Employing T Cell Homeostasis as an Antitumor Strategy

  • Shawn M. Jensen
  • Christopher C. Paustain
  • Bernard A. Fox
Chapter
First Online:
Part of the Current Cancer Research book series (CUCR)

Abstract

In the arena of cancer treatments, chemotherapeutic agents and radiotherapy were originally designed to kill rapidly dividing cancer cells and deletion of lymphoid cells was simply considered collateral damage. The last few decades have witnessed a growing appreciation for immunologic control of tumor burdens, and consequently, numerous strategies designed to harness the immune system to combat cancers have been developed. While on the surface the combination of immune-depleting chemo/radiotherapies and immunotherapies may seem counterintuitive, the fact that the immune system has mechanisms in place for compensatory expansion after depletion, an effect called homeostasis-driven T cell expansion, has been exploited in both preclinical models as well as clinical therapies. This chapter examines both.

Keywords

Homeostasis Lymphopenia T cell Antitumor immune response Clinical trial Antitumor vaccination Adoptive immunotherapy 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Cannon WB. Organization for physiological homeostasis. Physiol Rev. 1929;9(3):399–431.Google Scholar
  2. 2.
    Badovinac VP, Porter BB, Harty JT. Programmed contraction of CD8(+) T cells after infection. Nat Immunol. 2002;3(7):619–26. doi: 10.1038/ni804.PubMedGoogle Scholar
  3. 3.
    Goronzy JJ, Weyand CM. T cell development and receptor diversity during aging. Curr Opin Immunol. 2005;17(5):468–75. doi: 10.1016/j.coi.2005.07.020.PubMedCrossRefGoogle Scholar
  4. 4.
    Martin B. On the role of MHC class II molecules in the survival and lymphopenia-induced proliferation of peripheral CD4+ T cells. Proc Natl Acad Sci U S A. 2003;100(10):6021–6. doi: 10.1073/pnas.1037754100.PubMedCrossRefGoogle Scholar
  5. 5.
    Surh CD, Sprent J. Homeostasis of naive and memory T cells. Immunity. 2008;29(6):848–62. doi: 10.1016/j.immuni.2008.11.002.PubMedCrossRefGoogle Scholar
  6. 6.
    Takeda S, Rodewald HR, Arakawa H, Bluethmann H, Shimizu T. MHC class II molecules are not required for survival of newly generated CD4+ T cells, but affect their long-term life span. Immunity. 1996;5(3):217–28. doi: 10.1016/S1074-7613(00)80317-9.PubMedCrossRefGoogle Scholar
  7. 7.
    Tanchot C, Lemonnier FA, Rarnau BP, Freitas AA, Rocha B. Differential requirements for survival and proliferation of CD8 naïve or memory T cells. Science. 1997;276(5321):2057–62.PubMedCrossRefGoogle Scholar
  8. 8.
    Prlic M, Blazar BR, Khoruts A, Zell T, Jameson SC. Homeostatic expansion occurs independently of costimulatory signals. J Immunol. 2001;167(10):5664–8.PubMedGoogle Scholar
  9. 9.
    Tan JT, Dudl E, LeRoy E, Murray R, Sprent J, Weinberg KI, Surh CD. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc Natl Acad Sci U S A. 2001;98(15):8732–7. doi: 10.1073/pnas.161126098.PubMedCrossRefGoogle Scholar
  10. 10.
    Fry TJ, Mackall CL. The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance. J Immunol. 2005;174(11):6571–6.PubMedGoogle Scholar
  11. 11.
    Schluns KS, Kieper WC, Jameson SC, Lefrançois L. Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo. Nat Immunol. 2000;1(5):426–32. doi: 10.1038/80868.PubMedCrossRefGoogle Scholar
  12. 12.
    Berard M, Brandt K, Bulfone-Paus S, Tough DF. IL-15 promotes the survival of naive and memory phenotype CD8+ T cells. J Immunol. 2003;170(10):5018–26.PubMedGoogle Scholar
  13. 13.
    Heufler C, Topar G, Grasseger A, Stanzl U, Koch F, Romani N, Namen AE, Schuler G. Interleukin 7 is produced by murine and human keratinocytes. J Exp Med. 1993;178(3):1109–14.PubMedCrossRefGoogle Scholar
  14. 14.
    Watanabe M, Ueno Y, Yajima T, Iwao Y, Tsuchiya M, Ishikawa H, Aiso S, Hibi T, Ishii H. Interleukin 7 is produced by human intestinal epithelial cells and regulates the proliferation of intestinal mucosal lymphocytes. J Clin Invest. 1995;95(6):2945–53. doi: 10.1172/JCI118002.PubMedCrossRefGoogle Scholar
  15. 15.
    Sorg RV, McLellan AD, Hock BD, Fearnley DB, Hart DN. Human dendritic cells express functional interleukin-7. Immunobiology. 1998;198(5):514–26. doi: 10.1016/S0171-2985(98)80075-2.PubMedCrossRefGoogle Scholar
  16. 16.
    Kieper WCW, Tan JTJ, Bondi-Boyd BB, Gapin LL, Sprent JJ, Ceredig RR, Surh CDC. Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8+ T cells. J Exp Med. 2002;195(12):1533–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Jacobs SR, Michalek RD, Rathmell JC. IL-7 is essential for homeostatic control of T cell metabolism in vivo. J Immunol. 2010;184(7):3461–9. doi: 10.4049/jimmunol.0902593.PubMedCrossRefGoogle Scholar
  18. 18.
    Dai Z, Lakkis FG. Cutting edge: secondary lymphoid organs are essential for maintaining the CD4, but not CD8, naive T cell pool. J Immunol. 2001;167(12):6711–5.PubMedGoogle Scholar
  19. 19.
    Link A, Vogt TK, Favre S, Britschgi MR, Acha-Orbea H, Hinz B, Cyster JG, Luther SA. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat Immunol. 2007;8(11):1255–65. doi: 10.1038/ni1513.PubMedCrossRefGoogle Scholar
  20. 20.
    Park J-H, Yu Q, Erman B, Appelbaum JS, Montoya-Durango D, Grimes HL, Singer A. Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity. 2004;21(2):289–302. doi: 10.1016/j.immuni.2004.07.016.PubMedCrossRefGoogle Scholar
  21. 21.
    Kim KK, Lee CKC, Sayers TJT, Muegge KK, Durum SKS. The trophic action of IL-7 on pro-T cells: inhibition of apoptosis of pro-T1, -T2, and -T3 cells correlates with Bcl-2 and Bax levels and is independent of Fas and p53 pathways. J Immunol. 1998;160(12):5735–41.PubMedGoogle Scholar
  22. 22.
    Li WQ, Jiang Q, Khaled AR, Keller JR, Durum SK. Interleukin-7 inactivates the pro-apoptotic protein Bad promoting T cell survival. J Biol Chem. 2004;279(28):29160–6. doi: 10.1074/jbc.M401656200.PubMedCrossRefGoogle Scholar
  23. 23.
    Carrette F, Surh CD. IL-7 signaling and CD127 receptor regulation in the control of T cell homeostasis. Semin Immunol. 2012;24(3):209–17. doi: 10.1016/j.smim.2012.04.010.PubMedCrossRefGoogle Scholar
  24. 24.
    Wofford JA, Wieman HL, Jacobs SR, Zhao Y, Rathmell JC. IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood. 2008;111(4):2101–11. doi: 10.1182/blood-2007-06-096297.PubMedCrossRefGoogle Scholar
  25. 25.
    Rathmell JC, Farkash EA, Gao W, Thompson CB. IL-7 enhances the survival and maintains the size of naive T cells. J Immunol. 2001;167(12):6869–76.PubMedGoogle Scholar
  26. 26.
    Tough DFD, Sprent JJ. Turnover of naive- and memory-phenotype T cells. J Exp Med. 1994;179(4):1127–35.PubMedCrossRefGoogle Scholar
  27. 27.
    Murali-Krishna K, Lau LL, Sambhara S, Lemonnier F, Altman J, Ahmed R. Persistence of memory CD8 T cells in MHC class I-deficient mice. Science. 1999;286(5443):1377–81.PubMedCrossRefGoogle Scholar
  28. 28.
    Judge AD, Zhang X, Fujii H, Surh CD, Sprent J. Interleukin 15 controls both proliferation and survival of a subset of memory-phenotype CD8(+) T cells. J Exp Med. 2002;196(7):935–46.PubMedCrossRefGoogle Scholar
  29. 29.
    Becker TC, Wherry EJ, Boone D, Murali-Krishna K, Antia R, Ma A, Ahmed R. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J Exp Med. 2002;195(12):1541–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Boyman O, Purton JF, Surh CD, Sprent J. Cytokines and T-cell homeostasis. Curr Opin Immunol. 2007;19(3):320–6. doi: 10.1016/j.coi.2007.04.015.PubMedCrossRefGoogle Scholar
  31. 31.
    Kennedy MKM, Glaccum MM, Brown SNS, et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med. 2000;191(5):771–80.PubMedCrossRefGoogle Scholar
  32. 32.
    Lenz DC, Kurz SK, Lemmens E, Schoenberger SP, Sprent J, Oldstone MBA, Homann D. IL-7 regulates basal homeostatic proliferation of antiviral CD4 + T cell memory. Proc Natl Acad Sci U S A. 2004;101(25):9357–62. doi: 10.1073/pnas.0400640101.PubMedCrossRefGoogle Scholar
  33. 33.
    Jameson S. Maintaining the norm: T-cell homeostasis. Nat Rev Immunol. 2002;2:547–56. doi: 10.1083/nri853.PubMedGoogle Scholar
  34. 34.
    Surh CD, Sprent J. Regulation of naïve and memory T-cell homeostasis. Microbes Infect. 2002;4(1):51–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Tanchot C, Le Campion A, Martin B, Léaument S, Dautigny N, Lucas B. Conversion of naive T cells to a memory-like phenotype in lymphopenic hosts is not related to a homeostatic mechanism that fills the peripheral naive T cell pool. J Immunol. 2002;168(10):5042–6.PubMedGoogle Scholar
  36. 36.
    Goldrath AW, Bogatzki LY, Bevan MJ. Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J Exp Med. 2000;192(4):557–64.PubMedCrossRefGoogle Scholar
  37. 37.
    Gudmundsdottir H, Turka LA. A closer look at homeostatic proliferation of CD4+ T cells: costimulatory requirements and role in memory formation. J Immunol. 2001;167(7):3699–707.PubMedGoogle Scholar
  38. 38.
    Ge Q, Rao VP, Cho BK, Eisen HN, Chen J. Dependence of lymphopenia-induced T cell proliferation on the abundance of peptide/ MHC epitopes and strength of their interaction with T cell receptors. Proc Natl Acad Sci U S A. 2001;98(4):1728–33. doi: 10.1073/pnas.98.4.1728.PubMedCrossRefGoogle Scholar
  39. 39.
    Kieper WC, Burghardt JT, Surh CD. A role for TCR affinity in regulating naive T cell homeostasis. J Immunol. 2004;172(1):40–4.PubMedGoogle Scholar
  40. 40.
    Mackall CL, Bare CV, Granger LA, Sharrow SO, Titus JA, Gress RE. Thymic-independent T cell regeneration occurs via antigen-driven expansion of peripheral T cells resulting in a repertoire that is limited in diversity and prone to skewing. J Immunol. 1996;156(12):4609–16.PubMedGoogle Scholar
  41. 41.
    Freitas AAA, Agenes FF, Coutinho GCG. Cellular competition modulates survival and selection of CD8+ T cells. Eur J Immunol. 1996;26(11):2640–9. doi: 10.1002/eji.1830261115.PubMedCrossRefGoogle Scholar
  42. 42.
    Gruta N, Driel IR, Gleeson PA. Peripheral T cell expansion in lymphopenic mice results in a restricted T cell repertoire. Eur J Immunol. 2000;30(12):3380–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Kassiotis G, Zamoyska R, Stockinger B. Involvement of avidity for major histocompatibility complex in homeostasis of naive and memory T cells. J Exp Med. 2003;197(8):1007–16. doi: 10.1084/jem.20021812.PubMedCrossRefGoogle Scholar
  44. 44.
    Troy AE, Shen H. Cutting edge: homeostatic proliferation of peripheral T lymphocytes is regulated by clonal competition. J Immunol. 2003;170(2):672–6.PubMedGoogle Scholar
  45. 45.
    Moses CTC, Thorstenson KMK, Jameson SCS, Khoruts AA. Competition for self ligands restrains homeostatic proliferation of naive CD4 T cells. Proc Natl Acad Sci U S A. 2003;100(3):1185–90. doi: 10.2307/3138307.PubMedCrossRefGoogle Scholar
  46. 46.
    Annacker O, Pimenta-Araujo R, Burlen-Defranoux O, Barbosa TC, Cumano A, Bandeira A. CD25+ CD4+ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10. J Immunol. 2001;166(5):3008–18.PubMedGoogle Scholar
  47. 47.
    Almeida ARM, Legrand N, Papiernik M, Freitas AA. Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J Immunol. 2002;169(9):4850–60.PubMedGoogle Scholar
  48. 48.
    Shen S. Control of homeostatic proliferation by regulatory T cells. J Clin Invest. 2005;115(12):3517–26. doi: 10.1172/JCI25463DS1.PubMedCrossRefGoogle Scholar
  49. 49.
    Tivol EAE, Borriello FF, Schweitzer ANA, Lynch WPW, Bluestone JAJ, Sharpe AHA. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3(5):541–7. doi: 10.1016/1074-7613(95)90125-6.PubMedCrossRefGoogle Scholar
  50. 50.
    Lucas PJ, Kim SJ, Melby SJ, Gress RE. Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor beta II receptor. J Exp Med. 2000;191(7):1187–96.PubMedCrossRefGoogle Scholar
  51. 51.
    Workman CJ, Vignali DAA. Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). J Immunol. 2005;174(2):688–95.PubMedGoogle Scholar
  52. 52.
    Theofilopoulos AN, Dummer W, Kono DH. T cell homeostasis and systemic autoimmunity. J Clin Invest. 2001;108(3):335–40. doi: 10.1172/JCI12173.PubMedGoogle Scholar
  53. 53.
    McHugh RS, Shevach EM. Cutting edge: depletion of CD4 + CD25+ regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease. J Immunol. 2002;168(12):5979–83.PubMedGoogle Scholar
  54. 54.
    Goronzy JJ, Weyand CM. Thymic function and peripheral T-cell homeostasis in rheumatoid arthritis. Trends Immunol. 2001;22(5):251–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Morrissey PJ, Charrier K, Braddy S, Liggitt D, Watson JD. CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells. J Exp Med. 1993;178(1):237–44.PubMedCrossRefGoogle Scholar
  56. 56.
    Nishizuka Y, Sakakura T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science. 1969;166(3906):753–5. doi: 10.1126/science.166.3906.753.PubMedCrossRefGoogle Scholar
  57. 57.
    Kojima A, Taguchi O, Nishizuka Y. Experimental production of possible autoimmune castritis followed by macrocytic anemia in athymic nude mice. Lab Invest. 1980;42(4):387–95.PubMedGoogle Scholar
  58. 58.
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. 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. 1995;155(3):1151–64.PubMedGoogle Scholar
  59. 59.
    Asano M, Toda M, Sakaguchi N, Sakaguchi S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med. 1996;184(2):387–96.PubMedCrossRefGoogle Scholar
  60. 60.
    Sakaguchi N, Miyai K, Sakaguchi S. Ionizing radiation and autoimmunity. Induction of autoimmune disease in mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells. J Immunol. 1994;152(5):2586–95.PubMedGoogle Scholar
  61. 61.
    Paulos CM, Wrzesinski C, Kaiser A, et al. Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J Clin Invest. 2007;117(8):2197–204. doi: 10.1172/JCI32205.PubMedCrossRefGoogle Scholar
  62. 62.
    Eyrich M, Burger G, Marquardt K, Budach W, Schilbach K, Niethammer D, Schlegel PG. 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. 2005;11(5):371–82. doi: 10.1016/j.bbmt.2005.02.002.PubMedCrossRefGoogle Scholar
  63. 63.
    Mitchison NAN. Adoptive transfer of immune reactions by cells. J Cell Physiol Suppl. 1957;50 Suppl 1:247–64.PubMedGoogle Scholar
  64. 64.
    North R. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. J Exp Med. 1982;55:1063–74.CrossRefGoogle Scholar
  65. 65.
    Berenson JRJ, Einstein ABA, Fefer AA. Syngeneic adoptive immunotherapy and chemoimmunotherapy of a Friend leukemia: requirement for T cells. J Immunol. 1975;115(1):234–8.PubMedGoogle Scholar
  66. 66.
    Cheever MA, Greenberg PD, Fefer A. Specificity of adoptive chemoimmunotherapy of established syngeneic tumors. J Immunol. 1980;125(2):711–4.PubMedGoogle Scholar
  67. 67.
    Cheever MA, Greenberg PD, Fefer A. Tumor neutralization, immunotherapy, and chemoimmunotherapy of a Friend leukemia with cells secondarily sensitized in vitro: II. Comparison of cells cultured with and without tumor to noncultured immune cells. J Immunol. 1978;121(6):2220–7.PubMedGoogle Scholar
  68. 68.
    Awwad M, North RJ. 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. 1988;65(1):87–92.PubMedGoogle Scholar
  69. 69.
    Machiels JP, Reilly RT, Emens LA, Ercolini AM, Lei RY, Weintraub D, Okoye FI, Jaffee EM. 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. 2001;61(9):3689–97.PubMedGoogle Scholar
  70. 70.
    Motoyoshi Y, Kaminoda K, Saitoh O, Hamasaki K, Nakao K, Ishii N, Nagayama Y, Eguchi K. Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide. Oncol Rep. 2006;16(1):141–6.PubMedGoogle Scholar
  71. 71.
    Hu H-M, Poehlein CH, Urba WJ, Fox BA. Development of antitumor immune responses in reconstituted lymphopenic hosts. Cancer Res. 2002;62(14):3914–9.PubMedGoogle Scholar
  72. 72.
    Dummer WW, Niethammer AGA, Baccala RR, Lawson BRB, Wagner NN, Reisfeld RAR, Theofilopoulos ANA. T cell homeostatic proliferation elicits effective antitumor autoimmunity. J Clin Invest. 2002;110(2):185–92. doi: 10.1172/JCI15175.PubMedGoogle Scholar
  73. 73.
    Ma J, Urba WJ, Si L, Wang Y, Fox BA, Hu H-M. Anti-tumor T cell response and protective immunity in mice that received sublethal irradiation and immune reconstitution. Eur J Immunol. 2003;33(8):2123–32. doi: 10.1002/eji.200324034.PubMedCrossRefGoogle Scholar
  74. 74.
    Poehlein CH, Haley DP, Walker EB, Fox BA. Depletion of tumor-induced Treg prior to reconstitution rescues enhanced priming of tumor-specific, therapeutic effector T cells in lymphopenic hosts. Eur J Immunol. 2009;39(11):3121–33. doi: 10.1002/eji.200939453.PubMedCrossRefGoogle Scholar
  75. 75.
    Turk MJ, Guevara-Patiño JA, Rizzuto GA, Engelhorn ME, Houghton AN. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med. 2004;200(6):771–82. doi: 10.1084/jem.20041130.PubMedCrossRefGoogle Scholar
  76. 76.
    Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 1986;233(4770):1318–21.PubMedCrossRefGoogle Scholar
  77. 77.
    Gattinoni L, Finkelstein SE, Klebanoff CA, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005;202(7):907–12. doi: 10.1084/jem.20050732.PubMedCrossRefGoogle Scholar
  78. 78.
    Wang LX. Interleukin-7-dependent expansion and persistence of melanoma-specific T cells in lymphodepleted mice lead to tumor regression and editing. Cancer Res. 2005;65(22):10569–77. doi: 10.1158/0008-5472.CAN-05-2117.PubMedCrossRefGoogle Scholar
  79. 79.
    Antony PA, Piccirillo CA, Akpinarli A, 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. J Immunol. 2005;174(5):2591–601.PubMedGoogle Scholar
  80. 80.
    Zhang H, Chua KS, Guimond M, et al. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4 + CD25+ regulatory T cells. Nat Med. 2005;11(11):1238–43. doi: 10.1038/nm1312.PubMedCrossRefGoogle Scholar
  81. 81.
    Wrzesinski C, Paulos CM, Gattinoni L, Palmer DC, Kaiser A, Yu Z, Rosenberg SA, Restifo NP. Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J Clin Invest. 2007;117(2):492–501. doi: 10.1172/JCI30414.PubMedCrossRefGoogle Scholar
  82. 82.
    Wrzesinski C, Paulos CM, Kaiser A, Muranski P, Palmer DC, Gattinoni L, Yu Z, Rosenberg SA, Restifo NP. Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. J Immunother. 2010;33(1):1–7. doi: 10.1097/CJI.0b013e3181b88ffc.PubMedCrossRefGoogle Scholar
  83. 83.
    Lorenzi AR, Clarke AM, Wooldridge T, Waldmann H, Hale G, Symmons D, Hazleman BL, Isaacs JD. Morbidity and mortality in rheumatoid arthritis patients with prolonged therapy-induced lymphopenia: twelve-year outcomes. Arthritis Rheum. 2008;58(2):370–5. doi: 10.1002/art.23122.PubMedCrossRefGoogle Scholar
  84. 84.
    Mackall CL, Fleisher TA, Brown MR, Magrath IT, Shad AT, Horowitz ME, Wexler LH, Adde MA, McClure LL, Gress RE. Lymphocyte depletion during treatment with intensive chemotherapy for cancer. Blood. 1994;84(7):2221–8.PubMedGoogle Scholar
  85. 85.
    Storek J, Gooley T, Witherspoon RP, Sullivan KM, Storb R. Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am J Hematol. 1997;54(2):131–8. doi: 10.1002/(SICI)1096-8652(199702)54:2<131::AID-AJH6>3.0.CO;2-Y.PubMedCrossRefGoogle Scholar
  86. 86.
    Fry TJ, Connick E, Falloon J, et al. A potential role for interleukin-7 in T-cell homeostasis. Blood. 2001;97(10):2983–90. doi: 10.1182/blood.V97.10.2983.PubMedCrossRefGoogle Scholar
  87. 87.
    Cui Y, Zhang H, Meadors J, Poon R, Guimond M, Mackall CL. Harnessing the physiology of lymphopenia to support adoptive immunotherapy in lymphoreplete hosts. Blood. 2009;114(18):3831–40. doi: 10.1182/blood-2009-03-212134.PubMedCrossRefGoogle Scholar
  88. 88.
    Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, Azuma M, Krummel MF, Bluestone JA. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR–induced stop signal. Nat Immunol. 2009;10(11):1185–92. doi: 10.1038/ni.1790.PubMedCrossRefGoogle Scholar
  89. 89.
    Woo S-R, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012. doi: 10.1158/0008-5472.CAN-11-1620.Google Scholar
  90. 90.
    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. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298(5594):850–4. doi: 10.1126/science.1076514 1076514 [pii].PubMedCrossRefGoogle Scholar
  91. 91.
    Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008;8(4):299–308. doi: nrc2355 [pii] 10.1038/nrc2355.PubMedCrossRefGoogle Scholar
  92. 92.
    Dudley ME, Wunderlich JR, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry RM, Marincola FM, Leitman SF, Seipp CA, Rogers-Freezer L, Morton KE, Nahvi A, Mavroukakis SA, White DE, Rosenberg SA. A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma. J Immunother. 2002;25(3):243–51.PubMedCrossRefGoogle Scholar
  93. 93.
    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. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23(10):2346–57. doi: 23/10/2346 [pii] 10.1200/JCO.2005.00.240.PubMedCrossRefGoogle Scholar
  94. 94.
    Hoffmann G, Schobersberger W. Anti-inflammatory and nitric oxide-inhibiting properties of granulocyte colony-stimulating factor. Zhongguo Yao Li Xue Bao. 1999;20(8):673–81.PubMedGoogle Scholar
  95. 95.
    Zhou J, Shen X, Huang J, Hodes RJ, Rosenberg SA, Robbins PF. Telomere length of transferred lymphocytes correlates with in vivo persistence and tumor regression in melanoma patients receiving cell transfer therapy. J Immunol. 2005;175(10):7046–52. doi: 175/10/7046 [pii].PubMedGoogle Scholar
  96. 96.
    Dudley ME, Gross CA, Langhan MM, Garcia MR, Sherry RM, Yang JC, Phan GQ, Kammula US, Hughes MS, Citrin DE, Restifo NP, Wunderlich JR, Prieto PA, Hong JJ, Langan RC, Zlott DA, Morton KE, White DE, Laurencot CM, Rosenberg SA. CD8+ enriched “young” tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. Clin Cancer Res. 2010;16(24):6122–31. doi: 1078–0432.CCR-10-1297 [pii] 10.1158/1078-0432.CCR-10-1297.PubMedCrossRefGoogle Scholar
  97. 97.
    Berd D, Mastrangelo MJ, Engstrom PF, Paul A, Maguire H. Augmentation of the human immune response by cyclophosphamide. Cancer Res. 1982;42(11):4862–6.PubMedGoogle Scholar
  98. 98.
    Berd D, Maguire Jr HC, Mastrangelo MJ. 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. 1986;46(5):2572–7.PubMedGoogle Scholar
  99. 99.
    Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE. Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Rep. 1966;50(4):219–44.PubMedGoogle Scholar
  100. 100.
    Appay V, Voelter V, Rufer N, Reynard S, Jandus C, Gasparini D, Lienard D, Speiser DE, Schneider P, Cerottini JC, Romero P, Leyvraz S. Combination of transient lymphodepletion with busulfan and fludarabine and peptide vaccination in a phase I clinical trial for patients with advanced melanoma. J Immunother. 2007;30(2):240–50. doi: 10.1097/01.cji.0000211332.68643.98 00002371-200702000-00011 [pii].PubMedCrossRefGoogle Scholar
  101. 101.
    Laurent J, Speiser DE, Appay V, Touvrey C, Vicari M, Papaioannou A, Canellini G, Rimoldi D, Rufer N, Romero P, Leyvraz S, Voelter V. Impact of 3 different short-term chemotherapy regimens on lymphocyte-depletion and reconstitution in melanoma patients. J Immunother. 2010;33(7):723–34. doi: 10.1097/CJI.0b013e3181ea7e6e.PubMedCrossRefGoogle Scholar
  102. 102.
    Zippelius A, Pittet MJ, Batard P, Rufer N, de Smedt M, Guillaume P, Ellefsen K, Valmori D, Lienard D, Plum J, MacDonald HR, Speiser DE, Cerottini JC, Romero P. Thymic selection generates a large T cell pool recognizing a self-peptide in humans. J Exp Med. 2002;195(4):485–94.PubMedCrossRefGoogle Scholar
  103. 103.
    Jaffee EM, Hruban RH, Biedrzycki B, Laheru D, Schepers K, Sauter PR, Goemann M, Coleman J, Grochow L, Donehower RC, Lillemoe KD, O'Reilly S, Abrams RA, Pardoll DM, Cameron JL, Yeo CJ. Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol. 2001;19(1):145–56.PubMedGoogle Scholar
  104. 104.
    Rapoport AP, Stadtmauer EA, Aqui N, Badros A, Cotte J, Chrisley L, Veloso E, Zheng Z, Westphal S, Mair R, Chi N, Ratterree B, Pochran MF, Natt S, Hinkle J, Sickles C, Sohal A, Ruehle K, Lynch C, Zhang L, Porter DL, Luger S, Guo C, Fang HB, Blackwelder W, Hankey K, Mann D, Edelman R, Frasch C, Levine BL, Cross A, June CH. Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nat Med. 2005;11(11):1230–7. doi: nm1310 [pii] 10.1038/nm1310.PubMedCrossRefGoogle Scholar
  105. 105.
    Gandhi MK, Egner W, Sizer L, Inman I, Zambon M, Craig JI, Marcus RE. Antibody responses to vaccinations given within the first two years after transplant are similar between autologous peripheral blood stem cell and bone marrow transplant recipients. Bone Marrow Transplant. 2001;28(8):775–81. doi: 10.1038/sj.bmt.1703239.PubMedCrossRefGoogle Scholar
  106. 106.
    Guinan EC, Molrine DC, Antin JH, Lee MC, Weinstein HJ, Sallan SE, Parsons SK, Wheeler C, Gross W, McGarigle C, et al. Polysaccharide conjugate vaccine responses in bone marrow transplant patients. Transplantation. 1994;57(5):677–84.PubMedCrossRefGoogle Scholar
  107. 107.
    Berd D, Sato T, Maguire Jr HC, Kairys J, Mastrangelo MJ. Immunopharmacologic analysis of an autologous, hapten-modified human melanoma vaccine. J Clin Oncol. 2004;22(3):403–15. 10.1200/JCO.2004.06.043 JCO.2004.06.043 [pii].PubMedCrossRefGoogle Scholar
  108. 108.
    Viguier M, Lemaitre F, Verola O, Cho MS, Gorochov G, Dubertret L, Bachelez H, Kourilsky P, Ferradini L. Foxp3 expressing CD4 + CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol. 2004;173(2):1444–53.PubMedGoogle Scholar
  109. 109.
    Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B. Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res. 2003;9(2):606–12.PubMedGoogle Scholar
  110. 110.
    Audia S, Nicolas A, Cathelin D, Larmonier N, Ferrand C, Foucher P, Fanton A, Bergoin E, Maynadie M, Arnould L, Bateman A, Lorcerie B, Solary E, Chauffert B, Bonnotte B. Increase of CD4+ CD25+ regulatory T cells in the peripheral blood of patients with metastatic carcinoma: a Phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4+ CD25+ T lymphocytes. Clin Exp Immunol. 2007;150(3):523–30. doi: CEI3521 [pii] 10.1111/j.1365-2249.2007.03521.x.PubMedCrossRefGoogle Scholar
  111. 111.
    Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res. 2005;65(6):2457–64. doi: 65/6/2457 [pii] 10.1158/0008-5472.CAN-04-3232.PubMedCrossRefGoogle Scholar
  112. 112.
    Somasundaram R, Jacob L, Swoboda R, Caputo L, Song H, Basak S, Monos D, Peritt D, Marincola F, Cai D, Birebent B, Bloome E, Kim J, Berencsi K, Mastrangelo M, Herlyn D. Inhibition of cytolytic T lymphocyte proliferation by autologous CD4+/CD25+ regulatory T cells in a colorectal carcinoma patient is mediated by transforming growth factor-beta. Cancer Res. 2002;62(18):5267–72.PubMedGoogle Scholar
  113. 113.
    Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169(5):2756–61.PubMedGoogle Scholar
  114. 114.
    Petrausch U, Poehlein CH, Jensen SM, Twitty C, Thompson JA, Assmann I, Puri S, LaCelle MG, Moudgil T, Maston L, Friedman K, Church S, Cardenas E, Haley DP, Walker EB, Akporiaye E, Weinberg AD, Rosenheim S, Crocenzi TS, Hu HM, Curti BD, Urba WJ, Fox BA. Cancer immunotherapy: the role regulatory T cells play and what can be done to overcome their inhibitory effects. Curr Mol Med. 2009;9(6):673–82.PubMedCrossRefGoogle Scholar
  115. 115.
    Powell Jr DJ, de Vries CR, Allen T, Ahmadzadeh M, Rosenberg SA. Inability to mediate prolonged reduction of regulatory T Cells after transfer of autologous CD25-depleted PBMC and interleukin-2 after lymphodepleting chemotherapy. J Immunother. 2007;30(4):438–47. doi: 10.1097/CJI.0b013e3180600ff9 00002371-200705000-00008 [pii].PubMedCrossRefGoogle Scholar
  116. 116.
    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. 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. 2009;27(35):5911–8. JCO.2009.23.3494 [pii] 10.1200/JCO.2009.23.3494.PubMedCrossRefGoogle Scholar
  117. 117.
    Ge Y, Domschke C, Stoiber N, Schott S, Heil J, Rom J, Blumenstein M, Thum J, Sohn C, Schneeweiss A, Beckhove P, Schuetz F. Metronomic cyclophosphamide treatment in metastasized breast cancer patients: immunological effects and clinical outcome. Cancer Immunol Immunother. 2012;61(3):353–62. doi: 10.1007/s00262-011-1106-3.PubMedCrossRefGoogle Scholar
  118. 118.
    Cerullo V, Diaconu I, Kangasniemi L, Rajecki M, Escutenaire S, Koski A, Romano V, Rouvinen N, Tuuminen T, Laasonen L, Partanen K, Kauppinen S, Joensuu T, Oksanen M, Holm SL, Haavisto E, Karioja-Kallio A, Kanerva A, Pesonen S, Arstila PT, Hemminki A. Immunological effects of low-dose cyclophosphamide in cancer patients treated with oncolytic adenovirus. Mol Ther. 2011;19(9):1737–46. doi: 10.1038/mt.2011.113 mt2011113 [pii].PubMedCrossRefGoogle Scholar
  119. 119.
    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. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26(32):5233–9. doi: JCO.2008.16.5449 [pii] 10.1200/JCO.2008.16.5449.PubMedCrossRefGoogle Scholar
  120. 120.
    Ljungman P, Wiklund-Hammarsten M, Duraj V, Hammarstrom L, Lonnqvist B, Paulin T, Ringden O, Pepe MS, Gahrton G. Response to tetanus toxoid immunization after allogeneic bone marrow transplantation. J Infect Dis. 1990;162(2):496–500.PubMedCrossRefGoogle Scholar
  121. 121.
    Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306. doi: 10.1038/nrc3245 nrc3245 [pii].PubMedCrossRefGoogle Scholar
  122. 122.
    Jensen SM, Maston LD, Gough MJ, Ruby CE, Redmond WL, Crittenden M, Li Y, Puri S, Poehlein CH, Morris N, Kovacsovics-Bankowski M, Moudgil T, Twitty C, Walker EB, Hu HM, Urba WJ, Weinberg AD, Curti B, Fox BA. Signaling through OX40 enhances antitumor immunity. Semin Oncol. 2010;37(5):524–32. doi: S0093-7754(10)00167-3 [pii] 10.1053/j.seminoncol.2010.09.013. PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Shawn M. Jensen
    • 1
  • Christopher C. Paustain
    • 1
  • Bernard A. Fox
    • 1
    • 2
  1. 1.Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research CenterEarle A. Chiles Research Institute, Providence Cancer CenterPortlandUSA
  2. 2.Department of Molecular Microbiology and Immunology, and Knight Cancer InstituteOregon Health and Science UniversityPortlandUSA

Personalised recommendations