Table of Contents Author Guidelines Submit a Manuscript
Clinical and Developmental Immunology
Volume 2012, Article ID 890178, 12 pages
http://dx.doi.org/10.1155/2012/890178
Review Article

Cytotoxic Chemotherapy and CD4+ Effector T Cells: An Emerging Alliance for Durable Antitumor Effects

1Cancer Immunotherapy Program, Cancer Center, Georgia Health Sciences University, Augusta, GA 30912, USA
2Hematology/Oncology Section, Department of Medicine, School of Medicine, Georgia Health Sciences University, Augusta, GA, USA

Received 12 July 2011; Revised 1 November 2011; Accepted 5 November 2011

Academic Editor: Takami Sato

Copyright © 2012 Zhi-Chun Ding and Gang Zhou. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. L. A. Emens, J. P. Machiels, R. T. Reilly, and E. M. Jaffee, “Chemotherapy: friend or foe to cancer vaccines?” Current Opinion in Molecular Therapeutics, vol. 3, no. 1, pp. 77–84, 2001. View at Google Scholar · View at Scopus
  2. R. A. Lake and B. W. S. Robinson, “Immunotherapy and chemotherapy—a practical partnership,” Nature Reviews Cancer, vol. 5, no. 5, pp. 397–405, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  3. G. C. Prendergast and E. M. Jaffee, “Cancer immunologists and cancer biologists: why we didn't talk then but need to now,” Cancer Research, vol. 67, no. 8, pp. 3500–3504, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  4. K. Hung, R. Hayashi, A. Lafond-Walker, C. Lowenstein, D. Pardoll, and H. Levitsky, “The central role of CD4+ T cells in the antitumor immune response,” Journal of Experimental Medicine, vol. 188, no. 12, pp. 2357–2368, 1998. View at Publisher · View at Google Scholar · View at Scopus
  5. P. A. Antony, C. A. Piccirillo, A. Akpinarli et al., “CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells,” Journal of Immunology, vol. 174, no. 5, pp. 2591–2601, 2005. View at Google Scholar · View at Scopus
  6. A. Corthay, D. K. Skovseth, K. U. Lundin et al., “Primary antitumor immune response mediated by CD4+ T cells,” Immunity, vol. 22, no. 3, pp. 371–383, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  7. A. Perez-Diez, N. T. Joncker, K. Choi et al., “CD4 cells can be more efficient at tumor rejection than CD8 cells,” Blood, vol. 109, no. 12, pp. 5346–5354, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  8. N. N. Hunder, H. Wallen, J. Cao et al., “Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1,” The New England Journal of Medicine, vol. 358, no. 25, pp. 2698–2703, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  9. K. Rakhra, P. Bachireddy, T. Zabuawala et al., “CD4+ T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation,” Cancer Cell, vol. 18, no. 5, pp. 485–498, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  10. T. Borsos, R. C. Bast Jr., and S. H. Ohanian, “Induction of tumor immunity by intratumoral chemotherapy,” Annals of the New York Academy of Sciences, vol. 276, pp. 565–572, 1976. View at Google Scholar · View at Scopus
  11. A. Fefer, A. B. Einstein, and M. A. Cheever, “Adoptive chemoimmunotherapy of cancer in animals: a review of results, principles, and problems,” Annals of the New York Academy of Sciences, vol. 277, pp. 492–504, 1976. View at Google Scholar · View at Scopus
  12. L. Zitvogel, L. Apetoh, F. Ghiringhelli, F. André, A. Tesniere, and G. Kroemer, “The anticancer immune response: indispensable for therapeutic success?” Journal of Clinical Investigation, vol. 118, no. 6, pp. 1991–2001, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  13. M. Obeid, A. Tesniere, F. Ghiringhelli et al., “Calreticulin exposure dictates the immunogenicity of cancer cell death,” Nature Medicine, vol. 13, no. 1, pp. 54–61, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. L. Apetoh, F. Ghiringhelli, A. Tesniere et al., “Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy,” Nature Medicine, vol. 13, no. 9, pp. 1050–1059, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  15. F. Ghiringhelli, L. Apetoh, A. Tesniere et al., “Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors,” Nature Medicine, vol. 15, no. 10, pp. 1170–1178, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. J. L. Guerriero, D. Ditsworth, J. M. Catanzaro et al., “DNA alkylating therapy induces tumor regression through an HMGB1-mediated activation of innate immunity,” Journal of Immunology, vol. 186, no. 6, pp. 3517–3526, 2011. View at Publisher · View at Google Scholar · View at PubMed
  17. G. Schiavoni, A. Sistigu, M. Valentini et al., “Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis,” Cancer Research, vol. 71, no. 3, pp. 768–778, 2011. View at Publisher · View at Google Scholar · View at PubMed
  18. A. K. Nowak, R. A. Lake, A. L. Marzo 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,” Journal of Immunology, vol. 170, no. 10, pp. 4905–4913, 2003. View at Google Scholar · View at Scopus
  19. D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, pp. 646–674, 2011. View at Google Scholar
  20. H. T. Khong and N. P. Restifo, “Natural selection of tumor variants in the generation of "tumor escape" phenotypes,” Nature Immunology, vol. 3, no. 11, pp. 999–1005, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. G. P. Dunn, A. T. Bruce, H. Ikeda, L. J. Old, and R. D. Schreiber, “Cancer immunoediting: from immunosurveillance to tumor escape,” Nature Immunology, vol. 3, no. 11, pp. 991–998, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  22. W. Zou, “Immunosuppressive networks in the tumour environment and their therapeutic relevance,” Nature Reviews Cancer, vol. 5, no. 4, pp. 263–274, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. M. E. C. Lutsiak, R. T. Semnani, R. De Pascalis, S. V. S. Kashmiri, J. Schlom, and H. Sabzevari, “Inhibition of CD4+25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide,” Blood, vol. 105, no. 7, pp. 2862–2868, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  24. R. G. Van Der Most, A. J. Currie, S. Mahendran et al., “Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy,” Cancer Immunology, Immunotherapy, vol. 58, no. 8, pp. 1219–1228, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  25. M. Awwad and R. J. North, “Cyclophosphamide (Cy)-facilitated adoptive immunotherapy of a Cy-resistant tumour. Evidence that Cy permits the expression of adoptive T-cell mediated immunity by removing suppressor T cells rather than by reducing tumour burden,” Immunology, vol. 65, no. 1, pp. 87–92, 1988. View at Google Scholar · View at Scopus
  26. F. Ghiringhelli, C. Menard, P. E. Puig 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 Immunology, Immunotherapy, vol. 56, no. 5, pp. 641–648, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. A. M. Ercolini, B. H. Ladle, E. A. Manning et al., “Recruitment of latent pools of high-avidity CD8+ T cells to the antitumor immune response,” Journal of Experimental Medicine, vol. 201, no. 10, pp. 1591–1602, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. T. Nakahara, H. Uchi, A. M. Lesokhin et al., “Cyclophosphamide enhances immunity by modulating the balance of dendritic cell subsets in lymphoid organs,” Blood, vol. 115, no. 22, pp. 4384–4392, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. E. Suzuki, V. Kapoor, A. S. Jassar, L. R. Kaiser, and S. M. Albelda, “Gemcitabine selectively eliminates splenic Gr-1+/CD11b + myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity,” Clinical Cancer Research, vol. 11, no. 18, pp. 6713–6721, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  30. J. P. H. Machiels, R. Todd Reilly, L. A. Emens et al., “Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice,” Cancer Research, vol. 61, no. 9, pp. 3689–3697, 2001. View at Google Scholar · View at Scopus
  31. C. A. Klebanoff, H. T. Khong, P. A. Antony, D. C. Palmer, and N. P. Restifo, “Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy,” Trends in Immunology, vol. 26, no. 2, pp. 111–117, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  32. L. Gattinoni, S. E. Finkelstein, C. A. Klebanoff et al., “Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells,” Journal of Experimental Medicine, vol. 202, no. 7, pp. 907–912, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  33. L. Bracci, F. Moschella, P. Sestili et al., “Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration,” Clinical Cancer Research, vol. 13, no. 2 I, pp. 644–653, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  34. F. Moschella, M. Valentini, E. Aricò et al., “Unraveling cancer chemoimmunotherapy mechanisms by gene and protein expression profiling of responses to cyclophosphamide,” Cancer Research, vol. 71, no. 10, pp. 3528–3539, 2011. View at Publisher · View at Google Scholar · View at PubMed
  35. M. Montoya, G. Schiavoni, F. Mattei et al., “Type I interferons produced by dendritic cells promote their phenotypic and functional activation,” Blood, vol. 99, no. 9, pp. 3263–3271, 2002. View at Publisher · View at Google Scholar · View at Scopus
  36. G. Schiavoni, F. Mattei, T. Di Pucchio et al., “Cyclophosphamide induces type I interferon and augments the number of CD44(hi) T lymphocytes in mice: implications for strategies of chemoimmunotherapy of cancer,” Blood, vol. 95, no. 6, pp. 2024–2030, 2000. View at Google Scholar · View at Scopus
  37. J. M. Curtsinger, J. O. Valenzuela, P. Agarwal, D. Lins, and M. F. Mescher, “Cutting edge: type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation,” Journal of Immunology, vol. 174, no. 8, pp. 4465–4469, 2005. View at Google Scholar · View at Scopus
  38. M. L. Salem, A. N. Kadima, S. A. El-Naggar et al., “Defining the ability of cyclophosphamide preconditioning to enhance the antigen-specific CD8+ T-cell response to peptide vaccination: creation of a beneficial host microenvironment involving type I IFNs and myeloid cells,” Journal of Immunotherapy, vol. 30, no. 1, pp. 40–53, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  39. B. A. Pockaj, R. M. Sherry, J. P. Wei et al., “Localization of 111indium-labeled tumor infiltrating lymphocytes to tumor in patients receiving adoptive immunotherapy: augmentation with cyclophosphamide and correlation with response,” Cancer, vol. 73, no. 6, pp. 1731–1737, 1994. View at Google Scholar · View at Scopus
  40. R. Ramakrishnan, D. Assudani, S. Nagaraj et al., “Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice,” Journal of Clinical Investigation, vol. 120, no. 4, pp. 1111–1124, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. R. G. van der Most, A. J. Currie, A. L. Cleaver et al., “Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth,” PLoS ONE, vol. 4, no. 9, article e6982, 2009. View at Publisher · View at Google Scholar · View at PubMed
  42. D. Hirschhorn-Cymerman, G. A. Rizzuto, T. Merghoub et al., “OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis,” Journal of Experimental Medicine, vol. 206, no. 5, pp. 1103–1116, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  43. M. J. Turk, J. A. Guevara-Patiño, G. A. Rizzuto, M. E. Engelhorn, and A. N. Houghton, “Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells,” Journal of Experimental Medicine, vol. 200, no. 6, pp. 771–782, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  44. M. L. Salem, S. A. El-Naggar, and D. J. Cole, “Cyclophosphamide induces bone marrow to yield higher numbers of precursor dendritic cells in vitro capable of functional antigen presentation to T cells in vivo,” Cellular Immunology, vol. 261, no. 2, pp. 134–143, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. V. Radojcic, K. B. Bezak, M. Skarica et al., “Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination,” Cancer Immunology, Immunotherapy, vol. 59, no. 1, pp. 137–148, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  46. S. L. Constant and K. Bottomly, “Induction of TH1 and TH2 CD4+ T cell responses: the alternative approaches,” Annual Review of Immunology, vol. 15, pp. 297–322, 1997. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  47. J. Zhu, H. Yamane, and W. E. Paul, “Differentiation of effector CD4+ T cell populations,” Annual Review of Immunology, vol. 28, pp. 445–489, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  48. J. O'Shea and W. E. Paul, “Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells,” Science, vol. 327, no. 5969, pp. 1098–1102, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  49. D. G. DeNardo, J. B. Barreto, P. Andreu et al., “CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages,” Cancer Cell, vol. 16, no. 2, pp. 91–102, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  50. T. Nishimura, K. Iwakabe, M. Sekimoto et al., “Distinct role of antigen-specific T helper type 1 (Th1) and Th2 cells in tumor eradication in vivo,” Journal of Experimental Medicine, vol. 190, no. 5, pp. 617–627, 1999. View at Publisher · View at Google Scholar · View at Scopus
  51. G. Murugaiyan and B. Saha, “Protumor vs antitumor functions of IL-17,” Journal of Immunology, vol. 183, no. 7, pp. 4169–4175, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  52. P. Muranski, A. Boni, P. A. Antony et al., “Tumor-specific Th17-polarized cells eradicate large established melanoma,” Blood, vol. 112, no. 2, pp. 362–373, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  53. N. Martin-Orozco, P. Muranski, Y. Chung et al., “T helper 17 cells promote cytotoxic T cell activation in tumor immunity,” Immunity, vol. 31, no. 5, pp. 787–798, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  54. S. Wu, K. J. Rhee, E. Albesiano et al., “A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses,” Nature Medicine, vol. 15, no. 9, pp. 1016–1022, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  55. L. Wang, T. Yi, M. Kortylewski, D. M. Pardoll, D. Zeng, and H. Yu, “IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway,” Journal of Experimental Medicine, vol. 206, no. 7, pp. 1457–1464, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. G. Zhou, C. G. Drake, and H. I. Levitsky, “Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines,” Blood, vol. 107, no. 2, pp. 628–636, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  57. T. Hiura, H. Kagamu, S. Miura et al., “Both regulatory T cells and antitumor effector T cells are primed in the same draining lymph nodes during tumor progression,” Journal of Immunology, vol. 175, no. 8, pp. 5058–5066, 2005. View at Google Scholar · View at Scopus
  58. S. A. Quezada, K. S. Peggs, M. A. Curran, and J. P. Allison, “CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells,” Journal of Clinical Investigation, vol. 116, no. 7, pp. 1935–1945, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  59. F. Ghiringhelli, C. Ménard, M. Terme et al., “CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-β-dependent manner,” Journal of Experimental Medicine, vol. 202, no. 8, pp. 1075–1085, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  60. S. Roux, L. Apetoh, F. Chalmin et al., “CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer,” Journal of Clinical Investigation, vol. 118, no. 11, pp. 3751–3761, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. P. D. Greenberg, M. A. Cheever, and A. Fefer, “Eradication of disseminated murine leukemia by chemoimmunotherapy with cyclophosphamide and adoptively transferred immune syngeneic Lyt-1+2- lymphocytes,” Journal of Experimental Medicine, vol. 154, no. 3, pp. 952–963, 1981. View at Google Scholar · View at Scopus
  62. E. Proietti, G. Greco, B. Garrone et al., “Importance of cyclophosphamide-induced bystander effect on T cells for a successful tumor eradication in response to adoptive immunotherapy in mice,” Journal of Clinical Investigation, vol. 101, no. 2, pp. 429–441, 1998. View at Google Scholar · View at Scopus
  63. K. Chamoto, T. Tsuji, H. Funamoto et al., “Potentiation of tumor eradication by adoptive immunotherapy with T-cell receptor gene-transduced T-helper type 1 cells,” Cancer Research, vol. 64, no. 1, pp. 386–390, 2004. View at Publisher · View at Google Scholar · View at Scopus
  64. Z. C. Ding, B. R. Blazar, A. L. Mellor, D. H. Munn, and G. Zhou, “Chemotherapy rescues tumor-driven aberrant CD4+ T-cell differentiation and restores an activated polyfunctional helper phenotype,” Blood, vol. 115, no. 12, pp. 2397–2406, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  65. P. Matar, V. R. Rozados, S. I. Gervasoni, and O. G. Scharovsky, “Th2/Th1 switch induced by a single low dose of cyclophosphamide in a rat metastatic lymphoma model,” Cancer Immunology, Immunotherapy, vol. 50, no. 11, pp. 588–596, 2002. View at Publisher · View at Google Scholar · View at PubMed
  66. S. A. Quezada, T. R. Simpson, K. S. Peggs et al., “Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts,” Journal of Experimental Medicine, vol. 207, no. 3, pp. 637–650, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  67. S. Viaud, C. Flament, M. Zoubir et al., “Cyclophosphamide induces differentiation of Th17 cells in cancer patients,” Cancer Research, vol. 71, no. 3, pp. 661–665, 2011. View at Publisher · View at Google Scholar · View at PubMed
  68. Y. Ma, L. Aymeric, C. Locher et al., “Contribution of IL-17-producing γδ T cells to the efficacy of anticancer chemotherapy,” Journal of Experimental Medicine, vol. 208, no. 3, pp. 491–503, 2011. View at Publisher · View at Google Scholar · View at PubMed
  69. A. Le Bon and D. F. Tough, “Links between innate and adaptive immunity via type I interferon,” Current Opinion in Immunology, vol. 14, no. 4, pp. 432–436, 2002. View at Publisher · View at Google Scholar · View at Scopus
  70. M. P. Longhi, C. Trumpfheller, J. Idoyaga et al., “Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant,” Journal of Experimental Medicine, vol. 206, no. 7, pp. 1589–1602, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  71. L. Pace, S. Vitale, B. Dettori et al., “APC activation by IFN-α decreases regulatory T cell and enhances Th cell functions,” Journal of Immunology, vol. 184, no. 11, pp. 5969–5979, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  72. M. Pellegrini, T. Calzascia, A. R. Elford et al., “Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies,” Nature Medicine, vol. 15, no. 5, pp. 528–536, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  73. S. A. Rosenberg, C. Sportès, M. Ahmadzadeh et al., “IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells,” Journal of Immunotherapy, vol. 29, no. 3, pp. 313–319, 2006. View at Publisher · View at Google Scholar · View at Scopus
  74. A. Andersson, S. C. Yang, M. Huang et al., “IL-7 promotes CXCR3 ligand-dependent T cell antitumor reactivity in lung cancer,” Journal of Immunology, vol. 182, no. 11, pp. 6951–6958, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  75. S. R. M. Bennett, F. R. Carbone, F. Karamalis, R. A. Flavell, J. F. A. P. Miller, and W. R. Heath, “Help for cytotoxic-T-cell responses is mediated by CD4O signalling,” Nature, vol. 393, no. 6684, pp. 478–480, 1998. View at Google Scholar · View at Scopus
  76. J. P. Ridge, F. Di Rosa, and P. Matzinger, “A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell,” Nature, vol. 393, no. 6684, pp. 474–478, 1998. View at Google Scholar · View at Scopus
  77. S. P. Schoenberger, R. E. M. Toes, E. I. H. Van Dervoort, R. Offringa, and C. J. M. Melief, “T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD4OL interactions,” Nature, vol. 393, no. 6684, pp. 480–483, 1998. View at Google Scholar · View at Scopus
  78. K. A. Shafer-Weaver, S. K. Watkins, M. J. Anderson et al., “Immunity to murine prostatic tumors: continuous provision of T-cell help prevents CD8 T-cell tolerance and activates tumor-infiltrating dendritic cells,” Cancer Research, vol. 69, no. 15, pp. 6256–6264, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  79. Y. C. Nesbeth, D. G. Martinez, S. Toraya et al., “CD4+ T cells elicit host immune responses to MHC class II - ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells,” Journal of Immunology, vol. 184, no. 10, pp. 5654–5662, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  80. A. L. Marzo, B. F. Kinnear, R. A. Lake et al., “Tumor-specific CD4+ T cells have a major 'post-licensing' role in CTL mediated anti-tumor immunity,” Journal of Immunology, vol. 165, no. 11, pp. 6047–6055, 2000. View at Google Scholar · View at Scopus
  81. Y. Nakanishi, B. Lu, C. Gerard, and A. Iwasaki, “CD8 + T lymphocyte mobilization to virus-infected tissue requires CD4 + T-cell help,” Nature, vol. 462, no. 7272, pp. 510–513, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  82. R. Bos and L. A. Sherman, “CD4+ T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8+ T lymphocytes,” Cancer Research, vol. 70, no. 21, pp. 8368–8377, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  83. Z. Qin and T. Blankenstein, “CD4+ T cell-mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFNγ receptor expression by nonhematopoietic cells,” Immunity, vol. 12, no. 6, pp. 677–686, 2000. View at Google Scholar · View at Scopus
  84. B. Zhang, T. Karrison, D. A. Rowley, and H. Schreiber, “IFN-γ- and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers,” Journal of Clinical Investigation, vol. 118, no. 4, pp. 1398–1404, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  85. O. A. W. Haabeth, K. B. Lorvik, C. Hammarström et al., “Inflammation driven by tumour-specific Th1 cells protects against B-cell cancer,” Nature Communications, vol. 2, no. 1, article 240, 2011. View at Publisher · View at Google Scholar · View at PubMed
  86. G. L. Beatty, E. G. Chiorean, M. P. Fishman et al., “CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans,” Science, vol. 331, no. 6024, pp. 1612–1616, 2011. View at Publisher · View at Google Scholar · View at PubMed
  87. A. Mantovani, P. Allavena, A. Sica, and F. Balkwill, “Cancer-related inflammation,” Nature, vol. 454, no. 7203, pp. 436–444, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  88. S. I. Grivennikov, F. R. Greten, and M. Karin, “Immunity, inflammation, and cancer,” Cell, vol. 140, no. 6, pp. 883–899, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  89. E. Von Stebut, J. M. Ehrchen, Y. Belkaid et al., “Interleukin 1α promotes TH1 differentiation and inhibits disease progression in Leishmania major-susceptible BALB/c mice,” Journal of Experimental Medicine, vol. 198, no. 2, pp. 191–199, 2003. View at Publisher · View at Google Scholar · View at PubMed
  90. S. Z. Ben-Sasson, J. Hu-Li, J. Quiel et al., “IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 17, pp. 7119–7124, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  91. K. M. E. Gallagher, S. Lauder, I. W. Rees, A. M. Gallimore, and A. J. Godkin, “Type I interferon (IFNα) acts directly on human memory CD4+ T cells altering their response to antigen,” Journal of Immunology, vol. 183, no. 5, pp. 2915–2920, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  92. C. Havenar-Daughton, G. A. Kolumam, and K. Murali-Krishna, “Cutting edge: the direct action of type I IFN on CD4 T cells is critical for sustaining clonal expansion in response to a viral but not a bacterial infection,” Journal of Immunology, vol. 176, no. 6, pp. 3315–3319, 2006. View at Google Scholar · View at Scopus
  93. A. G. Sikora, N. Jaffarzad, Y. Hailemichael et al., “IFN-α enhances peptide vaccine-induced CD8+ T cell numbers, effector function, and antitumor activity,” Journal of Immunology, vol. 182, no. 12, pp. 7398–7407, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  94. C. Pasare and R. Medzhitov, “Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells,” Science, vol. 299, no. 5609, pp. 1033–1036, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  95. B. Baban, P. R. Chandler, M. D. Sharma et al., “IDO activates regulatory T cells and blocks their conversion into Th17-like T cells,” Journal of Immunology, vol. 183, no. 4, pp. 2475–2483, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  96. M. D. Sharma, D. Y. Hou, Y. Liu et al., “Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes,” Blood, vol. 113, no. 24, pp. 6102–6111, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  97. L. Li, J. Kim, and V. A. Boussiotis, “IL-1β-mediated signals preferentially drive conversion of regulatory T cells but not conventional T cells into IL-17-producing cells,” Journal of Immunology, vol. 185, no. 7, pp. 4148–4153, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  98. X. Song, E. Voronov, T. Dvorkin et al., “Differential effects of IL-1α and IL-1β on Tumorigenicity Patterns and Invasiveness,” Journal of Immunology, vol. 171, no. 12, pp. 6448–6456, 2003. View at Google Scholar · View at Scopus
  99. F. Vidal-Vanaclocha, C. Amezaga, A. Asumendi, G. Kaplanski, and C. A. Dinarello, “Interleukin-1 receptor blockade reduces the number and size of murine B16 melanoma hepatic metastases,” Cancer Research, vol. 54, no. 10, pp. 2667–2672, 1994. View at Google Scholar · View at Scopus
  100. E. Voronov, D. S. Shouval, Y. Krelin et al., “IL-1 is required for tumor invasiveness and angiogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 5, pp. 2645–2650, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  101. P. Sansone, G. Storci, S. Tavolari et al., “IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland,” Journal of Clinical Investigation, vol. 117, no. 12, pp. 3988–4002, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  102. S. P. Gao, K. G. Mark, K. Leslie et al., “Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas,” Journal of Clinical Investigation, vol. 117, no. 12, pp. 3846–3856, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  103. S. Grivennikov, E. Karin, J. Terzic et al., “IL-6 and Stat3 are required for survival of intestinal epithelial cells anddevelopment of colitis-associated cancer,” Cancer Cell, vol. 15, no. 2, pp. 103–113, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  104. S. K. Bunt, P. Sinha, V. K. Clements, J. Leips, and S. Ostrand-Rosenberg, “Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression,” Journal of Immunology, vol. 176, no. 1, pp. 284–290, 2006. View at Google Scholar · View at Scopus
  105. S. K. Bunt, L. Yang, P. Sinha, V. K. Clements, J. Leips, and S. Ostrand-Rosenberg, “Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression,” Cancer Research, vol. 67, no. 20, pp. 10019–10026, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  106. X. Song, Y. Krelin, T. Dvorkin et al., “CD11b+/Gr-1+ immature myeloid cells mediate suppression of T cells in mice bearing tumors of IL-1β-secreting cells,” Journal of Immunology, vol. 175, no. 12, pp. 8200–8208, 2005. View at Google Scholar · View at Scopus
  107. W. Zou and L. Chen, “Inhibitory B7-family molecules in the tumour microenvironment,” Nature Reviews Immunology, vol. 8, no. 6, pp. 467–477, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  108. S. Terawaki, S. Chikuma, S. Shibayama et al., “IFN-alpha directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity,” The Journal of Immunology, vol. 186, pp. 2772–2779, 2011. View at Google Scholar
  109. B. Baban, A. M. Hansen, P. R. Chandler et al., “A minor population of splenic dendritic cells expressing CD19 mediates IDO-dependent T cell suppression via type I IFN signaling following B7 ligation,” International Immunology, vol. 17, no. 7, pp. 909–919, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  110. A. J. Muller, M. D. Sharma, P. R. Chandler et al., “Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 44, pp. 17073–17078, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  111. L. A. Gilbert and M. T. Hemann, “DNA damage-mediated induction of a chemoresistant niche,” Cell, vol. 143, no. 3, pp. 355–366, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  112. D. L. Porter, B. L. Levine, M. Kalos, A. Bagg, and C. H. June, “Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia,” The New England Journal of Medicine, vol. 365, no. 8, pp. 725–733, 2011. View at Publisher · View at Google Scholar · View at PubMed
  113. S. R. Mattarollo, S. Loi, H. Duret, Y. Ma, L. Zitvogel, and M. J. Smyth, “Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors,” Cancer Research, vol. 71, no. 14, pp. 4809–4820, 2011. View at Publisher · View at Google Scholar · View at PubMed
  114. B. J. Nickoloff, Y. Ben-Neriah, and E. Pikarsky, “Inflammation and cancer: is the link as simple as we think?” Journal of Investigative Dermatology, vol. 124, pp. 10–14, 2005. View at Google Scholar
  115. E. J. Schattner, J. Mascarenhas, J. Bishop et al., “CD4+ T-cell induction of Fas-mediated apoptosis in Burkitt's lymphoma B cells,” Blood, vol. 88, no. 4, pp. 1375–1382, 1996. View at Google Scholar · View at Scopus
  116. W. D. Thomas and P. Hersey, “TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in Fas ligand-resistant melanoma cells and mediates CD4 T cell killing of target cells,” Journal of Immunology, vol. 161, no. 5, pp. 2195–2200, 1998. View at Google Scholar · View at Scopus
  117. J. H. Finke, P. Rayman, J. Alexander et al., “Characterization of the cytolytic activity of CD4+ and CD8+ tumor-infiltrating lymphocytes in human renal cell carcinoma,” Cancer Research, vol. 50, no. 8, pp. 2363–2370, 1990. View at Google Scholar · View at Scopus
  118. N. S. Williams and V. H. Engelhard, “Identification of a population of CD4+ CTL that utilizes a perforin- rather than a Fas ligand-dependent cytotoxic mechanism,” Journal of Immunology, vol. 156, no. 1, pp. 153–159, 1996. View at Google Scholar · View at Scopus
  119. E. S. Schultz, B. Lethe, C. L. Cambiaso et al., “A MAGE-A3 peptide presented by HLA-DP4 is recognized on tumor cells by CD4+ cytolytic T lymphocytes,” Cancer Research, vol. 60, no. 22, pp. 6272–6275, 2000. View at Google Scholar · View at Scopus
  120. Q. Sun, R. L. Burton, and K. G. Lucas, “Cytokine production and cytolytic mechanism of CD4+ cytotoxic T lymphocytes in ex vivo expanded therapeutic Epstein-Barr virus-specific T-cell cultures,” Blood, vol. 99, no. 9, pp. 3302–3309, 2002. View at Publisher · View at Google Scholar · View at Scopus
  121. V. Appay, J. J. Zaunders, L. Papagno et al., “Characterization of CD4+ CTLs ex vivo,” Journal of Immunology, vol. 168, no. 11, pp. 5954–5958, 2002. View at Google Scholar · View at Scopus
  122. Y. Xie, A. Akpinarli, C. Maris et al., “Naive tumor-specific CD4+ T cells differentiated in vivo eradicate established melanoma,” Journal of Experimental Medicine, vol. 207, no. 3, pp. 651–667, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  123. H. Z. Qui, A. T. Hagymasi, S. Bandyopadhyay et al., “CD134 plus CD137 dual costimulation induces eomesodermin in CD4 T cells to program cytotoxic Th1 differentiation,” Journal of Immunology, vol. 187, no. 7, pp. 3555–3564, 2011. View at Publisher · View at Google Scholar · View at PubMed
  124. L. H. Butterfield, A. Ribas, V. B. Dissette et al., “Determinant spreading associated with clinical response in dendritic cell-based immunotherapy for malignant melanoma,” Clinical Cancer Research, vol. 9, no. 3, pp. 998–1008, 2003. View at Google Scholar · View at Scopus
  125. C. Lurquin, B. Lethé, E. De Plaen et al., “Contrasting frequencies of antitumor and anti-vaccine T cells in metastases of a melanoma patient vaccinated with a MAGE tumor antigen,” Journal of Experimental Medicine, vol. 201, no. 2, pp. 249–257, 2005. View at Publisher · View at Google Scholar · View at PubMed
  126. V. Corbière, J. Chapiro, V. Stroobant et al., “Antigen spreading contributes to MAGE vaccination-induced regression of melanoma metastases,” Cancer Research, vol. 71, no. 4, pp. 1253–1262, 2011. View at Publisher · View at Google Scholar · View at PubMed
  127. P. D. Greenberg, D. E. Kern, and M. A. Cheever, “Therapy of disseminated murine leukemia with cyclophosphamide and immune Lyt-1+,2- T cells. Tumor eradication does not require participation of cytotoxic T cells,” Journal of Experimental Medicine, vol. 161, no. 5, pp. 1122–1134, 1985. View at Google Scholar · View at Scopus
  128. F. Ossendorp, E. Mengedé, M. Camps, R. Filius, and C. J. M. Melief, “Specific T helper cell requirement for optimal induction of cytotoxic T lymphocytes against major histocompatibility complex class II negative tumors,” Journal of Experimental Medicine, vol. 187, no. 5, pp. 693–702, 1998. View at Publisher · View at Google Scholar · View at Scopus
  129. M. E. Dudley, J. R. Wunderlich, P. F. Robbins et al., “Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes,” Science, vol. 298, no. 5594, pp. 850–854, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  130. K. Chamoto, A. Kosaka, T. Tsuji et al., “Critical role of the Th1/Tc1 circuit for the generation of tumor-specific CTL during tumor eradication in vivo by Th1-cell therapy,” Cancer Science, vol. 94, no. 10, pp. 924–928, 2003. View at Publisher · View at Google Scholar · View at Scopus
  131. A. P. Rapoport, E. A. Stadtmauer, N. Aqui et al., “Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer,” Nature Medicine, vol. 11, no. 11, pp. 1230–1237, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  132. L. X. Wang, S. Shu, M. L. Disis, and G. E. Plautz, “Adoptive transfer of tumor-primed, in vitro-activated, CD4+ T effector cells (TEs) combined with CD8+ TEs provides intratumoral TE proliferation and synergistic antitumor response,” Blood, vol. 109, no. 11, pp. 4865–4876, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  133. A. Schietinger, M. Philip, R. B. Liu, K. Schreiber, and H. Schreiber, “Bystander killing of cancer requires the cooperation of CD4+ and CD8+ T cells during the effector phase,” Journal of Experimental Medicine, vol. 207, no. 11, pp. 2469–2477, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  134. K. Chamoto, D. Wakita, Y. Narita et al., “An essential role of antigen-presenting cell/T-helper type 1 cell-cell interactions in draining lymph node during complete eradication of class II-negative tumor tissue by T-helper type 1 cell therapy,” Cancer Research, vol. 66, no. 3, pp. 1809–1817, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  135. M. J. Goldstein, B. Varghese, J. D. Brody et al., “A CpG-loaded tumor cell vaccine induces antitumor CD4+ T cells that are effective in adoptive therapy for large and established tumors,” Blood, vol. 117, no. 1, pp. 118–127, 2011. View at Publisher · View at Google Scholar · View at PubMed
  136. K. Staveley-O'Carroll, E. Sotomayor, J. Montgomery et al., “Induction of antigen-specific T cell anergy: an early event in the course of tumor progression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 3, pp. 1178–1183, 1998. View at Publisher · View at Google Scholar · View at Scopus
  137. M. Kuczma, M. Kopij, I. Pawlikowska, C. Y. Wang, G. A. Rempala, and P. Kraj, “Intratumoral convergence of the TCR repertoires of effector and Foxp3+ CD4+ t cells,” PLoS ONE, vol. 5, no. 10, article e13623, 2010. View at Publisher · View at Google Scholar · View at PubMed
  138. G. Zhou and H. I. Levitsky, “Natural regulatory T cells and de novo-induced regulatory T cells contribute independently to tumor-specific tolerance,” Journal of Immunology, vol. 178, no. 4, pp. 2155–2162, 2007. View at Google Scholar · View at Scopus
  139. B. Valzasina, S. Piconese, C. Guiducci, and M. P. Colombo, “Tumor-induced expansion of regulatory T cells by conversion of CD4+CD25- lymphocytes is thymus and proliferation independent,” Cancer Research, vol. 66, no. 8, pp. 4488–4495, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  140. J. A. Hill, J. A. Hall, C. M. Sun et al., “Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi cells,” Immunity, vol. 29, no. 5, pp. 758–770, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  141. D. Caretto, S. D. Katzman, A. V. Villarino, E. Gallo, and A. K. Abbas, “Cutting edge: the Th1 response inhibits the generation of peripheral regulatory T cells,” Journal of Immunology, vol. 184, no. 1, pp. 30–34, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  142. C. E. Tadokoro, G. Shakhar, S. Shen et al., “Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo,” Journal of Experimental Medicine, vol. 203, no. 3, pp. 505–511, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  143. Q. Tang, J. Y. Adams, A. J. Tooley et al., “Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice,” Nature Immunology, vol. 7, no. 1, pp. 83–92, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  144. T. R. Mempel, M. J. Pittet, K. Khazaie et al., “Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation,” Immunity, vol. 25, no. 1, pp. 129–141, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  145. X. Cao, S. F. Cai, T. A. Fehniger et al., “Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance,” Immunity, vol. 27, no. 4, pp. 635–646, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  146. A. Boissonnas, A. Scholer-Dahirel, V. Simon-Blancal et al., “Foxp3+ T cells induce perforin-dependent dendritic cell death in tumor-draining lymph nodes,” Immunity, vol. 32, no. 2, pp. 266–278, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  147. B. Huang, P. Y. Pan, Q. Li et al., “Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host,” Cancer Research, vol. 66, no. 2, pp. 1123–1131, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  148. P. Serafini, S. Mgebroff, K. Noonan, and I. Borrello, “Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells,” Cancer Research, vol. 68, no. 13, pp. 5439–5449, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  149. M. D. Sharma, B. Baban, P. Chandler et al., “Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase,” Journal of Clinical Investigation, vol. 117, no. 9, pp. 2570–2582, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  150. D. L. Barber, E. J. Wherry, D. Masopust et al., “Restoring function in exhausted CD8 T cells during chronic viral infection,” Nature, vol. 439, no. 7077, pp. 682–687, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  151. M. Ahmadzadeh, L. A. Johnson, B. Heemskerk et al., “Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired,” Blood, vol. 114, no. 8, pp. 1537–1544, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  152. S. Mumprecht, C. Schürch, J. Schwaller, M. Solenthaler, and A. F. Ochsenbein, “Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression,” Blood, vol. 114, no. 8, pp. 1528–1536, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  153. L. M. Francisco, V. H. Salinas, K. E. Brown et al., “PD-L1 regulates the development, maintenance, and function of induced regulatory T cells,” Journal of Experimental Medicine, vol. 206, no. 13, pp. 3015–3029, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  154. L. Wang, K. Pino-Lagos, V. C. De Vries, I. Guleria, M. H. Sayegh, and R. J. Noelle, “Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 27, pp. 9331–9336, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  155. H. Dong, S. E. Strome, D. R. Salomao et al., “Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion,” Nature Medicine, vol. 8, no. 9, pp. 793–800, 2002. View at Publisher · View at Google Scholar · View at Scopus
  156. M. J. Butte, M. E. Keir, T. B. Phamduy, A. H. Sharpe, and G. J. Freeman, “Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses,” Immunity, vol. 27, no. 1, pp. 111–122, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  157. J. J. Park, R. Omiya, Y. Matsumura et al., “B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance,” Blood, vol. 116, no. 8, pp. 1291–1298, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  158. R. Yamamoto, M. Nishikori, T. Kitawaki et al., “PD-1 PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma,” Blood, vol. 111, no. 6, pp. 3220–3224, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  159. Z. Z. Yang, A. J. Novak, M. J. Stenson, T. E. Witzig, and S. M. Ansell, “Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma,” Blood, vol. 107, no. 9, pp. 3639–3646, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  160. H. Ghebeh, E. Barhoush, A. Tulbah, N. Elkum, T. Al-Tweigeri, and S. Dermime, “FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: implication for immunotherapy,” BMC Cancer, vol. 8, article 57, 2008. View at Publisher · View at Google Scholar · View at PubMed
  161. J. F. M. Jacobs, A. J. Idema, K. F. Bol et al., “Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors,” Neuro-Oncology, vol. 11, no. 4, pp. 394–402, 2009. View at Publisher · View at Google Scholar · View at PubMed
  162. S. Wei, A. B. Shreiner, N. Takeshita, L. Chen, W. Zou, and A. E. Chang, “Tumor-induced immune suppression of in vivo effector T-cell priming is mediated by the B7-H1/PD-1 axis and transforming growth factor β,” Cancer Research, vol. 68, no. 13, pp. 5432–5438, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  163. Q. Zhou, M. E. Munger, S. L. Highfill et al., “Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia,” Blood, vol. 116, no. 14, pp. 2484–2493, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  164. M. A. Cheever, “Twelve immunotherapy drugs that could cure cancers,” Immunological Reviews, vol. 222, no. 1, pp. 357–368, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  165. E. M. Sotomayor, I. Borrello, E. Tubb et al., “Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of cd40,” Nature Medicine, vol. 5, no. 7, pp. 780–787, 1999. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  166. J. R. Brahmer, C. G. Drake, I. Wollner et al., “Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates,” Journal of Clinical Oncology, vol. 28, no. 19, pp. 3167–3175, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  167. J. Rosenblatt, B. Vasir, L. Uhl et al., “Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma,” Blood, vol. 117, no. 2, pp. 393–402, 2011. View at Publisher · View at Google Scholar · View at PubMed
  168. J. Yuan, S. Gnjatic, H. Li et al., “CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 51, pp. 20410–20415, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  169. P. Attia, A. V. Maker, L. R. Haworth, L. Rogers-Freezer, and S. A. Rosenberg, “Inability of a fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma,” Journal of Immunotherapy, vol. 28, no. 6, pp. 582–592, 2005. View at Google Scholar · View at Scopus
  170. J. Dannull, Z. Su, D. Rizzieri et al., “Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells,” Journal of Clinical Investigation, vol. 115, no. 12, pp. 3623–3633, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  171. M. D. Sharma, D. Y. Hou, B. Baban et al., “Reprogrammed Foxp3+ regulatory T cells provide essential help to support cross-presentation and CD8+ T cell priming in naive mice,” Immunity, vol. 33, no. 6, pp. 942–954, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus