Cancer Immunology, Immunotherapy

, Volume 59, Issue 3, pp 341–353

Dendritic cell recovery post-lymphodepletion: a potential mechanism for anti-cancer adoptive T cell therapy and vaccination

Review

Abstract

Adoptive transfer of autologous tumor-reactive T cells holds promise as a cancer immunotherapy. In this approach, T cells are harvested from a tumor-bearing host, expanded in vitro and infused back to the same host. Conditioning of the recipient host with a lymphodepletion regimen of chemotherapy or radiotherapy before adoptive T cell transfer has been shown to substantially improve survival and anti-tumor responses of the transferred cells. These effects are further enhanced when the adoptive T cell transfer is followed by vaccination with tumor antigens in combination with a potent immune adjuvant. Although significant progress has been made toward an understanding of the reasons underlying the beneficial effects of lymphodepletion to T cell adoptive therapy, the precise mechanisms remain poorly understood. Recent studies, including ours, would indicate a more central role for antigen presenting cells, in particular dendritic cells. Unraveling the exact role of these important cells in mediation of the beneficial effects of lymphodepletion could provide novel pathways toward the rational design of more effective anti-cancer immunotherapy. This article focuses on how the frequency, phenotype, and functions of dendritic cells are altered during the lymphopenic and recovery phases post-induction of lymphodepletion, and how they affect the anti-tumor responses of adoptively transferred T cells.

Keywords

Adoptive T cell transfer Cancer Chemotherapy Dendritic cells Lymphodepletion Tumor Vaccination 

References

  1. 1.
    Abad JD, Wrzensinski C, Overwijk W, De Witte MA, Jorritsma A, Hsu C, Gattinoni L, Cohen CJ, Paulos CM, Palmer DC, Haanen JB, Schumacher TN, Rosenberg SA, Restifo NP, Morgan RA (2008) T-cell receptor gene therapy of established tumors in a murine melanoma model. J Immunother 31:1–6PubMedGoogle Scholar
  2. 2.
    Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI (2001) Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 166:678–689PubMedGoogle Scholar
  3. 3.
    Angulo I, de las Heras FG, Garcia-Bustos JF, Gargallo D, Munoz-Fernandez MA, Fresno M (2000) Nitric oxide-producing CD11b(+)Ly-6G(Gr-1)(+)CD31(ER-MP12)(+) cells in the spleen of cyclophosphamide-treated mice: implications for T-cell responses in immunosuppressed mice. Blood 95:212–220PubMedGoogle Scholar
  4. 4.
    Angulo I, Jimenez-Diaz MB, Garcia-Bustos JF, Gargallo D, de las Heras FG, Munoz-Fernandez MA, Fresno M (2002) Candida albicans infection enhances immunosuppression induced by cyclophosphamide by selective priming of suppressive myeloid progenitors for NO production. Cell Immunol 218:46–58PubMedGoogle Scholar
  5. 5.
    Antony PA, Paulos CM, Ahmadzadeh M, Akpinarli A, Palmer DC, Sato N, Kaiser A, Hinrichs CS, Klebanoff CA, Tagaya Y, Restifo NP (2006) Interleukin-2-dependent mechanisms of tolerance and immunity in vivo. J Immunol 176:5255–5266PubMedGoogle Scholar
  6. 6.
    Antony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, Surman DR, Palmer DC, Chan CC, Klebanoff CA, Overwijk WW, Rosenberg SA, Restifo NP (2005) CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol 174:2591–2601PubMedGoogle Scholar
  7. 7.
    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 13:1050–1059PubMedGoogle Scholar
  8. 8.
    Apostolopoulos V, Popovski V, McKenzie IF (1998) Cyclophosphamide enhances the CTL precursor frequency in mice immunized with MUC1-mannan fusion protein (M-FP). J Immunother 21:109–113PubMedGoogle Scholar
  9. 9.
    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 65:87–92PubMedGoogle Scholar
  10. 10.
    Belardelli F, Ferrantini M (2002) Cytokines as a link between innate and adaptive antitumor immunity. Trends Immunol 23:201–208PubMedGoogle Scholar
  11. 11.
    Bellone M (2000) Apoptosis, cross-presentation, and the fate of the antigen specific immune response. Apoptosis 5:307–314PubMedGoogle Scholar
  12. 12.
    Ben-Hur H, Kossoy G, Kossoy N, Zusman I (2002) Response of the immune system of mammary tumor-bearing rats to cyclophosphamide and soluble low-molecular-mass tumor-associated antigens: the bone marrow and thymus. Int J Mol Med 10:517–521PubMedGoogle Scholar
  13. 13.
    Ben-Hur H, Kossoy G, Tendler Y, Kossoy N, Zusman I (2002) Effects of cyclophosphamide and soluble tumor-associated antigens on lymphoid infiltration, proliferative activity and rate of apoptosis in chemically-induced rat mammary tumors. In Vivo 16:287–292PubMedGoogle Scholar
  14. 14.
    Ben-Hur H, Kossoy G, Zandbank J, Zusman I (2002) Response of the immune system of mammary tumor-bearing rats to cyclophosphamide and soluble low-molecular-mass tumor-associated antigens: rate of lymphoid infiltration and distribution of T lymphocytes in tumors. Int J Mol Med 9:425–430PubMedGoogle Scholar
  15. 15.
    Berenson JR, Einstein AB Jr, Fefer A (1975) Syngeneic adoptive immunotherapy and chemoimmunotherapy of a Friend leukemia: requirement for T cells. J Immunol 115:234–238PubMedGoogle Scholar
  16. 16.
    Berraondo P, Nouze C, Preville X, Ladant D, Leclerc C (2007) Eradication of large tumors in mice by a tritherapy targeting the innate, adaptive, and regulatory components of the immune system. Cancer Res 67:8847–8855PubMedGoogle Scholar
  17. 17.
    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 13:644–653PubMedGoogle Scholar
  18. 18.
    Brode S, Cooke A (2008) Immune-potentiating effects of the chemotherapeutic drug cyclophosphamide. Crit Rev Immunol 28:109–126PubMedGoogle Scholar
  19. 19.
    Carbone FR, Belz GT, Heath WR (2004) Transfer of antigen between migrating and lymph node-resident DCs in peripheral T-cell tolerance and immunity. Trends Immunol 25:655–658PubMedGoogle Scholar
  20. 20.
    Cavanagh WA, Tjoa BA, Ragde H (2007) Chemotherapy followed by syngeneic dendritic cell injection in the mouse: findings and implications for human treatment. Urology 70:36–41PubMedGoogle Scholar
  21. 21.
    Cohen S, Haimovich J, Hollander N (2009) Dendritic cell-based therapeutic vaccination against myeloma: vaccine formulation determines efficacy against light chain myeloma. J Immunol 182:1667–1673PubMedGoogle Scholar
  22. 22.
    Corzo CA, Cotter MJ, Cheng P, Cheng F, Kusmartsev S, Sotomayor E, Padhya T, McCaffrey TV, McCaffrey JC, Gabrilovich DI (2009) Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J Immunol 182:5693–5701PubMedGoogle Scholar
  23. 23.
    Curtsinger JM, Lins DC, Mescher MF (1998) CD8+ memory T cells (CD44high, Ly-6C+) are more sensitive than naive cells to (CD44low, Ly-6C-) to TCR/CD8 signaling in response to antigen. J Immunol 160:3236–3243PubMedGoogle Scholar
  24. 24.
    Diaz-Montero CM, El Naggar S, Al Khami A, El Naggar R, Montero AJ, Cole DJ, Salem ML (2008) Priming of naive CD8+ T cells in the presence of IL-12 selectively enhances the survival of CD8+CD62Lhi cells and results in superior anti-tumor activity in a tolerogenic murine model. Cancer Immunol Immunother 57:563–572PubMedGoogle Scholar
  25. 25.
    Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ (2009) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 58:49–59PubMedGoogle Scholar
  26. 26.
    Eberlein TJ, Rosenstein M, Rosenberg SA (1982) Regression of a disseminated syngeneic solid tumor by systemic transfer of lymphoid cells expanded in interleukin 2. J Exp Med 156:385–397PubMedGoogle Scholar
  27. 27.
    Eggert AA, Schreurs MW, Boerman OC, Oyen WJ, de Boer AJ, Punt CJ, Figdor CG, Adema GJ (1999) Biodistribution and vaccine efficiency of murine dendritic cells are dependent on the route of administration. Cancer Res 59:3340–3345PubMedGoogle Scholar
  28. 28.
    Eyrich M, Burger G, Marquardt K, Budach W, Schilbach K, Niethammer D, Schlegel PG (2005) Sequential expression of adhesion and costimulatory molecules in graft-versus-host disease target organs after murine bone marrow transplantation across minor histocompatibility antigen barriers. Biol Blood Marrow Transplant 11:371–382PubMedGoogle Scholar
  29. 29.
    Fong L, Hou Y, Rivas A, Benike C, Yuen A, Fisher GA, Davis MM, Engleman EG (2001) Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc Natl Acad Sci USA 98:8809–8814PubMedGoogle Scholar
  30. 30.
    Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174PubMedGoogle Scholar
  31. 31.
    Gallucci S, Lolkema M, Matzinger P (1999) Natural adjuvants: endogenous activators of dendritic cells. Nat Med 5:1249–1255PubMedGoogle Scholar
  32. 32.
    Garrity T, Pandit R, Wright MA, Benefield J, Keni S, Young MR (1997) Increased presence of CD34+ cells in the peripheral blood of head and neck cancer patients and their differentiation into dendritic cells. Int J Cancer 73:663–669PubMedGoogle Scholar
  33. 33.
    Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, Hwang LN, Yu Z, Wrzesinski C, Heimann DM, Surh CD, Rosenberg SA, Restifo NP (2005) Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med 202:907–912PubMedGoogle Scholar
  34. 34.
    Gattinoni L, Powell DJ Jr, Rosenberg SA, Restifo NP (2006) Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 6:383–393PubMedGoogle Scholar
  35. 35.
    Gazitt Y, Akay C, Thomas C 3rd (2006) No polarization of type 1 or type 2 precursor dendritic cells in peripheral blood stem cell collections of non-hodgkin’s lymphoma patients mobilized with cyclophosphamide plus G-CSF, GM-CSF, or GM-CSF followed by G-CSF. Stem Cells Dev 15:269–277PubMedGoogle Scholar
  36. 36.
    Gruber A, Brocker T (2005) MHC class I-positive dendritic cells (DC) control CD8 T cell homeostasis in vivo: T cell lymphopenia as a prerequisite for DC-mediated homeostatic proliferation of naive CD8 T cells. J Immunol 175:201–206PubMedGoogle Scholar
  37. 37.
    Guo F, Chang CK, Fan HH, Nie XX, Ren YN, Liu YY, Zhao LH (2008) Anti-tumour effects of exosomes in combination with cyclophosphamide and polyinosinic–polycytidylic acid. J Int Med Res 36:1342–1353PubMedGoogle Scholar
  38. 38.
    Hallahan DE, Spriggs DR, Beckett MA, Kufe DW, Weichselbaum RR (1989) Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation. Proc Natl Acad Sci USA 86:10104–10107PubMedGoogle Scholar
  39. 39.
    Hallahan DE, Staba-Hogan MJ, Virudachalam S, Kolchinsky A (1998) X-ray-induced P-selectin localization to the lumen of tumor blood vessels. Cancer Res 58:5216–5220PubMedGoogle Scholar
  40. 40.
    Hallahan DE, Virudachalam S (1999) Accumulation of P-selectin in the lumen of irradiated blood vessels. Radiat Res 152:6–13PubMedGoogle Scholar
  41. 41.
    He H, Wisner P, Yang G, Hu HM, Haley D, Miller W, O’Hara A, Alvord WG, Clegg CH, Fox BA, Urba WJ, Walker EB (2006) Combined IL-21 and Low-Dose IL-2 therapy induces anti-tumor immunity and long-term curative effects in a murine melanoma tumor model. J Transl Med 4:24PubMedGoogle Scholar
  42. 42.
    Hinrichs CS, Spolski R, Paulos CM, Gattinoni L, Kerstann KW, Palmer DC, Klebanoff CA, Rosenberg SA, Leonard WJ, Restifo NP (2008) IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood 111:5326–5333PubMedGoogle Scholar
  43. 43.
    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 206:1103–1116PubMedGoogle Scholar
  44. 44.
    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 54:663–670PubMedGoogle Scholar
  45. 45.
    Hong JH, Chiang CS, Tsao CY, Lin PY, McBride WH, Wu CJ (1999) Rapid induction of cytokine gene expression in the lung after single and fractionated doses of radiation. Int J Radiat Biol 75:1421–1427PubMedGoogle Scholar
  46. 46.
    Hoover SK, Barrett SK, Turk TM, Lee TC, Bear HD (1990) Cyclophosphamide and abrogation of tumor-induced suppressor T cell activity. Cancer Immunol Immunother 31:121–127PubMedGoogle Scholar
  47. 47.
    Horvath R, Budinsky V, Kayserova J, Kalina T, Formankova R, Stary J, Bartunkova J, Sedlacek P, Spisek R (2009) Kinetics of dendritic cells reconstitution and costimulatory molecules expression after myeloablative allogeneic haematopoetic stem cell transplantation: implications for the development of acute graft-versus host disease. Clin Immunol 131:60–69PubMedGoogle Scholar
  48. 48.
    Hu DE, Moore AM, Thomsen LL, Brindle KM (2004) Uric acid promotes tumor immune rejection. Cancer Res 64:5059–5062PubMedGoogle Scholar
  49. 49.
    Huang J, Wang Y, Guo J, Lu H, Lin X, Ma L, Teitz-Tennenbaum S, Chang AE, Li Q (2007) Radiation-induced apoptosis along with local and systemic cytokine elaboration is associated with DC plus radiotherapy-mediated renal cell tumor regression. Clin Immunol 123:298–310PubMedGoogle Scholar
  50. 50.
    Huck SP, Tang SC, Andrew KA, Yang J, Harper JL, Ronchese F (2008) Activation and route of administration both determine the ability of bone marrow-derived dendritic cells to accumulate in secondary lymphoid organs and prime CD8+ T cells against tumors. Cancer Immunol Immunother 57:63–71PubMedGoogle Scholar
  51. 51.
    Hwang LN, Yu Z, Palmer DC, Restifo NP (2006) The in vivo expansion rate of properly stimulated transferred CD8+ T cells exceeds that of an aggressively growing mouse tumor. Cancer Res 66:1132–1138PubMedGoogle Scholar
  52. 52.
    Ibe S, Qin Z, Schuler T, Preiss S, Blankenstein T (2001) Tumor rejection by disturbing tumor stroma cell interactions. J Exp Med 194:1549–1559PubMedGoogle Scholar
  53. 53.
    Ikezawa Y, Nakazawa M, Tamura C, Takahashi K, Minami M, Ikezawa Z (2005) Cyclophosphamide decreases the number, percentage and the function of CD25(+) CD4(+) regulatory T cells, which suppress induction of contact hypersensitivity. J Dermatol SciGoogle Scholar
  54. 54.
    Ishihara H, Tanaka I, Nemoto K, Tsuneoka K, Cheeramakara C, Yoshida K, Ohtsu H (1995) Immediate-early, transient induction of the interleukin-1 beta gene in mouse spleen macrophages by ionizing radiation. J Radiat Res (Tokyo) 36:112–124Google Scholar
  55. 55.
    Jabbari A, Harty JT (2005) Cutting edge: differential self-peptide/MHC requirement for maintaining CD8 T cell function versus homeostatic proliferation. J Immunol 175:4829–4833PubMedGoogle Scholar
  56. 56.
    Jahrsdorfer B, Weiner GJ (2008) CpG oligodeoxynucleotides as immunotherapy in cancer. Update Cancer Ther 3:27–32PubMedGoogle Scholar
  57. 57.
    Kawashima H (2006) Roles of sulfated glycans in lymphocyte homing. Biol Pharm Bull 29:2343–2349PubMedGoogle Scholar
  58. 58.
    Kedl RM, Rees WA, Hildeman DA, Schaefer B, Mitchell T, Kappler J, Marrack P (2000) T cells compete for access to antigen-bearing antigen-presenting cells. J Exp Med 192:1105–1113PubMedGoogle Scholar
  59. 59.
    Kepp O, Tesniere A, Schlemmer F, Michaud M, Senovilla L, Zitvogel L, Kroemer G (2009) Immunogenic cell death modalities and their impact on cancer treatment. Apoptosis 14:364–375PubMedGoogle Scholar
  60. 60.
    Klebanoff CA, Finkelstein SE, Surman DR, Lichtman MK, Gattinoni L, Theoret MR, Grewal N, Spiess PJ, Antony PA, Palmer DC, Tagaya Y, Rosenberg SA, Waldmann TA, Restifo NP (2004) IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc Natl Acad Sci USA 101:1969–1974PubMedGoogle Scholar
  61. 61.
    Klebanoff CA, Gattinoni L, Torabi-Parizi P, Kerstann K, Cardones AR, Finkelstein SE, Palmer DC, Antony PA, Hwang ST, Rosenberg SA, Waldmann TA, Restifo NP (2005) Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci USA 102:9571–9576PubMedGoogle Scholar
  62. 62.
    Klebanoff CA, Gattioni L, Restifo NP (2006) CD8+ T-cell memory in tumot immunology and immunotherapy. Immunol Rev 211:214–224PubMedGoogle Scholar
  63. 63.
    Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP (2005) Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol 26:111–117PubMedGoogle Scholar
  64. 64.
    Ko HJ, Lee JM, Kim YJ, Kim YS, Lee KA, Kang CY (2009) Immunosuppressive myeloid-derived suppressor cells can be converted into immunogenic APCs with the help of activated NKT cells: an alternative cell-based antitumor vaccine. J Immunol 182:1818–1828PubMedGoogle Scholar
  65. 65.
    Ko JS, Bukowski RM, Fincke JH (2009) Myeloid-derived suppressor cells: a novel therapeutic target. Curr Oncol Rep 11:87–93PubMedGoogle Scholar
  66. 66.
    Kohlmeyer J, Cron M, Landsberg J, Bald T, Renn M, Mikus S, Bondong S, Wikasari D, Gaffal E, Hartmann G, Tuting T (2009) Complete regression of advanced primary and metastatic mouse melanomas following combination chemoimmunotherapy. Cancer Res 69:6265–6274PubMedGoogle Scholar
  67. 67.
    Koike N, Pilon-Thomas S, Mule JJ (2008) Nonmyeloablative chemotherapy followed by T-cell adoptive transfer and dendritic cell-based vaccination results in rejection of established melanoma. J Immunother 31:402–412PubMedGoogle Scholar
  68. 68.
    Lappin MB, Weiss JM, Delattre V, Mai B, Dittmar H, Maier C, Manke K, Grabbe S, Martin S, Simon JC (1999) Analysis of mouse dendritic cell migration in vivo upon subcutaneous and intravenous injection. Immunology 98:181–188PubMedGoogle Scholar
  69. 69.
    Lau J, Sartor M, Bradstock KF, Vuckovic S, Munster DJ, Hart DN (2007) Activated circulating dendritic cells after hematopoietic stem cell transplantation predict acute graft-versus-host disease. Transplantation 83:839–846PubMedGoogle Scholar
  70. 70.
    Limpens J, Van Meijer M, Van Santen HM, Germeraad WT, Hoeben-Schornagel K, Breel M, Scheper RJ, Kraal G (1991) Alterations in dendritic cell phenotype and function associated with immunoenhancing effects of a subcutaneously administered cyclophosphamide derivative. Immunology 73:255–263PubMedGoogle Scholar
  71. 71.
    Liu F, Poursine-Laurent J, Link DC (1997) The granulocyte colony-stimulating factor receptor is required for the mobilization of murine hematopoietic progenitors into peripheral blood by cyclophosphamide or interleukin-8 but not flt-3 ligand. Blood 90:2522–2528PubMedGoogle Scholar
  72. 72.
    Liu JY, Wu Y, Zhang XS, Yang JL, Li HL, Mao YQ, Wang Y, Cheng X, Li YQ, Xia JC, Masucci M, Zeng YX (2007) Single administration of low dose cyclophosphamide augments the antitumor effect of dendritic cell vaccine. Cancer Immunol Immunother 56:1597–1604PubMedGoogle Scholar
  73. 73.
    Lotze MT, Rosenberg SA (1986) Results of clinical trials with the administration of interleukin 2 and adoptive immunotherapy with activated cells in patients with cancer. Immunobiology 172:420–437PubMedGoogle Scholar
  74. 74.
    Lou Y, Wang G, Lizee G, Kim GJ, Finkelstein SE, Feng C, Restifo NP, Hwu P (2004) Dendritic cells strongly boost the antitumor activity of adoptively transferred T cells in vivo. Cancer Res 64:6783–6790PubMedGoogle Scholar
  75. 75.
    Ma J, Urba WJ, Si L, Wang Y, Fox BA, Hu HM (2003) Anti-tumor T cell response and protective immunity in mice that received sublethal irradiation and immune reconstitution. Eur J Immunol 33:2123–2132PubMedGoogle Scholar
  76. 76.
    Marigo I, Dolcetti L, Serafini P, Zanovello P, Bronte V (2008) Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev 222:162–179PubMedGoogle Scholar
  77. 77.
    Marincola FM, Ettinghausen S, Cohen PA, Cheshire LB, Restifo NP, Mule JJ, Rosenberg SA (1994) Treatment of established lung metastases with tumor-infiltrating lymphocytes derived from a poorly immunogenic tumor engineered to secrete human TNF-alpha. J Immunol 152:3500–3513PubMedGoogle Scholar
  78. 78.
    MartIn-Fontecha A, Sebastiani S, Hopken UE, Uguccioni M, Lipp M, Lanzavecchia A, Sallusto F (2003) Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J Exp Med 198:615–621PubMedGoogle Scholar
  79. 79.
    McBride WH, Chiang CS, Olson JL, Wang CC, Hong JH, Pajonk F, Dougherty GJ, Iwamoto KS, Pervan M, Liao YP (2004) A sense of danger from radiation. Radiat Res 162:1–19PubMedGoogle Scholar
  80. 80.
    Mihalyo MA, Doody AD, McAleer JP, Nowak EC, Long M, Yang Y, Adler AJ (2004) In vivo cyclophosphamide and IL-2 treatment impedes self-antigen-induced effector CD4 cell tolerization: implications for adoptive immunotherapy. J Immunol 172:5338–5345PubMedGoogle Scholar
  81. 81.
    Mokyr MB, Place AT, Artwohl JE, Valli VE (2006) Importance of signaling via the IFN-alpha/beta receptor on host cells for the realization of the therapeutic benefits of cyclophosphamide for mice bearing a large MOPC-315 tumor. Cancer Immunol Immunother 55:459–468PubMedGoogle Scholar
  82. 82.
    Morrison SJ, Wright DE, Weissman IL (1997) Cyclophosphamide/granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization. Proc Natl Acad Sci USA 94:1908–1913PubMedGoogle Scholar
  83. 83.
    Muranski P, Boni A, Wrzesinski C, Citrin DE, Rosenberg SA, Childs R, Restifo NP (2006) Increased intensity lymphodepletion and adoptive immunotherapy–how far can we go? Nat Clin Pract Oncol 3:668–681PubMedGoogle Scholar
  84. 84.
    Nagaraj S, Collazo M, Corzo CA, Youn JI, Ortiz M, Quiceno D, Gabrilovich DI (2009) Regulatory myeloid suppressor cells in health and disease. Cancer Res 69:7503–7506PubMedGoogle Scholar
  85. 85.
    Nakayama M, Itoh K, Takahashi E (1997) Cyclophosphamide-induced bacterial translocation in Escherichia coli C25-monoassociated specific pathogen-free mice. Microbiol Immunol 41:587–593PubMedGoogle Scholar
  86. 86.
    Ndejembi MP, Tang AL, Farber DL (2007) Reshaping the past: Strategies for modulating T-cell memory immune responses. Clin Immunol 122:1–12PubMedGoogle Scholar
  87. 87.
    Neben S, Marcus K, Mauch P (1993) Mobilization of hematopoietic stem and progenitor cell subpopulations from the marrow to the blood of mice following cyclophosphamide and/or granulocyte colony-stimulating factor. Blood 81:1960–1967PubMedGoogle Scholar
  88. 88.
    Nemoto K, Ishihara H, Tanaka I, Suzuki G, Tsuneoka K, Yoshida K, Ohtsu H (1995) Expression of IL-1 beta mRNA in mice after whole body X-irradiation. J Radiat Res (Tokyo) 36:125–133Google Scholar
  89. 89.
    Okada N, Tsujino M, Hagiwara Y, Tada A, Tamura Y, Mori K, Saito T, Nakagawa S, Mayumi T, Fujita T, Yamamoto A (2001) Administration route-dependent vaccine efficiency of murine dendritic cells pulsed with antigens. Br J Cancer 84:1564–1570PubMedGoogle Scholar
  90. 90.
    Overwijk WW, de Visser KE, Tirion FH, de Jong LA, Pols TW, van der Velden YU, van den Boorn JG, Keller AM, Buurman WA, Theoret MR, Blom B, Restifo NP, Kruisbeek AM, Kastelein RA, Haanen JB (2006) Immunological and antitumor effects of IL-23 as a cancer vaccine adjuvant. J Immunol 176:5213–5222PubMedGoogle Scholar
  91. 91.
    Overwijk WW, Theoret MR, Finkelstein SE, Surman DR, de Jong LA, Vyth-Dreese FA, Dellemijn TA, Antony PA, Spiess PJ, Palmer DC, Heimann DM, Klebanoff CA, Yu Z, Hwang LN, Feigenbaum L, Kruisbeek AM, Rosenberg SA, Restifo NP (2003) Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J Exp Med 198:569–580PubMedGoogle Scholar
  92. 92.
    Overwijk WW, Tsung A, Irvine KR, Parkhurst MR, Goletz TJ, Tsung K, Carroll MW, Liu C, Moss B, Rosenberg SA, Restifo NP (1998) gp100/pmel 17 is a murine tumor rejection antigen: induction of “self”-reactive, tumoricidal T cells using high-affinity, altered peptide ligand. J Exp Med 188:277–286PubMedGoogle Scholar
  93. 93.
    Pak AS, Wright MA, Matthews JP, Collins SL, Petruzzelli GJ, Young MR (1995) Mechanisms of immune suppression in patients with head and neck cancer: presence of CD34(+) cells which suppress immune functions within cancers that secrete granulocyte-macrophage colony-stimulating factor. Clin Cancer Res 1:95–103PubMedGoogle Scholar
  94. 94.
    Pandit R, Lathers DM, Beal NM, Garrity T, Young MR (2000) CD34+ immune suppressive cells in the peripheral blood of patients with head and neck cancer. Ann Otol Rhinol Laryngol 109:749–754PubMedGoogle Scholar
  95. 95.
    Paulos CM, Kaiser A, Wrzesinski C, Hinrichs CS, Cassard L, Boni A, Muranski P, Sanchez-Perez L, Palmer DC, Yu Z, Antony PA, Gattinoni L, Rosenberg SA, Restifo NP (2007) Toll-like receptors in tumor immunotherapy. Clin Cancer Res 13:5280–5289PubMedGoogle Scholar
  96. 96.
    Paulos CM, Wrzesinski C, Kaiser A, Hinrichs CS, Chieppa M, Cassard L, Palmer DC, Boni A, Muranski P, Yu Z, Gattinoni L, Antony PA, Rosenberg SA, Restifo NP (2007) Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J Clin Invest 117:2197–2204PubMedGoogle Scholar
  97. 97.
    Pelaez B, Campillo JA, Lopez-Asenjo JA, Subiza JL (2001) Cyclophosphamide induces the development of early myeloid cells suppressing tumor cell growth by a nitric oxide-dependent mechanism. J Immunol 166:6608–6615PubMedGoogle Scholar
  98. 98.
    Phipps RP, Mandel TE, Schnizlein CT, Tew JG (1984) Anamnestic responses induced by antigen persisting on follicular dendritic cells from cyclophosphamide-treated mice. Immunology 51:387–397PubMedGoogle Scholar
  99. 99.
    Prins RM, Shu CJ, Radu CG, Vo DD, Khan-Farooqi H, Soto H, Yang MY, Lin MS, Shelly S, Witte ON, Ribas A, Liau LM (2008) Anti-tumor activity and trafficking of self, tumor-specific T cells against tumors located in the brain. Cancer Immunol Immunother 57:1279–1289PubMedGoogle Scholar
  100. 100.
    Probst HC, van den Broek M (2005) Priming of CTLs by lymphocytic choriomeningitis virus depends on dendritic cells. J Immunol 174:3920–3924PubMedGoogle Scholar
  101. 101.
    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 Invest 101:429–441PubMedGoogle Scholar
  102. 102.
    Pulendran B, Ahmed R (2006) Translating innate immunity into immunological memory: implications for vaccine development. Cell 124:849–863PubMedGoogle Scholar
  103. 103.
    Radcliff FJ, Caruso DA, Koina C, Riordan MJ, Roberts AW, Tang ML, Baum CM, Woulfe SL, Ashley DM (2002) Mobilization of dendritic cells in cancer patients treated with granulocyte colony-stimulating factor and chemotherapy. Br J Haematol 119:204–211PubMedGoogle Scholar
  104. 104.
    Radojcic V, Bezak KB, Skarica M, Pletneva MA, Yoshimura K, Schulick RD, Luznik L (2009) Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination. Cancer Immunol Immunother 59(1):137–148PubMedGoogle Scholar
  105. 105.
    Ramakrishnan R, Antonia S, Gabrilovich DI (2008) Combined modality immunotherapy and chemotherapy: a new perspective. Cancer Immunol Immunother 57:1523–1529PubMedGoogle Scholar
  106. 106.
    Reis e Sousa C (2006) Dendritic cells in a mature age. Nat Rev Immunol 6:476–483PubMedGoogle Scholar
  107. 107.
    Rigby SM, Rouse T, Field EH (2003) Total lymphoid irradiation nonmyeloablative preconditioning enriches for IL-4-producing CD4+-TNK cells and skews differentiation of immunocompetent donor CD4+ cells. Blood 101:2024–2032PubMedGoogle Scholar
  108. 108.
    Rosen SD (2004) Ligands for l-selectin: homing, inflammation, and beyond. Annu Rev Immunol 22:129–156PubMedGoogle Scholar
  109. 109.
    Rosenberg SA (1984) Immunotherapy of cancer by systemic administration of lymphoid cells plus interleukin-2. J Biol Response Mod 3:501–511PubMedGoogle Scholar
  110. 110.
    Rosenberg SA (2001) Progress in human tumour immunology and immunotherapy. Nature 411:380–384PubMedGoogle Scholar
  111. 111.
    Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, Yang JC, Seipp CA et al (1988) Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med 319:1676–1680PubMedCrossRefGoogle Scholar
  112. 112.
    Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME (2008) Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 8:299–308PubMedGoogle Scholar
  113. 113.
    Roses RE, Xu M, Koski GK, Czerniecki BJ (2008) Radiation therapy and Toll-like receptor signaling: implications for the treatment of cancer. Oncogene 27:200–207PubMedGoogle Scholar
  114. 114.
    Salem ML, AL-Khami AA, EL-Naggar SA, Díaz-Montero CM, Chen Y, Cole DJ (2009) Cyclophosphamide induces dynamic alterations in the host microenvironments resulting in a FLT3L-dependent expansion of dendritic cells. J Immunol (under revision)Google Scholar
  115. 115.
    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 182:2030–2040PubMedGoogle Scholar
  116. 116.
    Salem ML, El-Naggar SA, Cole DJ (2009) 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 (submitted)Google Scholar
  117. 117.
    Salem ML, El-Naggar SA, Kadima A, Gillanders WE, Cole DJ (2006) The adjuvant effects of the toll-like receptor 3 ligand polyinosinic-cytidylic acid poly (I:C) on antigen-specific CD8+ T cell responses are partially dependent on NK cells with the induction of a beneficial cytokine milieu. Vaccine 24:5119–5132PubMedGoogle Scholar
  118. 118.
    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 30:40–53PubMedGoogle Scholar
  119. 119.
    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 95:2024–2030PubMedGoogle Scholar
  120. 120.
    Schumacher TN, Restifo NP (2009) Adoptive T cell therapy of cancer. Curr Opin Immunol 21:187–189PubMedGoogle Scholar
  121. 121.
    Shackleton M, Davis ID, Hopkins W, Jackson H, Dimopoulos N, Tai T, Chen Q, Parente P, Jefford M, Masterman KA, Caron D, Chen W, Maraskovsky E, Cebon J (2004) The impact of imiquimod, a Toll-like receptor-7 ligand (TLR7L), on the immunogenicity of melanoma peptide vaccination with adjuvant Flt3 ligand. Cancer Immun 4:9PubMedGoogle Scholar
  122. 122.
    Shi Y, Evans JE, Rock KL (2003) Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425:516–521PubMedGoogle Scholar
  123. 123.
    Shi Y, Galusha SA, Rock KL (2006) Cutting edge: elimination of an endogenous adjuvant reduces the activation of CD8 T lymphocytes to transplanted cells and in an autoimmune diabetes model. J Immunol 176:3905–3908PubMedGoogle Scholar
  124. 124.
    Song W, Levy R (2005) Therapeutic vaccination against murine lymphoma by intratumoral injection of naive dendritic cells. Cancer Res 65:5958–5964PubMedGoogle Scholar
  125. 125.
    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 176:2722–2729PubMedGoogle Scholar
  126. 126.
    Tesniere A, Panaretakis T, Kepp O, Apetoh L, Ghiringhelli F, Zitvogel L, Kroemer G (2008) Molecular characteristics of immunogenic cancer cell death. Cell Death Differ 15:3–12PubMedGoogle Scholar
  127. 127.
    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 61:7530–7535PubMedGoogle Scholar
  128. 128.
    Torihata H, Ishikawa F, Okada Y, Tanaka Y, Uchida T, Suguro T, Kakiuchi T (2004) Irradiation up-regulates CD80 expression through two different mechanisms in spleen B cells, B lymphoma cells, and dendritic cells. Immunology 112:219–227PubMedGoogle Scholar
  129. 129.
    Vierboom MP, Bos GM, Ooms M, Offringa R, Melief CJ (2000) Cyclophosphamide enhances anti-tumor effect of wild-type p53-specific CTL. Int J Cancer 87:253–260PubMedGoogle Scholar
  130. 130.
    Vuckovic S, Kim M, Khalil D, Turtle CJ, Crosbie GV, Williams N, Brown L, Williams K, Kelly C, Stravos P, Rodwell R, Hill GR, Wright S, Taylor K, Gill D, Marlton P, Bradstock K, Hart DN (2003) Granulocyte-colony stimulating factor increases CD123hi blood dendritic cells with altered CD62L and CCR7 expression. Blood 101:2314–2317PubMedGoogle Scholar
  131. 131.
    Wada S, Yoshimura K, Hipkiss EL, Harris TJ, Yen HR, Goldberg MV, Grosso JF, Getnet D, Demarzo AM, Netto GJ, Anders R, Pardoll DM, Drake CG (2009) Cyclophosphamide augments antitumor immunity: studies in an autochthonous prostate cancer model. Cancer Res 69:4309–4318PubMedGoogle Scholar
  132. 132.
    Wang LX, Li R, Yang G, Lim M, O’Hara A, Chu Y, Fox BA, Restifo NP, Urba WJ, Hu HM (2005) Interleukin-7-dependent expansion and persistence of melanoma-specific T cells in lymphodepleted mice lead to tumor regression and editing. Cancer Res 65:10569–10577PubMedGoogle Scholar
  133. 133.
    Wright DE, Cheshier SH, Wagers AJ, Randall TD, Christensen JL, Weissman IL (2001) Cyclophosphamide/granulocyte colony-stimulating factor causes selective mobilization of bone marrow hematopoietic stem cells into the blood after M phase of the cell cycle. Blood 97:2278–2285PubMedGoogle Scholar
  134. 134.
    Wrzesinski C, Paulos CM, Gattinoni L, Palmer DC, Kaiser A, Yu Z, Rosenberg SA, Restifo NP (2007) Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J Clin Invest 117:492–501PubMedGoogle Scholar
  135. 135.
    Wrzesinski C, Restifo NP (2005) Less is more: lymphodepletion followed by hematopoietic stem cell transplant augments adoptive T-cell-based anti-tumor immunotherapy. Curr Opin Immunol 17:195–201PubMedGoogle Scholar
  136. 136.
    Xun CQ, Thompson JS, Jennings CD, Brown SA, Widmer MB (1994) Effect of total body irradiation, busulfan-cyclophosphamide, or cyclophosphamide conditioning on inflammatory cytokine release and development of acute and chronic graft-versus-host disease in H-2-incompatible transplanted SCID mice. Blood 83:2360–2367PubMedGoogle Scholar
  137. 137.
    Youn JI, Nagaraj S, Collazo M, Gabrilovich DI (2008) Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 181:5791–5802PubMedGoogle Scholar
  138. 138.
    Zaft T, Sapoznikov A, Krauthgamer R, Littman DR, Jung S (2005) CD11chigh dendritic cell ablation impairs lymphopenia-driven proliferation of naive and memory CD8+ T cells. J Immunol 175:6428–6435PubMedGoogle Scholar
  139. 139.
    Zeng R, Spolski R, Finkelstein SE, Oh S, Kovanen PE, Hinrichs CS, Pise-Masison CA, Radonovich MF, Brady JN, Restifo NP, Berzofsky JA, Leonard WJ (2005) Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J Exp Med 201:139–148PubMedGoogle Scholar
  140. 140.
    Zhang B, Bowerman NA, Salama JK, Schmidt H, Spiotto MT, Schietinger A, Yu P, Fu YX, Weichselbaum RR, Rowley DA, Kranz DM, Schreiber H (2007) Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. J Exp Med 204:49–55PubMedGoogle Scholar
  141. 141.
    Zhang Y, Louboutin JP, Zhu J, Rivera AJ, Emerson SG (2002) Preterminal host dendritic cells in irradiated mice prime CD8+ T cell-mediated acute graft-versus-host disease. J Clin Invest 109:1335–1344PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Surgery DepartmentMedical University of South CarolinaCharlestonUSA
  2. 2.Hollings Cancer CenterMedical University of South CarolinaCharlestonUSA

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