Seminars in Immunopathology

, Volume 33, Issue 4, pp 369–383 | Cite as

Immunomodulatory effects of cyclophosphamide and implementations for vaccine design

  • Antonella Sistigu
  • Sophie Viaud
  • Nathalie Chaput
  • Laura Bracci
  • Enrico Proietti
  • Laurence Zitvogel
Review

Abstract

Drug repositioning refers to the utilization of a known compound in a novel indication underscoring a new mode of action that predicts innovative therapeutic options. Since 1959, alkylating agents, such as the lead compound cyclophosphamide (CTX), have always been conceived, at high dosages, as potent cytotoxic and lymphoablative drugs, indispensable for dose intensity and immunosuppressive regimen in the oncological and internal medicine armamentarium. However, more recent work highlighted the immunostimulatory and/or antiangiogenic effects of low dosing CTX (also called “metronomic CTX”) opening up novel indications in the field of cancer immunotherapy. CTX markedly influences dendritic cell homeostasis and promotes IFN type I secretion, contributing to the induction of antitumor cytotoxic T lymphocytes and/or the proliferation of adoptively transferred T cells, to the polarization of CD4+ T cells into TH1 and/or TH17 lymphocytes eventually affecting the Treg/Teffector ratio in favor of tumor regression. Moreover, CTX has intrinsic “pro-immunogenic” activities on tumor cells, inducing the hallmarks of immunogenic cell death on a variety of tumor types. Fifty years after its Food and Drug Administration approval, CTX remains a safe and affordable compound endowed with multifaceted properties and plethora of clinical indications. Here we review its immunomodulatory effects and advocate why low dosing CTX could be successfully combined to new-generation cancer vaccines.

Keywords

Cyclophosphamide Chemotherapy Immunotherapy Cancer vaccine Immunomodulation Cancer 

Notes

Disclosure of potential conflict of interest

The authors declare no potential conflicts of interest.

References

  1. 1.
    Zitvogel L, Kepp O, Kroemer G (2010) Decoding cell death signals in inflammation and immunity. Cell 140(6):798–804PubMedCrossRefGoogle Scholar
  2. 2.
    Ramakrishnan R, Assudani D, Nagaraj S, Hunter T, Cho HI, Antonia S, Altiok S, Celis E, Gabrilovich DI (2010) Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J Clin Invest 120(4):1111–1124PubMedCrossRefGoogle Scholar
  3. 3.
    Brock N (1996) The history of the oxazaphosphorine cytostatics. Cancer 78(3):542–547PubMedCrossRefGoogle Scholar
  4. 4.
    Brock N (1946) Effect of a cyclic nitrogen mustard-phosphamidester on experimentally induced tumors in rats; chemotherapeutic effect and pharmacological properties of B 518 ASTA. Dtsch Med Wochenschr 83(12):453–458CrossRefGoogle Scholar
  5. 5.
    Gross R (1959) Cytostatic therapy with radiations and chemically effective cell poisons in carcinomas and sarcomas. Strahlentherapie Suppl 43:243–253Google Scholar
  6. 6.
    Otterness IG, Chang YH (1976) Comparative study of cyclophosphamide, 6-mercaptopurine, azathiopurine and methotrexate. Relative effects on the humoral and the cellular immune response in the mouse. Clin Exp Immunol 26(2):346–354PubMedGoogle Scholar
  7. 7.
    Awwad M, North RJ (1988) 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 65(1):87–92PubMedGoogle Scholar
  8. 8.
    Man S, Bocci G, Francia G, Green SK, Jothy S, Hanahan D, Bohlen P, Hicklin DJ, Bergers G, Kerbel RS (2002) Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res 62(10):2731–2735PubMedGoogle Scholar
  9. 9.
    Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O’Reilly MS, Folkman J (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60(7):1878–1886PubMedGoogle Scholar
  10. 10.
    Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nole F, Peruzzotti G, Robertson C, Orlando L, Cinieri S, de BF, Viale G, Goldhirsch A (2002) Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 13(1):73–80PubMedCrossRefGoogle Scholar
  11. 11.
    Matar P, Rozados VR, Gervasoni SI, Scharovsky GO (2002) Th2/Th1 switch induced by a single low dose of cyclophosphamide in a rat metastatic lymphoma model. Cancer Immunol Immunother 50(11):588–596PubMedCrossRefGoogle Scholar
  12. 12.
    Viaud S, Flament C, Zoubir M, Pautier P, Lecesne A, Ribrag V, Soria JC, Marty V, Vielh P, Robert C, Chaput N, Zitvogel L, (2011) Cyclophosphamide induces differentiation of Th17 cells in cancer patients. Cancer Res 71(3):661–665Google Scholar
  13. 13.
    Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D, Garrido C, Chauffert B, Solary E, Bonnotte B, Martin F (2004) CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 34(2):336–344PubMedCrossRefGoogle Scholar
  14. 14.
    Proietti E, Greco G, Garrone B, Baccarini S, Mauri C, Venditti M, Carlei D, Belardelli F (1998) Importance of cyclophosphamide-induced bystander effect on T cells for a successful tumor eradication in response to adoptive immunotherapy in mice. J Clin Investig 101(2):429–441PubMedCrossRefGoogle Scholar
  15. 15.
    Schiavoni G, Mattei F, Di Pucchio T, Santini SM, Bracci L, Belardelli F, Proietti E (2000) Cyclophosphamide induces type I interferon and augments the number of CD44(hi) T lymphocytes in mice: implications for strategies of chemoimmunotherapy of cancer. Blood 95(6):2024–2030PubMedGoogle Scholar
  16. 16.
    Bracci L, Moschella F, Sestili P, La Sorsa V, Valentini M, Canini I, Baccarini S, Maccari S, Ramoni C, Belardelli F, Proietti E (2007) 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. Clin Cancer Res 13(2 Pt 1):644–653PubMedCrossRefGoogle Scholar
  17. 17.
    Salem ML, Al-Khami AA, El-Naggar SA, Diaz-Montero CM, Chen Y, Cole DJ (2010) Cyclophosphamide induces dynamic alterations in the host microenvironments resulting in a Flt3 ligand-dependent expansion of dendritic cells. J Immunol 184(4):1737–1747PubMedCrossRefGoogle Scholar
  18. 18.
    Salem ML, El-Naggar SA, Cole DJ (2010) Cyclophosphamide induces bone marrow to yield higher numbers of precursor dendritic cells in vitro capable of functional antigen presentation to T cells in vivo. Cell Immunol 261(2):134–143PubMedCrossRefGoogle Scholar
  19. 19.
    Salem ML, Diaz-Montero CM, Al-Khami AA, El-Naggar SA, Naga O, Montero AJ, Khafagy A, Cole DJ (2009) Recovery from cyclophosphamide-induced lymphopenia results in expansion of immature dendritic cells which can mediate enhanced prime-boost vaccination antitumor responses in vivo when stimulated with the TLR3 agonist poly(I:C). J Immunol 182(4):2030–2040PubMedCrossRefGoogle Scholar
  20. 20.
    Salem ML, Kadima AN, El-Naggar SA, Rubinstein MP, Chen Y, Gillanders WE, Cole DJ (2007) 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. J Immunother 30(1):40–53PubMedCrossRefGoogle Scholar
  21. 21.
    Nakahara T, Uchi H, Lesokhin AM, Avogadri F, Rizzuto GA, Hirschhorn-Cymerman D, Panageas KS, Merghoub T, Wolchok JD, Houghton AN (2010) Cyclophosphamide enhances immunity by modulating the balance of dendritic cell subsets in lymphoid organs. Blood 115(22):4384–4392PubMedCrossRefGoogle Scholar
  22. 22.
    Schiavoni G, Sistigu A, Valentini M, Mattei F, Sestili P, Spadaro F, Sanchez M, Lorenzi S, D’urso MT, Belardelli F, Gabrielle L, Proietti E, Bracci L (2011) Cyclophosphamide synergize with type 1 interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. Cancer Res 71(3):768–778Google Scholar
  23. 23.
    Hellstrom KE, Hellstrom I (2007) Vaccines to treat cancer—an old approach whose time has arrived. J Cell Biochem 102(2):291–300PubMedCrossRefGoogle Scholar
  24. 24.
    Inoue S, Leitner WW, Golding B, Scott D (2006) Inhibitory effects of B cells on antitumor immunity. Cancer Res 66(15):7741–7747PubMedCrossRefGoogle Scholar
  25. 25.
    Shah S, Divekar AA, Hilchey SP, Cho HM, Newman CL, Shin SU, Nechustan H, Challita-Eid PM, Segal BM, Yi KH, Rosenblatt JD (2005) Increased rejection of primary tumors in mice lacking B cells: inhibition of anti-tumor CTL and TH1 cytokine responses by B cells. Int J Cancer 117(4):574–586PubMedCrossRefGoogle Scholar
  26. 26.
    Qin Z, Richter G, Schuler T, Ibe S, Cao X, Blankenstein T (1998) B cells inhibit induction of T cell-dependent tumor immunity. Nat Med 4(5):627–630PubMedCrossRefGoogle Scholar
  27. 27.
    Andreu P, Johansson M, Affara NI, Pucci F, Tan T, Junankar S, Korets L, Lam J, Tawfik D, DeNardo DG, Naldini L, de Visser KE, De Palma M, Coussens LM (2010) FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17(2):121–134PubMedCrossRefGoogle Scholar
  28. 28.
    Mizoguchi A, Bhan AK (2006) A case for regulatory B cells. J Immunol 176(2):705–710PubMedGoogle Scholar
  29. 29.
    DiLillo DJ, Matsushita T, Tedder TF (2010) B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer. Ann NY Acad Sci 1183:38–57PubMedCrossRefGoogle Scholar
  30. 30.
    Finn OJ (2008) Cancer immunology. N Engl J Med 358(25):2704–2715PubMedCrossRefGoogle Scholar
  31. 31.
    Soiffer R, Lynch T, Mihm M, Jung K, Rhuda C, Schmollinger JC, Hodi FS, Liebster L, Lam P, Mentzer S, Singer S, Tanabe KK, Cosimi AB, Duda R, Sober A, Bhan A, Daley J, Neuberg D, Parry G, Rokovich J, Richards L, Drayer J, Berns A, Clift S, Cohen LK, Mulligan RC, Dranoff G (1998) Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma. Proc Natl Acad Sci USA 95(22):13141–13146PubMedCrossRefGoogle Scholar
  32. 32.
    Jinushi M, Hodi FS, Dranoff G (2006) Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity. Proc Natl Acad Sci USA 103(24):9190–9195PubMedCrossRefGoogle Scholar
  33. 33.
    Valmori D, Souleimanian NE, Tosello V, Bhardwaj N, Adams S, O’Neill D, Pavlick A, Escalon JB, Cruz CM, Angiulli A, Angiulli F, Mears G, Vogel SM, Pan L, Jungbluth AA, Hoffmann EW, Venhaus R, Ritter G, Old LJ, Ayyoub M (2007) Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming. Proc Natl Acad Sci USA 104(21):8947–8952PubMedCrossRefGoogle Scholar
  34. 34.
    Fong L, Kwek SS, O’Brien S, Kavanagh B, McNeel DG, Weinberg V, Lin AM, Rosenberg J, Ryan CJ, Rini BI, Small EJ (2009) Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res 69(2):609–615PubMedCrossRefGoogle Scholar
  35. 35.
    Spadaro M, Lanzardo S, Curcio C, Forni G, Cavallo F (2004) Immunological inhibition of carcinogenesis. Cancer Immunol Immunother 53(3):204–216PubMedCrossRefGoogle Scholar
  36. 36.
    Zhu LP, Cupps TR, Whalen G, Fauci AS (1987) Selective effects of cyclophosphamide therapy on activation, proliferation, and differentiation of human B cells. J Clin Investig 79(4):1082–1090PubMedCrossRefGoogle Scholar
  37. 37.
    Montero E, Valdes M, Avellanet J, Lopez A, Perez R, Lage A (2009) Chemotherapy induced transient B-cell depletion boosts antibody-forming cells expansion driven by an epidermal growth factor-based cancer vaccine. Vaccine 27(16):2230–2239PubMedCrossRefGoogle Scholar
  38. 38.
    Shortman K, Liu YJ (2002) Mouse and human dendritic cell subtypes. Nat Rev 2(3):151–161Google Scholar
  39. 39.
    Lin ML, Zhan Y, Villadangos JA, Lew AM (2008) The cell biology of cross-presentation and the role of dendritic cell subsets. Immunol Cell Biol 86(4):353–362PubMedCrossRefGoogle Scholar
  40. 40.
    Shortman K, Heath WR (2010) The CD8+ dendritic cell subset. Immunol Rev 234(1):18–31PubMedCrossRefGoogle Scholar
  41. 41.
    Bevan MJ (2006) Cross-priming. Nat Immunol 7(4):363–365PubMedCrossRefGoogle Scholar
  42. 42.
    Shen L, Rock KL (2006) Priming of T cells by exogenous antigen cross-presented on MHC class I molecules. Curr Opin Immunol 18(1):85–91PubMedCrossRefGoogle Scholar
  43. 43.
    Villadangos JA, Heath WR, Carbone FR (2007) Outside looking in: the inner workings of the cross-presentation pathway within dendritic cells. Trends Immunol 28(2):45–47PubMedCrossRefGoogle Scholar
  44. 44.
    Jongbloed SL, Kassianos AJ, McDonald KJ, Clark GJ, Ju X, Angel CE, Chen CJ, Dunbar PR, Wadley RB, Jeet V, Vulink AJ, Hart DN, Radford KJ (2010) Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med 207(6):1247–1260PubMedCrossRefGoogle Scholar
  45. 45.
    Bachem A, Guttler S, Hartung E, Ebstein F, Schaefer M, Tannert A, Salama A, Movassaghi K, Opitz C, Mages HW, Henn V, Kloetzel PM, Gurka S, Kroczek RA (2010) Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells. J Exp Med 207(6):1273–1281PubMedCrossRefGoogle Scholar
  46. 46.
    Crozat K, Guiton R, Contreras V, Feuillet V, Dutertre CA, Ventre E, Vu Manh TP, Baranek T, Storset AK, Marvel J, Boudinot P, Hosmalin A, Schwartz-Cornil I, Dalod M (2010) The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8alpha+ dendritic cells. J Exp Med 207(6):1283–1292PubMedCrossRefGoogle Scholar
  47. 47.
    Radojcic V, Bezak KB, Skarica M, Pletneva MA, Yoshimura K, Schulick RD, Luznik L (2010) Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination. Cancer Immunol Immunother 59(1):137–148PubMedCrossRefGoogle Scholar
  48. 48.
    Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, Metivier D, Larochette N, van Endert P, Ciccosanti F, Piacentini M, Zitvogel L, Kroemer G (2007) Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 13(1):54–61PubMedCrossRefGoogle Scholar
  49. 49.
    Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P, Yang H, Amigorena S, Ryffel B, Barrat FJ, Saftig P, Levi F, Lidereau R, Nogues C, Mira JP, Chompret A, Joulin V, Clavel-Chapelon F, Bourhis J, Andre F, Delaloge S, Tursz T, Kroemer G, Zitvogel L (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13(9):1050–1059PubMedCrossRefGoogle Scholar
  50. 50.
    Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145–173PubMedCrossRefGoogle Scholar
  51. 51.
    Mosmann TR, Sad S (1996) The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 17(3):138–146PubMedCrossRefGoogle Scholar
  52. 52.
    Mosmann TR, Moore KW (1991) The role of IL-10 in crossregulation of TH1 and TH2 responses. Immunol Today 12(3):A49–A53PubMedCrossRefGoogle Scholar
  53. 53.
    Matar P, Rozados VR, Gonzalez AD, Dlugovitzky DG, Bonfil RD, Scharovsky OG (2000) Mechanism of antimetastatic immunopotentiation by low-dose cyclophosphamide. Eur J Cancer 36(8):1060–1066PubMedCrossRefGoogle Scholar
  54. 54.
    Romagnani S (1992) Induction of TH1 and TH2 responses: a key role for the ‘natural’ immune response? Immunol Today 13(10):379–381PubMedCrossRefGoogle Scholar
  55. 55.
    Li L, Okino T, Sugie T, Yamasaki S, Ichinose Y, Kanaoka S, Kan N, Imamura M (1998) Cyclophosphamide given after active specific immunization augments antitumor immunity by modulation of Th1 commitment of CD4+ T cells. J Surg Oncol 67(4):221–227PubMedCrossRefGoogle Scholar
  56. 56.
    Taieb J, Chaput N, Schartz N, Roux S, Novault S, Menard C, Ghiringhelli F, Terme M, Carpentier AF, Darrasse-Jeze G, Lemonnier F, Zitvogel L (2006) Chemoimmunotherapy of tumors: cyclophosphamide synergizes with exosome based vaccines. J Immunol 176(5):2722–2729PubMedGoogle Scholar
  57. 57.
    Wei L, Laurence A, Elias KM, O’Shea JJ (2007) IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem 282(48):34605–34610PubMedCrossRefGoogle Scholar
  58. 58.
    Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, Fouser LA (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203(10):2271–2279PubMedCrossRefGoogle Scholar
  59. 59.
    Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126(6):1121–1133PubMedCrossRefGoogle Scholar
  60. 60.
    Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C (2008) T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28(1):29–39PubMedCrossRefGoogle Scholar
  61. 61.
    Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421(6924):744–748PubMedCrossRefGoogle Scholar
  62. 62.
    Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201(2):233–240PubMedCrossRefGoogle Scholar
  63. 63.
    Wynn TA (2005) T(H)-17: a giant step from T(H)1 and T(H)2. Nat Immunol 6(11):1069–1070PubMedCrossRefGoogle Scholar
  64. 64.
    Ji Y, Zhang W (2010) Th17 cells: positive or negative role in tumor? Cancer Immunol Immunother 59(7):979–987PubMedCrossRefGoogle Scholar
  65. 65.
    Zou W, Restifo NP (2010) T(H)17 cells in tumour immunity and immunotherapy. Nat Rev 10(4):248–256CrossRefGoogle Scholar
  66. 66.
    Ngiow SF, Smyth MJ, Teng MW (2010) Does IL-17 suppress tumor growth? Blood 115(12):2554–2555, author reply 2556–2557PubMedCrossRefGoogle Scholar
  67. 67.
    Murugaiyan G, Saha B (2009) Protumor vs antitumor functions of IL-17. J Immunol 183(7):4169–4175PubMedCrossRefGoogle Scholar
  68. 68.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441(7090):235–238PubMedCrossRefGoogle Scholar
  69. 69.
    Sharma MD, Hou DY, Liu Y, Koni PA, Metz R, Chandler P, Mellor AL, He Y, Munn DH (2009) Indoleamine 2, 3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood 113(24):6102–6111PubMedCrossRefGoogle Scholar
  70. 70.
    Valmori D, Raffin C, Raimbaud I, Ayyoub M (2010) Human ROR{gamma}t+ TH17 cells preferentially differentiate from naive FOXP3+Treg in the presence of lineage-specific polarizing factors. Proc Natl Acad Sci U S A 107:19402–19407PubMedCrossRefGoogle Scholar
  71. 71.
    Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, Huang E, Finlayson E, Simeone D, Welling TH, Chang A, Coukos G, Liu R, Zou W (2009) Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 114(6):1141–1149PubMedCrossRefGoogle Scholar
  72. 72.
    Gnerlich JL, Mitchem JB, Weir JS, Sankpal NV, Kashiwagi H, Belt BA, Porembka MR, Herndon JM, Eberlein TJ, Goedegebuure P, Linehan DC (2010) Induction of Th17 cells in the tumor microenvironment improves survival in a murine model of pancreatic cancer. J Immunol 185(7):4063–4071PubMedCrossRefGoogle Scholar
  73. 73.
    Su X, Ye J, Hsueh EC, Zhang Y, Hoft DF, Peng G (2010) Tumor microenvironments direct the recruitment and expansion of human Th17 cells. J Immunol 184(3):1630–1641PubMedCrossRefGoogle Scholar
  74. 74.
    Ye ZJ, Zhou Q, Gu YY, Qin SM, Ma WL, Xin JB, Tao XN, Shi HZ (2010) Generation and differentiation of IL-17-producing CD4+ T cells in malignant pleural effusion. J Immunol 185:6348–6354PubMedCrossRefGoogle Scholar
  75. 75.
    Maruyama T, Kono K, Mizukami Y, Kawaguchi Y, Mimura K, Watanabe M, Izawa S, Fujii H (2010) Distribution of Th17 cells and FoxP3(+) regulatory T cells in tumor-infiltrating lymphocytes, tumor-draining lymph nodes and peripheral blood lymphocytes in patients with gastric cancer. Cancer Sci 101:1947–1954PubMedCrossRefGoogle Scholar
  76. 76.
    Staveley-O’Carroll K, Sotomayor E, Montgomery J, Borrello I, Hwang L, Fein S, Pardoll D, Levitsky H (1998) Induction of antigen-specific T cell anergy: An early event in the course of tumor progression. Proc Natl Acad Sci USA 95(3):1178–1183PubMedCrossRefGoogle Scholar
  77. 77.
    Berendt MJ, North RJ (1980) T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor. J Exp Med 151(1):69–80PubMedCrossRefGoogle Scholar
  78. 78.
    Smyth MJ, Godfrey DI, Trapani JA (2001) A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol 2(4):293–299PubMedCrossRefGoogle Scholar
  79. 79.
    Feinberg MB, Silvestri G (2002) T(S) cells and immune tolerance induction: a regulatory renaissance? Nat Immunol 3(3):215–217PubMedCrossRefGoogle Scholar
  80. 80.
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155(3):1151–1164PubMedGoogle Scholar
  81. 81.
    Stephens LA, Mason D (2000) CD25 is a marker for CD4+ thymocytes that prevent autoimmune diabetes in rats, but peripheral T cells with this function are found in both CD25+ and CD25- subpopulations. J Immunol 165(6):3105–3110PubMedGoogle Scholar
  82. 82.
    Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH (2001) Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med 193(11):1285–1294PubMedCrossRefGoogle Scholar
  83. 83.
    Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T (2001) Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 182:18–32PubMedCrossRefGoogle Scholar
  84. 84.
    Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163(10):5211–5218PubMedGoogle Scholar
  85. 85.
    Woo EY, Yeh H, Chu CS, Schlienger K, Carroll RG, Riley JL, Kaiser LR, June CH (2002) Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol 168(9):4272–4276PubMedGoogle Scholar
  86. 86.
    Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169(5):2756–2761PubMedGoogle Scholar
  87. 87.
    Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B (2003) Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 9(2):606–612PubMedGoogle Scholar
  88. 88.
    Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E (1999) Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59(13):3128–3133PubMedGoogle Scholar
  89. 89.
    Golgher D, Jones E, Powrie F, Elliott T, Gallimore A (2002) Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens. Eur J Immunol 32(11):3267–3275PubMedCrossRefGoogle Scholar
  90. 90.
    Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP, Toes RE, Offringa R, Melief CJ (2001) Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 194(6):823–832PubMedCrossRefGoogle Scholar
  91. 91.
    Steitz J, Bruck J, Lenz J, Knop J, Tuting T (2001) Depletion of CD25(+) CD4(+) T cells and treatment with tyrosinase-related protein 2-transduced dendritic cells enhance the interferon alpha-induced, CD8(+) T-cell-dependent immune defense of B16 melanoma. Cancer Res 61(24):8643–8646PubMedGoogle Scholar
  92. 92.
    Roux S, Apetoh L, Chalmin F, Ladoire S, Mignot G, Puig PE, Lauvau G, Zitvogel L, Martin F, Chauffert B, Yagita H, Solary E, Ghiringhelli F (2008) CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer. J Clin Investig 118(11):3751–3761PubMedCrossRefGoogle Scholar
  93. 93.
    Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science (New York, NY) 299(5609):1057–1061CrossRefGoogle Scholar
  94. 94.
    Kasprowicz DJ, Droin N, Soper DM, Ramsdell F, Green DR, Ziegler SF (2005) Dynamic regulation of FoxP3 expression controls the balance between CD4+ T cell activation and cell death. Eur J Immunol 35(12):3424–3432PubMedCrossRefGoogle Scholar
  95. 95.
    Brode S, Raine T, Zaccone P, Cooke A (2006) Cyclophosphamide-induced type-1 diabetes in the NOD mouse is associated with a reduction of CD4+CD25+Foxp3+ regulatory T cells. J Immunol 177(10):6603–6612PubMedGoogle Scholar
  96. 96.
    Ghiringhelli F, Menard C, Terme M, Flament C, Taieb J, Chaput N, Puig PE, Novault S, Escudier B, Vivier E, Lecesne A, Robert C, Blay JY, Bernard J, Caillat-Zucman S, Freitas A, Tursz T, Wagner-Ballon O, Capron C, Vainchencker W, Martin F, Zitvogel L (2005) CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med 202(8):1075–1085PubMedCrossRefGoogle Scholar
  97. 97.
    Ghiringhelli F, Menard C, Martin F, Zitvogel L (2006) The role of regulatory T cells in the control of natural killer cells: relevance during tumor progression. Immunol Rev 214:229–238PubMedCrossRefGoogle Scholar
  98. 98.
    Terme M, Chaput N, Combadiere B, Ma A, Ohteki T, Zitvogel L (2008) Regulatory T cells control dendritic cell/NK cell cross-talk in lymph nodes at the steady state by inhibiting CD4+ self-reactive T cells. J Immunol 180(7):4679–4686PubMedGoogle Scholar
  99. 99.
    Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L, Chauffert B (2007) 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(5):641–648PubMedCrossRefGoogle Scholar
  100. 100.
    Hirschhorn-Cymerman D, Perales MA (2010) Cytokine-FC fusion genes as molecular adjuvants for DNA vaccines. Methods Mol Biol (Clifton NJ) 651:131–155CrossRefGoogle Scholar
  101. 101.
    Taylor DK, Neujahr D, Turka LA (2004) Heterologous immunity and homeostatic proliferation as barriers to tolerance. Curr Opin Immunol 16(5):558–564PubMedCrossRefGoogle Scholar
  102. 102.
    Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133(5):775–787PubMedCrossRefGoogle Scholar
  103. 103.
    Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H (2005) Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105(7):2862–2868PubMedCrossRefGoogle Scholar
  104. 104.
    Cai XY, Gao Q, Qiu SJ, Ye SL, Wu ZQ, Fan J, Tang ZY (2006) Dendritic cell infiltration and prognosis of human hepatocellular carcinoma. J Cancer Res Clin Oncol 132(5):293–301PubMedCrossRefGoogle Scholar
  105. 105.
    Troy A, Davidson P, Atkinson C, Hart D (1998) Phenotypic characterisation of the dendritic cell infiltrate in prostate cancer. J Urol 160(1):214–219PubMedCrossRefGoogle Scholar
  106. 106.
    Nestle FO, Burg G, Fah J, Wrone-Smith T, Nickoloff BJ (1997) Human sunlight-induced basal-cell-carcinoma-associated dendritic cells are deficient in T cell co-stimulatory molecules and are impaired as antigen-presenting cells. Am J Pathol 150(2):641–651PubMedGoogle Scholar
  107. 107.
    Bergeron A, El-Hage F, Kambouchner M, Lecossier D, Tazi A (2006) Characterisation of dendritic cell subsets in lung cancer micro-environments. Eur Respir J 28(6):1170–1177PubMedCrossRefGoogle Scholar
  108. 108.
    Gerlini G, Tun-Kyi A, Dudli C, Burg G, Pimpinelli N, Nestle FO (2004) Metastatic melanoma secreted IL-10 down-regulates CD1 molecules on dendritic cells in metastatic tumor lesions. Am J Pathol 165(6):1853–1863PubMedCrossRefGoogle Scholar
  109. 109.
    Treilleux I, Blay JY, Bendriss-Vermare N, Ray-Coquard I, Bachelot T, Guastalla JP, Bremond A, Goddard S, Pin JJ, Barthelemy-Dubois C, Lebecque S (2004) Dendritic cell infiltration and prognosis of early stage breast cancer. Clin Cancer Res 10(22):7466–7474PubMedCrossRefGoogle Scholar
  110. 110.
    Movassagh M, Spatz A, Davoust J, Lebecque S, Romero P, Pittet M, Rimoldi D, Lienard D, Gugerli O, Ferradini L, Robert C, Avril MF, Zitvogel L, Angevin E (2004) Selective accumulation of mature DC-Lamp + dendritic cells in tumor sites is associated with efficient T-cell-mediated antitumor response and control of metastatic dissemination in melanoma. Cancer Res 64(6):2192–2198PubMedCrossRefGoogle Scholar
  111. 111.
    Chaux P, Hammann A, Martin F, Martin M (1993) Surface phenotype and functions of tumor-infiltrating dendritic cells: CD8 expression by a cell subpopulation. Eur J Immunol 23(10):2517–2525PubMedCrossRefGoogle Scholar
  112. 112.
    Chaux P, Favre N, Martin M, Martin F (1997) Tumor-infiltrating dendritic cells are defective in their antigen-presenting function and inducible B7 expression in rats. Int J Cancer 72(4):619–624PubMedCrossRefGoogle Scholar
  113. 113.
    Vicari AP, Chiodoni C, Vaure C, Ait-Yahia S, Dercamp C, Matsos F, Reynard O, Taverne C, Merle P, Colombo MP, O’Garra A, Trinchieri G, Caux C (2002) Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med 196(4):541–549PubMedCrossRefGoogle Scholar
  114. 114.
    Guiducci C, Vicari AP, Sangaletti S, Trinchieri G, Colombo MP (2005) Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res 65(8):3437–3446PubMedGoogle Scholar
  115. 115.
    Preynat-Seauve O, Schuler P, Contassot E, Beermann F, Huard B, French LE (2006) Tumor-infiltrating dendritic cells are potent antigen-presenting cells able to activate T cells and mediate tumor rejection. J Immunol 176(1):61–67PubMedGoogle Scholar
  116. 116.
    Gabrilovich D (2004) Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev 4(12):941–952CrossRefGoogle Scholar
  117. 117.
    Wesa AK, Storkus WJ (2008) Killer dendritic cells: mechanisms of action and therapeutic implications for cancer. Cell Death Differ 15(1):51–57PubMedCrossRefGoogle Scholar
  118. 118.
    Ullrich E, Chaput N, Zitvogel L (2008) Killer dendritic cells and their potential role in immunotherapy. Horm Metab Res 40(2):75–81PubMedCrossRefGoogle Scholar
  119. 119.
    Taieb J, Chaput N, Menard C, Apetoh L, Ullrich E, Bonmort M, Pequignot M, Casares N, Terme M, Flament C, Opolon P, Lecluse Y, Metivier D, Tomasello E, Vivier E, Ghiringhelli F, Martin F, Klatzmann D, Poynard T, Tursz T, Raposo G, Yagita H, Ryffel B, Kroemer G, Zitvogel L (2006) A novel dendritic cell subset involved in tumor immunosurveillance. Nat Med 12(2):214–219PubMedCrossRefGoogle Scholar
  120. 120.
    Chan CW, Crafton E, Fan HN, Flook J, Yoshimura K, Skarica M, Brockstedt D, Dubensky TW, Stins MF, Lanier LL, Pardoll DM, Housseau F (2006) Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity. Nat Med 12(2):207–213PubMedCrossRefGoogle Scholar
  121. 121.
    Terme M, Mignot G, Ullrich E, Bonmort M, Minard-Colin V, Jacquet A, Schultze JL, Kroemer G, Leclerc C, Chaput N, Zitvogel L (2009) The dendritic cell-like functions of IFN-producing killer dendritic cells reside in the CD11b+ subset and are licensed by tumor cells. Cancer Res 69(16):6590–6597PubMedCrossRefGoogle Scholar
  122. 122.
    Pletneva M, Fan H, Park JJ, Radojcic V, Jie C, Yu Y, Chan C, Redwood A, Pardoll D, Housseau F (2009) IFN-producing killer dendritic cells are antigen-presenting cells endowed with T-cell cross-priming capacity. Cancer Res 69(16):6607–6614PubMedCrossRefGoogle Scholar
  123. 123.
    Ma Y, Aymeric L, Locher C, Kroemer G, Zitvogel L (2010) The dendritic-cell-tumor cross-talk in cancer. Curr Opin Immunol 23(1):146–152Google Scholar
  124. 124.
    Bell D, Chomarat P, Broyles D, Netto G, Harb GM, Lebecque S, Valladeau J, Davoust J, Palucka KA, Banchereau J (1999) In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J Exp Med 190(10):1417–1426PubMedCrossRefGoogle Scholar
  125. 125.
    Perrot I, Blanchard D, Freymond N, Isaac S, Guibert B, Pacheco Y, Lebecque S (2007) Dendritic cells infiltrating human non-small cell lung cancer are blocked at immature stage. J Immunol 178(5):2763–2769PubMedGoogle Scholar
  126. 126.
    van der Most RG, Currie A, Robinson BW, Lake RA (2006) Cranking the immunologic engine with chemotherapy: using context to drive tumor antigen cross-presentation towards useful antitumor immunity. Cancer Res 66(2):601–604PubMedCrossRefGoogle Scholar
  127. 127.
    Ullrich E, Bonmort M, Mignot G, Jacobs B, Bosisio D, Sozzani S, Jalil A, Louache F, Bulanova E, Geissman F, Ryffel B, Chaput N, Bulfone-Paus S, Zitvogel L (2008) Trans-presentation of IL-15 dictates IFN-producing killer dendritic cells effector functions. J Immunol 180(12):7887–7897PubMedGoogle Scholar
  128. 128.
    Disis ML, Bernhard H, Jaffee EM (2009) Use of tumour-responsive T cells as cancer treatment. Lancet 373(9664):673–683PubMedCrossRefGoogle Scholar
  129. 129.
    Rosenberg SA, Yang JC, Restifo NP (2004) Cancer immunotherapy: moving beyond current vaccines. Nat Med 10(9):909–915PubMedCrossRefGoogle Scholar
  130. 130.
    Jahnisch H, Fussel S, Kiessling A, Wehner R, Zastrow S, Bachmann M, Rieber EP, Wirth MP, Schmitz M (2010) Dendritic cell-based immunotherapy for prostate cancer. Clin Dev Immunol 2010:517493PubMedCrossRefGoogle Scholar
  131. 131.
    Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, der Meer DM Berends-van, Vloon AP, Essahsah F, Fathers LM, Offringa R, Drijfhout JW, Wafelman AR, Oostendorp J, Fleuren GJ, van der Burg SH, Melief CJ (2009) Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N Engl J Med 361(19):1838–1847PubMedCrossRefGoogle Scholar
  132. 132.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. New Engl J Med 363(8):711–723PubMedCrossRefGoogle Scholar
  133. 133.
    Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science (New York, NY) 298(5594):850–854CrossRefGoogle Scholar
  134. 134.
    Mignot G, Ullrich E, Bonmort M, Menard C, Apetoh L, Taieb J, Bosisio D, Sozzani S, Ferrantini M, Schmitz J, Mack M, Ryffel B, Bulfone-Paus S, Zitvogel L, Chaput N (2008) The critical role of IL-15 in the antitumor effects mediated by the combination therapy imatinib and IL-2. J Immunol 180(10):6477–6483PubMedGoogle Scholar
  135. 135.
    Berd D, Mastrangelo MJ, Engstrom PF, Paul A, Maguire H (1982) Augmentation of the human immune response by cyclophosphamide. Cancer Res 42(11):4862–4866PubMedGoogle Scholar
  136. 136.
    Berd D, Maguire HC Jr, Mastrangelo MJ (1986) Induction of cell-mediated immunity to autologous melanoma cells and regression of metastases after treatment with a melanoma cell vaccine preceded by cyclophosphamide. Cancer Res 46(5):2572–2577PubMedGoogle Scholar
  137. 137.
    Berd D, Mastrangelo MJ (1987) Elimination of immune suppressor mechanisms in humans by oxazaphosphorines. Meth Find Exp Clin Pharmacol 9(9):569–577Google Scholar
  138. 138.
    Laheru D, Lutz E, Burke J, Biedrzycki B, Solt S, Onners B, Tartakovsky I, Nemunaitis J, Le D, Sugar E, Hege K, Jaffee E (2008) Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Clin Cancer Res 14(5):1455–1463PubMedCrossRefGoogle Scholar
  139. 139.
    Emens LA, Asquith JM, Leatherman JM, Kobrin BJ, Petrik S, Laiko M, Levi J, Daphtary MM, Biedrzycki B, Wolff AC, Stearns V, Disis ML, Ye X, Piantadosi S, Fetting JH, Davidson NE, Jaffee EM (2009) 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(35):5911–5918PubMedCrossRefGoogle Scholar
  140. 140.
    Nistico P, Capone I, Palermo B, Del Bello D, Ferraresi V, Moschella F, Arico E, Valentini M, Bracci L, Cognetti F, Ciccarese M, Vercillo G, Roselli M, Fossile E, Tosti ME, Wang E, Marincola F, Imberti L, Catricala C, Natali PG, Belardelli F, Proietti E (2009) Chemotherapy enhances vaccine-induced antitumor immunity in melanoma patients. Int J Cancer 124(1):130–139PubMedCrossRefGoogle Scholar
  141. 141.
    Palermo B, Del Bello D, Sottini A, Serana F, Ghidini C, Gualtieri N, Ferraresi V, Catricala C, Belardelli F, Proietti E, Natali PG, Imberti L, Nistico P (2010) Dacarbazine treatment before peptide vaccination enlarges T-cell repertoire diversity of melan-a-specific, tumor-reactive CTL in melanoma patients. Cancer Res 70(18):7084–7092PubMedCrossRefGoogle Scholar
  142. 142.
    Manning EA, Ullman JG, Leatherman JM, Asquith JM, Hansen TR, Armstrong TD, Hicklin DJ, Jaffee EM, Emens LA (2007) A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clin Cancer Res 13(13):3951–3959PubMedCrossRefGoogle Scholar
  143. 143.
    Tongu M, Harashima N, Yamada T, Harada T, Harada M (2010) Immunogenic chemotherapy with cyclophosphamide and doxorubicin against established murine carcinoma. Cancer Immunol Immunother 59(5):769–777PubMedCrossRefGoogle Scholar
  144. 144.
    Rosenberg SA, Spiess P, Lafreniere R (1986) A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233(4770):1318–1321PubMedCrossRefGoogle Scholar
  145. 145.
    Machiels JP, Reilly RT, Emens LA, Ercolini AM, Lei RY, Weintraub D, Okoye FI, Jaffee EM (2001) 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 Res 61(9):3689–3697PubMedGoogle Scholar
  146. 146.
    Ercolini AM, Ladle BH, Manning EA, Pfannenstiel LW, Armstrong TD, Machiels JP, Bieler JG, Emens LA, Reilly RT, Jaffee EM (2005) Recruitment of latent pools of high-avidity CD8(+) T cells to the antitumor immune response. J Exp Med 201(10):1591–1602PubMedCrossRefGoogle Scholar
  147. 147.
    Leao IC, Ganesan P, Armstrong TD, Jaffee EM (2008) Effective depletion of regulatory T cells allows the recruitment of mesothelin-specific CD8 T cells to the antitumor immune response against a mesothelin-expressing mouse pancreatic adenocarcinoma. Clin Transl Sci 1(3):228–239PubMedCrossRefGoogle Scholar
  148. 148.
    Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin JP, Boireau W, Rouleau A, Simon B, Lanneau D, De Thonel A, Multhoff G, Hamman A, Martin F, Chauffert B, Solary E, Zitvogel L, Garrido C, Ryffel B, Borg C, Apetoh L, Rebe C, Ghiringhelli F (2010) Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest 120(2):457–471PubMedGoogle Scholar
  149. 149.
    Tong Y, Song W, Crystal RG (2001) Combined intratumoral injection of bone marrow-derived dendritic cells and systemic chemotherapy to treat pre-existing murine tumors. Cancer Res 61(20):7530–7535PubMedGoogle Scholar
  150. 150.
    Hermans IF, Chong TW, Palmowski MJ, Harris AL, Cerundolo V (2003) Synergistic effect of metronomic dosing of cyclophosphamide combined with specific antitumor immunotherapy in a murine melanoma model. Cancer Res 63(23):8408–8413PubMedGoogle Scholar
  151. 151.
    Garaci E, Mastino A, Pica F, Favalli C (1990) Combination treatment using thymosin alpha 1 and interferon after cyclophosphamide is able to cure Lewis lung carcinoma in mice. Cancer Immunol Immunother 32(3):154–160PubMedCrossRefGoogle Scholar
  152. 152.
    Sobotkova E, Duskova M, Tachezy R, Petrackova M, Vonka V (2009) Combined chemo- and immunotherapy of tumors induced in mice by bcr-abl-transformed cells. Oncol Rep 21(3):793–799PubMedGoogle Scholar
  153. 153.
    Hirschhorn-Cymerman D, Rizzuto GA, Merghoub T, Cohen AD, Avogadri F, Lesokhin AM, Weinberg AD, Wolchok JD, Houghton AN (2009) OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis. J Exp Med 206(5):1103–1116PubMedCrossRefGoogle Scholar
  154. 154.
    Alexandru D, Van Horn DK, Bota DA (2010) Secondary fibrosarcoma of the brain stem treated with cyclophosphamide and Imatinib. J Neurooncol 99(1):123–128PubMedCrossRefGoogle Scholar
  155. 155.
    Ladoire S, Eymard JC, Zanetta S, Mignot G, Martin E, Kermarrec I, Mourey E, Michel F, Cormier L, Ghiringhelli G (2010) Metronomic oral cyclophosphamide prednisolone chemotherapy is an effective treatment for metastatic hormone-refractory prostate cancer after docetaxel failure. Anticancer Res 30(10):4317–4323PubMedGoogle Scholar
  156. 156.
    Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, Jones SA, Mangiameli DP, Pelletier MM, Gea-Banacloche J, Robinson MR, Berman DM, Filie AC, Abati A, Rosenberg SA (2005) Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 23(10):2346–2357PubMedCrossRefGoogle Scholar
  157. 157.
    Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA (2008) Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26(32):5233–5239PubMedCrossRefGoogle Scholar
  158. 158.
    Livingston PO, Wong GY, Adluri S, Tao Y, Padavan M, Parente R, Hanlon C, Calves MJ, Helling F, Ritter G et al (1994) Improved survival in stage III melanoma patients with GM2 antibodies: a randomized trial of adjuvant vaccination with GM2 ganglioside. J Clin Oncol 12(5):1036–1044PubMedGoogle Scholar
  159. 159.
    Berd D, Maguire HC Jr, Mastrangelo MJ (1984) Potentiation of human cell-mediated and humoral immunity by low-dose cyclophosphamide. Cancer Res 44(11):5439–5443PubMedGoogle Scholar
  160. 160.
    Berd D, Mastrangelo MJ (1988) Active immunotherapy of human melanoma exploiting the immunopotentiating effects of cyclophosphamide. Cancer Investig 6(3):337–349CrossRefGoogle Scholar
  161. 161.
    Berd D, Maguire HC Jr, McCue P, Mastrangelo MJ (1990) Treatment of metastatic melanoma with an autologous tumor-cell vaccine: clinical and immunologic results in 64 patients. J Clin Oncol 8(11):1858–1867PubMedGoogle Scholar
  162. 162.
    Hoon DS, Foshag LJ, Nizze AS, Bohman R, Morton DL (1990) Suppressor cell activity in a randomized trial of patients receiving active specific immunotherapy with melanoma cell vaccine and low dosages of cyclophosphamide. Cancer Res 50(17):5358–5364PubMedGoogle Scholar
  163. 163.
    Vaishampayan U, Abrams J, Darrah D, Jones V, Mitchell MS (2002) Active immunotherapy of metastatic melanoma with allogeneic melanoma lysates and interferon alpha. Clin Cancer Res 8(12):3696–3701PubMedGoogle Scholar
  164. 164.
    Holtl L, Ramoner R, Zelle-Rieser C, Gander H, Putz T, Papesh C, Nussbaumer W, Falkensammer C, Bartsch G, Thurnher M (2005) Allogeneic dendritic cell vaccination against metastatic renal cell carcinoma with or without cyclophosphamide. Cancer Immunol Immunother 54(7):663–670PubMedCrossRefGoogle Scholar
  165. 165.
    Berd D, Maguire HC Jr, Mastrangelo MJ (1984) Impairment of concanavalin A-inducible suppressor activity following administration of cyclophosphamide to patients with advanced cancer. Cancer Res 44(3):1275–1280PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Antonella Sistigu
    • 1
    • 2
    • 3
    • 4
  • Sophie Viaud
    • 1
    • 2
  • Nathalie Chaput
    • 1
    • 2
    • 5
    • 6
  • Laura Bracci
    • 4
  • Enrico Proietti
    • 4
  • Laurence Zitvogel
    • 1
    • 2
    • 3
    • 5
    • 7
  1. 1.INSERM, U1015VillejuifFrance
  2. 2.Institut Gustave RoussyVillejuifFrance
  3. 3.Université Paris-SudVillejuifFrance
  4. 4.Department of Cell Biology and NeurosciencesIstituto Superiore di SanitàRomeItaly
  5. 5.Centre d’Investigation Clinique en Biothérapie, CICBT 507VillejuifFrance
  6. 6.Laboratoire de Thérapie cellulaireInstitut Gustave RoussyVillejuifFrance
  7. 7.U1015 INSERMInstitut Gustave RoussyVillejuif CedexFrance

Personalised recommendations