. & Albelda, S. M. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin. Cancer Res. 11, 6713–6721 (2005).

    CAS  PubMed  Google Scholar 

  184. Beatty, G. L. et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Kodumudi, K. N. et al. A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin. Cancer Res. 16, 4583–4594 (2010).

    CAS  PubMed  Google Scholar 

  186. Vincent, J. et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 70, 3052–3061 (2010).

    CAS  PubMed  Google Scholar 

  187. Sevko, A. et al. Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model. J. Immunol. 190, 2464–2471 (2013).

    CAS  PubMed  Google Scholar 

  188. 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). This report describes synergy between cisplatin chemotherapy and a therapeutic cancer vaccine, an effect based in part on cisplatin-enhanced apoptosis of cancer cells by TNF released from vaccine-induced T cells.

    CAS  PubMed  Google Scholar 

  189. Sato, Y. et al. Immunological evaluation of personalized peptide vaccination in combination with a 5-fluorouracil derivative (TS-1) for advanced gastric or colorectal carcinoma patients. Cancer Sci. 98, 1113–1119 (2007).

    CAS  PubMed  Google Scholar 

  190. Arlen, P. M. et al. A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. Clin. Cancer Res. 12, 1260–1269 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Masuzawa, T. et al. Phase I/II study of S-1 plus cisplatin combined with peptide vaccines for human vascular endothelial growth factor receptor 1 and 2 in patients with advanced gastric cancer. Int. J. Oncol. 41, 1297–1304 (2012).

    CAS  PubMed  Google Scholar 

  192. Suzuki, N. et al. A phase I clinical trial of vaccination with KIF20A-derived peptide in combination with gemcitabine for patients with advanced pancreatic cancer. J. Immunother. 37, 36–42 (2014).

    CAS  PubMed  Google Scholar 

  193. Nishida, S. et al. Wilms tumor gene (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer. J. Immunother. 37, 105–114 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Geller, M. A., Bui-Nguyen, T. M., Rogers, L. M. & Ramakrishnan, S. Chemotherapy induces macrophage chemoattractant protein-1 production in ovarian cancer. Int. J. Gynecol. Cancer 20, 918–925 (2010).

    PubMed  Google Scholar 

  195. Qian, D. Z. et al. CCL2 is induced by chemotherapy and protects prostate cancer cells from docetaxel-induced cytotoxicity. Prostate 70, 433–442 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Emens, L. A. et al. Timed sequential treatment with cyclophosphamide, doxorubicin, and an allogeneic granulocyte–macrophage colony-stimulating factor-secreting breast tumor vaccine: a chemotherapy dose-ranging factorial study of safety and immune activation. J. Clin. Oncol. 27, 5911–5918 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Nistico, P. et al. Chemotherapy enhances vaccine-induced antitumor immunity in melanoma patients. Int. J. Cancer 124, 130–139 (2009).

    CAS  PubMed  Google Scholar 

  198. Palermo, B. et al. Dacarbazine treatment before peptide vaccination enlarges T-cell repertoire diversity of melan-A-specific, tumor-reactive CTL in melanoma patients. Cancer Res. 70, 7084–7092 (2010).

    CAS  PubMed  Google Scholar 

  199. Van Poelgeest, M. I. et al. HPV16 synthetic long peptide (HPV16-SLP) vaccination therapy of patients with advanced or recurrent HPV16-induced gynecological carcinoma, a phase II trial. J. Transl Med. 11, 88 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Welters, M. J. et al. Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T-cell responses. Sci. Transl Med. [in the press]

  201. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02128126 (2016).

  202. Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Kohlmeyer, J. et al. Complete regression of advanced primary and metastatic mouse melanomas following combination chemoimmunotherapy. Cancer Res. 69, 6265–6274 (2009).

    CAS  PubMed  Google Scholar 

  204. Pilon-Thomas, S., Mackay, A., Vohra, N. & Mule, J. J. Blockade of programmed death ligand 1 enhances the therapeutic efficacy of combination immunotherapy against melanoma. J. Immunol. 184, 3442–3449 (2010).

    CAS  PubMed  Google Scholar 

  205. Ly, L. V. et al. Peptide vaccination after T-cell transfer causes massive clonal expansion, tumor eradication, and manageable cytokine storm. Cancer Res. 70, 8339–8346 (2010).

    CAS  PubMed  Google Scholar 

  206. Verdegaal, E. M. et al. Successful treatment of metastatic melanoma by adoptive transfer of blood-derived polyclonal tumor-specific CD4+ and CD8+ T cells in combination with low-dose interferon-α. Cancer Immunol. Immunother. 60, 953–963 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Lattanzi, L. et al. IFN-α boosts epitope cross-presentation by dendritic cells via modulation of proteasome activity. Immunobiology 216, 537–547 (2011).

    CAS  PubMed  Google Scholar 

  208. Singh, S. K. et al. The simultaneous ex vivo detection of low-frequency antigen-specific CD4+ and CD8+ T-cell responses using overlapping peptide pools. Cancer Immunol. Immunother. 61, 1953–1963 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Zeestraten, E. C. et al. Addition of interferon-α to the p53-SLP(R) vaccine results in increased production of interferon-γ in vaccinated colorectal cancer patients: a phase I/II clinical trial. Int. J. Cancer 132, 1581–1591 (2013).

    CAS  PubMed  Google Scholar 

  210. Rapoport, A. P. et al. Combination immunotherapy after ASCT for multiple myeloma using MAGE-A3/poly-ICLC immunizations followed by adoptive transfer of vaccine-primed and costimulated autologous T cells. Clin. Cancer Res. 20, 1355–1365 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Nelson, B. H. CD20+ B cells: the other tumor-infiltrating lymphocytes. J. Immunol. 185, 4977–4982 (2010).

    CAS  PubMed  Google Scholar 

  212. Germain, C., Gnjatic, S. & Dieu-Nosjean, M. C. Tertiary lymphoid structure-associated B cells are key players in anti-tumor immunity. Front. Immunol. 6, 67 (2015).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  214. Van Poelgeest, M. I. et al. Therapeutic vaccination with or without imiquimod as adjuvant for vulvar/vaginal intraepithelial neoplasia: an open-label randomised controlled phase 1/2 trial. Clin. Cancer Res. http://dx.doi.org/10.1158/1078-0432.CCR-15-2594 (2015). References 213 and 214 together show that therapeutic vaccination as monotherapy has clinical benefit in patients with premalignant vulvar intraepithelial neoplasia lesions caused by the tumour-inducing HPV16 and that clinical benefit is positively associated with vaccine-induced T cell responses against the oncoproteins of this virus.

  215. Daayana, S. et al. Phase II trial of imiquimod and HPV therapeutic vaccination in patients with vulval intraepithelial neoplasia. Br. J. Cancer 102, 1129–1136 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Trimble, C. L. et al. Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial. Lancet 386, 2078–2088 (2015). This report shows that therapeutic vaccination against HPV16 has clinical benefit as monotherapy in patients with cervical intraepithelial neoplasia.

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Czerniecki, B. J. et al. Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion. Cancer Res. 67, 1842–1852 (2007).

    CAS  PubMed  Google Scholar 

  218. Romero, I., Garrido, F. & Garcia-Lora, A. M. Metastases in immune-mediated dormancy: a new opportunity for targeting cancer. Cancer Res. 74, 6750–6757 (2014).

    CAS  PubMed  Google Scholar 

  219. Koebel, C. M. et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450, 903–907 (2007).

    CAS  PubMed  Google Scholar 

  220. Manley, C. A. et al. Xenogeneic murine tyrosinase DNA vaccine for malignant melanoma of the digit of dogs. J. Vet. Intern. Med. 25, 94–99 (2011).

    CAS  PubMed  Google Scholar 

  221. Morse, M. A. et al. A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer. Ann. Surg. 258, 879–886 (2013).

    PubMed  Google Scholar 

  222. Ibrahim, N. K. et al. Survival advantage in patients with metastatic breast cancer receiving endocrine therapy plus sialyl Tn–KLH vaccine: post hoc analysis of a large randomized trial. J. Cancer 4, 577–584 (2013).

    PubMed  PubMed Central  Google Scholar 

  223. Holmes, J. P. et al. Optimal dose and schedule of an HER-2/neu (E75) peptide vaccine to prevent breast cancer recurrence: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Cancer 113, 1666–1675 (2008).

    CAS  PubMed  Google Scholar 

  224. Mittendorf, E. A. et al. Clinical trial results of the HER-2/neu (E75) vaccine to prevent breast cancer recurrence in high-risk patients: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Cancer 118, 2594–2602 (2012).

    CAS  PubMed  Google Scholar 

  225. Landsberg, J. et al. Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature 490, 412–416 (2012).

    CAS  PubMed  Google Scholar 

  226. Schlecker, E. et al. Metalloprotease-mediated tumor cell shedding of B7-H6, the ligand of the natural killer cell-activating receptor NKp30. Cancer Res. 74, 3429–3440 (2014).

    CAS  PubMed  Google Scholar 

  227. Medema, J. P., de Jong, J., van Hall, T., Melief, C. J. & Offringa, R. Immune escape of tumors in vivo by expression of cellular FLICE- inhibitory protein. J. Exp. Med. 190, 1033–1038 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Munn, D. H. & Mellor, A. L. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 34, 137–143 (2013).

    CAS  PubMed  Google Scholar 

  229. Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Fuertes, M. B. et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cells. J. Exp. Med. 208, 2005–2016 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Pozzi, L. A., Maciaszek, J. W. & Rock, K. L. Both dendritic cells and macrophages can stimulate naive CD8 T cells in vivo to proliferate, develop effector function, and differentiate into memory cells. J. Immunol. 175, 2071–2081 (2005).

    CAS  PubMed  Google Scholar 

  232. Lyman, M. A. et al. The fate of low affinity tumor-specific CD8+ T cells in tumor-bearing mice. J. Immunol. 174, 2563–2572 (2005).

    CAS  PubMed  Google Scholar 

  233. Wong, S. B., Bos, R. & Sherman, L. A. Tumor-specific CD4+ T cells render the tumor environment permissive for infiltration by low-avidity CD8+ T cells. J. Immunol. 180, 3122–3131 (2008).

    CAS  PubMed  Google Scholar 

  234. Driessens, G., Kline, J. & Gajewski, T. F. Costimulatory and coinhibitory receptors in anti-tumor immunity. Immunol. Rev. 229, 126–144 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Schwartz, R. H. T cell anergy. Annu. Rev. Immunol. 21, 305–334 (2003).

    CAS  PubMed  Google Scholar 

  236. Croft, M., Benedict, C. A. & Ware, C. F. Clinical targeting of the TNF and TNFR superfamilies. Nat. Rev. Drug Discov. 12, 147–268 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002).

    CAS  PubMed  Google Scholar 

  238. Parry, R. V. et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell. Biol. 25, 9543–9553 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  240. Curtsinger, J. M., Gerner, M. Y., Lins, D. C. & Mescher, M. F. Signal 3 availability limits the CD8 T cell response to a solid tumor. J. Immunol. 178, 6752–6760 (2007).

    CAS  PubMed  Google Scholar 

  241. Sikora, A. G. et al. IFN-alpha enhances peptide vaccine-induced CD8+ T cell numbers, effector function, and antitumor activity. J. Immunol. 182, 7398–7407 (2009).

    CAS  PubMed  Google Scholar 

  242. Boyman, O. & Sprent, J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat. Rev. Immunol. 12, 180–190 (2012).

    CAS  PubMed  Google Scholar 

  243. Redeker, A. et al. The quantity of autocrine IL-2 governs the expansion potential of CD8+ T cells. J. Immunol. 195, 4792–4801 (2015).

    CAS  PubMed  Google Scholar 

  244. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).

    CAS  PubMed  Google Scholar 

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Acknowledgements

Writing of this review was supported by Dutch Cancer Society grant KWO 2009-4400 to C.J.M.M. and S.H.v.d.B.

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Authors and Affiliations

  1. Department of Clinical Oncology, Leiden University Medical Center,

    Sjoerd H. van der Burg & Thorbald van Hall

  2. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands

    Ramon Arens, Ferry Ossendorp & Cornelis J. M. Melief

  3. ISA Pharmaceuticals, J. H. Oortweg 19, Leiden, 2333 CH, The Netherlands

    Cornelis J. M. Melief

Authors
  1. Sjoerd H. van der Burg
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  2. Ramon Arens
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  3. Ferry Ossendorp
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  4. Thorbald van Hall
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  5. Cornelis J. M. Melief
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Corresponding authors

Correspondence to Sjoerd H. van der Burg or Cornelis J. M. Melief.

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Competing interests

C.J.M.M. reports having a stock-appreciation right that is the equivalent of a stock option in 1% of the issued share capital of ISA Pharmaceuticals, Leiden, Netherlands, is being named as an inventor on the patent for the use of synthetic long peptides as vaccines and is employed as Chief Scientific Officer by ISA Pharmaceuticals, which exploits this patent. S.H.v.d.B. is one of the inventors on the patent for the use of synthetic long peptides as a vaccine but holds no financial interest. S.H.v.d.B. serves as a paid member of the strategy board of ISA Pharmaceuticals. S.H.v.d.B. and T.v.H. are named as inventor on a patent indicating natural killer cell receptor A (NKG2A) as checkpoint molecule involved in vaccine therapy and receive research support from Innate Pharma, Marseille, France, for their studies on this topic. F.O. and C.J.M.M. are named as inventor on a patent involving an improved Toll-like receptor 2 (TLR2) ligand (Amplivant, manufactured by ISA Pharmaceuticals) as an adjuvant for defined T cell vaccines. R.A. declares no competing interests.

Supplementary information

Supplementary information S1 (box)

Immunomonitoring (PDF 358 kb)

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Glossary

Adjuvants

Substances that can be added to vaccines to enhance the immunogenicity of an antigen.

Vaccine platform

The basic form that different vaccines are based on, such as peptides, recombinant DNA orh RNA, or dendritic cells.

Oncolytic vaccines

Vaccines containing oncolytic viruses, which preferentially kill tumour cells and stimulate immune responses to tumour antigens.

PANVAC

Recombinant viruses expressing carcinoembryonic antigen (CEA), mucin 1 (MUC1) and the co-stimulatory molecules B7.1 (also known as CD80), intercellular adhesion molecule 1 (ICAM1) and lymphocyte function-associated antigen 3 (LFA3).

Second-in-class mutant epitopes

Subdominant T cell epitopes that are still important mediators of tumour rejection.

Medullary thymic epithelial cells

Cells that display 'self'-antigens to developing T cells. Upon antigen recognition, these 'self-reactive' T cells die via programmed cell death and as such are deleted from the T cell repertoire. This process depends on the ectopic expression of tissue-specific antigens, which is regulated by the autoimmune regulator AIRE.

Neo-epitopes

T cell antigens that are newly created by mutations in the DNA encoding normal proteins.

Transporter associated with antigen processing

(TAP). A protein complex responsible for the delivery of peptides from the cytosol to the endoplasmic reticulum, where major histocompatibility complex (MHC) class I peptide loading takes place.

Toll-like receptors

One of several types of pattern recognition receptor that are expressed by antigen- presenting cells and are important for activation of the adaptive immune system.

Pattern recognition receptor

A type of receptor expressed by cells of the innate immune system that recognizes molecular patterns of pathogens or cell damage.

Polyinosinic:polycytidylic acid

(Poly(I:C)). A double-stranded RNA analogue that stimulates the immune system by binding to Toll-like receptor 3.

Stimulator of IFN genes

(STING). Also known as TMEM173, MITA, ERIS and MPYS. A transmembrane protein localized to the endoplasmic reticulum that works as a direct cytosolic DNA sensor and as an adaptor protein in type I interferon (IFN) signalling. Activation results in the production of IFNα and IFNβ. IFN-mediated activation of dendritic cells is important for the induction of tumour-specific T cells.

Host conditioning

Lymphodepletion to eliminate regulatory T cells and cytokine sinks, and to activate dendritic cells before adoptive cell transfer commences.

Mutanome

Neo-epitopes based on the total somatic mutations in the genome.

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van der Burg, S., Arens, R., Ossendorp, F. et al. Vaccines for established cancer: overcoming the challenges posed by immune evasion. Nat Rev Cancer 16, 219–233 (2016). https://doi.org/10.1038/nrc.2016.16

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