Skip to main content

Advertisement

Log in

Contribution of the immune system to the chemotherapeutic response

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

The immune system plays an important role in the surveillance of neoplastic cells by eliminating them before they manifest as full-blown cancer. Despite this, tumors do develop in the presence of a functioning immune system. Conventional chemotherapy and its ability to directly kill tumor cells is one of the most effective weapons in the fight against cancer, however, increasing evidence suggests that the therapeutic efficacy of some cytotoxic drugs relies on their capacity to interact with the immune system. Killing of tumor cells in a manner that favors their capture by immune cells or selective targeting of immunosuppressive pathways by specific chemotherapies promotes the generation of an effective anti-cancer response; however, this alone is rarely sufficient to cause elimination of advanced disease. An understanding of the immunological events occurring in both animal models and patients undergoing chemotherapy will guide decisions for the development of appropriate combinations and scheduling for the integration of chemotherapy with immunotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Hanahan D, Weinberg R (2000) The hallmarks of cancer. Cell 100:57–70

    PubMed  CAS  Google Scholar 

  2. Zitvogel L, Tesniere A, Kroemer G (2006) Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol 6:715–727

    PubMed  CAS  Google Scholar 

  3. Swann J, Smyth M (2007) Immune surveillance of tumors. J Clin Invest 117:1137–1146

    PubMed  CAS  Google Scholar 

  4. Clemente CG, Mihm MC Jr, Bufalino R, Zurrida S, Collini P, Cascinelli N (1996) Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77:1303–1310

    PubMed  CAS  Google Scholar 

  5. Haanen J, Baars A, Gomez R, Weder P, Smits M, De Gruijl T, Von Blomberg B, Bloemena E, Scheper R, Van Ham S, Pinedo H, Van Den Eertwegh A (2006) Melanoma-specific tumor-infiltrating lymphocytes but not circulating melanoma-specific T cells may predict survival in resected advanced-stage melanoma patients. Cancer Immunol Immunother 55:451–458

    PubMed  CAS  Google Scholar 

  6. Leffers N, Gooden MJ, de Jong RA, Hoogeboom BN, ten Hoor KA, Hollema H, Boezen HM, van der Zee AG, Daemen T, Nijman HW (2009) Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 58(3):449–459

    Google Scholar 

  7. Morris M, Platell C, Iacopetta B (2008) Tumor-infiltrating lymphocytes and perforation in colon cancer predict positive response to 5-fluorouracil chemotherapy. Clin Cancer Res 14:1413–1417

    PubMed  CAS  Google Scholar 

  8. Piersma S, Jordanova E, Poelgeest V, Mie K, Kmc VD, Hulst J, Drijfhout J, Melief C, Kenter G, Fleuren G, Offringa R, Van Der Burg SH (2007) High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer. Cancer Res 67:354–361

    PubMed  CAS  Google Scholar 

  9. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma VM (1997) Prognostic value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 182(3):318–324

    Google Scholar 

  10. Yamada N, Oizumi S, Kikuchi E, Shinagawa N, Konishi-Sakakibara J, Ishimine A, Aoe K, Gemba K, Kishimoto T, Torigoe T, Nishimura M (2010) CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection. Cancer Immunol Immunother 59(10): 1543–1549

    Google Scholar 

  11. Medzhitov R, Janeway CA Jr (1999) Innate immune induction of the adaptive immune response. Cold Spring Harb Symp Quant Biol 64:429–435

    PubMed  CAS  Google Scholar 

  12. Teng M, Swann J, Koebel C, Schreiber R, Smyth M (2008) Immune-mediated dormancy: an equilibrium with cancer. J Leukoc Biol 84:988–993

    PubMed  CAS  Google Scholar 

  13. Ferradini L, Mackensen A, Genevee C, Bosq J, Duvillard P, Avril M, Hercend T (1993) Analysis of T cell receptor variability in tumor-infiltrating lymphocytes from a human regressive melanoma. Evidence for in situ T cell clonal expansion. J Clin Invest 91:1183–1190

    PubMed  CAS  Google Scholar 

  14. Zorn E, Hercend T (1999) A natural cytotoxic T cell response in a spontaneously regressing human melanoma targets a neoantigen resulting from a somatic point mutation. Eur J Immunol 29:592–601

    PubMed  CAS  Google Scholar 

  15. Clark WH Jr, Elder De Guerry DT, Le B, Trock BJ, Schultz D, Synnestvedt M, Halpern AC (1989) Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst 81:1893–1904

    PubMed  Google Scholar 

  16. Sato E, Olson Sh, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth A, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen Y-T, Ohtani H, Old L, Odunsi K (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Nat Acad Sci USA 102:18538–18543

    PubMed  CAS  Google Scholar 

  17. Tomsová M, Melichar B, Sedláková I, Steiner I (2008) Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma. Gynecol Oncol 108:415–420

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  19. Rosenberg S, Restifo N, Yang J, Morgan R, Dudley M (2008) Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 8:299–308

    PubMed  CAS  Google Scholar 

  20. Harty J, Badovinac V (2008) Shaping and reshaping CD8+ T-cell memory. Nat Rev Immunol 8:107–119

    PubMed  CAS  Google Scholar 

  21. Masson F, Mount A, Wilson N, Belz G (2008) Dendritic cells: driving the differentiation programme of T cells in viral infections. Immunol Cell Biol 86:333–342

    PubMed  CAS  Google Scholar 

  22. Harty J, Tvinnereim A, White D (2000) CD8+ T cell effector mechanisms in resistance to infection. Annu Rev Immunol 18:275–308

    PubMed  CAS  Google Scholar 

  23. Cyster J (1999) Chemokines and cell migration in secondary lymphoid organs. Science 286:2098–2102

    PubMed  CAS  Google Scholar 

  24. Den Haan JM, Bevan MJ (2001) Antigen presentation to CD8+ T cells: cross-priming in infectious diseases. Curr Opin Immunol 13:437–441

    Google Scholar 

  25. Fu YX, Chaplin D (1999) Development and maturation of secondary lymphoid tissues. Annu Rev Immunol 17:399–433

    PubMed  CAS  Google Scholar 

  26. Gerner M, Casey K, Mescher M (2008) Defective MHC class II presentation by Dendritic Cells Limits CD4 T Cell Help for antitumor CD8 T cell responses. J Immunol 181:155–164

    PubMed  CAS  Google Scholar 

  27. Marzo A, Lake R, Lo D, Sherman L, Mcwilliam A, Nelson D, Robinson B, Scott B (1999) Tumor antigens are constitutively presented in the draining lymph nodes. J Immunol 162:5838–5845

    PubMed  CAS  Google Scholar 

  28. Nelson D, Mukherjee S, Bundell C, Fisher S, Van Hagen D, Robinson B (2001) Tumor progression despite efficient tumor antigen cross-presentation and effective “arming” of tumor antigen-specific CTL. J Immunol 166:5557–5566

    PubMed  CAS  Google Scholar 

  29. Van Mierlo GJD, Boonman ZFHM, Dumortier HMH, Den Boer AT, Fransen MF, Nouta J, Van Der Voort EIH, Offringa R, Rem T, Melief CJM (2004) Activation of dendritic cells that cross-present tumor-derived antigen licenses CD8+ CTL to cause tumor eradication. J Immunol 173:6753–6759

    PubMed  Google Scholar 

  30. Jabbari A, Harty J (2006) The generation and modulation of antigen-specific memory CD8 T cell responses. J Leukoc Biol 80:16–23

    PubMed  CAS  Google Scholar 

  31. Mescher M, Curtsinger J, Agarwal P, Casey K, Gerner M, Hammerbeck C, Popescu F, Xiao Z (2006) Signals required for programming effector and memory development by CD8+ T cells. Immunol Rev 211:81–92

    PubMed  CAS  Google Scholar 

  32. Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, Kohyama M, Calderon B, Schraml BU, Unanue ER, Diamond MS, Schreiber RD, Murphy TL, Murphy KM (2008) Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 322(5904): 1097-1100

    Google Scholar 

  33. Steinman R, Hawiger D, Liu K, Bonifaz L, Bonnyay D, Mahnke K, Iyoda T, Ravetch J, Dhodapkar M, Inaba K, Nussenzweig M (2003) Dendritic cell function in vivo during the steady state: a role in peripheral tolerance. Ann NY Acad Sci 987:15–25

    PubMed  CAS  Google Scholar 

  34. Hernandez J, Aung S, Marquardt K, Sherman L (2002) Uncoupling of proliferative potential and gain of effector function by CD8+ T Cells responding to self-antigens. J Exp Med 196:323–333

    PubMed  CAS  Google Scholar 

  35. Redmond W, Sherman L (2005) Peripheral tolerance of CD8 T lymphocytes. Immunity 22:275–284

    PubMed  CAS  Google Scholar 

  36. Boise Lh, Minn A, Noel P, June Ch, Accavitti M, Lindsten T, Thompson C (1995) CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. Immunity 3:87–98

    PubMed  CAS  Google Scholar 

  37. Melief C (2008) Cancer immunotherapy by dendritic cells. Immunity 29:372–383

    PubMed  CAS  Google Scholar 

  38. Harlin H, Kuna T, Peterson A, Meng Y, Gajewski T (2006) Tumor progression despite massive influx of activated CD8+ T cells in a patient with malignant melanoma ascites. Cancer Immunol Immunother 55:1185–1197

    PubMed  CAS  Google Scholar 

  39. Valmori D, Scheibenbogen C, Dutoit V, Nagorsen D, Asemissen A, Rubio-Godoy V, Rimoldi D, Guillaume P, Romero P, Schadendorf D, Lipp M, Dietrich P-Y, Thiel E, Cerottini J-C, Lienard D, Keilholz U (2002) Circulating tumor-reactive CD8+ T cells in melanoma patients contain a CD45RA+CCR7-effector subset exerting ex vivo tumor-specific cytolytic activity. Cancer Res 62:1743–1750

    PubMed  CAS  Google Scholar 

  40. Zippelius A, Batard P, Rubio-Godoy V, Bioley G, Lienard D, Lejeune F, Rimoldi D, Guillaume P, Meidenbauer N, Mackensen A, Rufer N, Lubenow N, Speiser D, Cerottini J-C, Romero P, Pittet M (2004) Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res 64:2865–2873

    PubMed  CAS  Google Scholar 

  41. Nagorsen D, Keilholz U, Rivoltini L, Schmittel A, Letsch A, Asemissen A, Berger G, Buhr H, Thiel E, Scheibenbogen C (2000) Natural T-cell response against MHC class I epitopes of epithelial cell adhesion molecule, her-2/neu, and carcinoembryonic antigen in patients with colorectal cancer. Cancer Res 60:4850–4854

    PubMed  CAS  Google Scholar 

  42. Nagorsen D, Scheibenbogen C, Schaller G, Leigh B, Schmittel A, Letsch A, Thiel E, Keilholz U (2003) Differences in T-cell immunity toward tumor-associated antigens in colorectal cancer and breast cancer patients. Int J Cancer 105:221–225

    PubMed  CAS  Google Scholar 

  43. Maccalli C, Di Cristanziano V, Fodale V, Corsi D, D’agostino G, Petrangeli V, Laurenti L, Guida S, Mazzocchi A, Arienti F, Perrone M, Castelli C, Rivoltini L, Zagonel V, Tartaglia M, Parmiani G, Belardelli F (2008) Induction of both CD8+ and CD4+ T-cell-mediated responses in colorectal cancer patients by colon antigen-1. Clin Cancer Res 14:7292–7303

    PubMed  CAS  Google Scholar 

  44. Rentzsch C, Kayser S, Stumm S, Watermann I, Walter S, Stevanovic S, Wallwiener D, Guckel B (2003) Evaluation of pre-existent immunity in patients with primary breast cancer: molecular and cellular assays to quantify antigen-specific T lymphocytes in peripheral blood mononuclear cells. Clin Cancer Res 9:4376–4386

    PubMed  CAS  Google Scholar 

  45. Ohlen C, Kalos M, Cheng L, Shur A, Hong D, Carson B, Kokot N, Lerner C, Sather B, Huseby E, Greenberg P (2002) CD8(+) T cell tolerance to a tumor-associated antigen is maintained at the level of expansion rather than effector function. J Exp Med 195:1407–1418

    PubMed  CAS  Google Scholar 

  46. Derre L, Rivals J-P, Jandus C, Pastor S, Rimoldi D, Romero P, Michielin O, Olive D, Speiser D (2010) BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination. J Clin Invest 120:157–167

    PubMed  CAS  Google Scholar 

  47. Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher I, Sander C, Kirkwood J, Kuchroo V, Zarour H (2010) Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med 207:2175–2186

    PubMed  CAS  Google Scholar 

  48. Sakuishi K, Apetoh L, Sullivan J, Blazar B, Kuchroo V, Anderson A (2010) Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 207:2187–2194

    PubMed  CAS  Google Scholar 

  49. Zou W, Chen L (2008) Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 8:467–477

    PubMed  CAS  Google Scholar 

  50. Ishida T, Oyama T, Carbone D, Gabrilovich D (1998) Defective function of Langerhans cells in tumor-bearing animals is the result of defective maturation from hemopoietic progenitors. J Immunol 161:4842–4851

    PubMed  CAS  Google Scholar 

  51. Lucas H (1999) Progressor but not regressor skin tumours inhibit Langerhans’ cell migration from epidermis to local lymph nodes. Immunology 97:130–137

    PubMed  CAS  Google Scholar 

  52. Preynat-Seauve O, Schuler P, Contassot E, Beermann F, Huard B, French L (2006) Tumor-infiltrating dendritic cells are potent antigen-presenting cells able to activate T cells and mediate tumor rejection. J Immunol 176:61–67

    PubMed  CAS  Google Scholar 

  53. Villablanca E, Raccosta L, Zhou D, Fontana R, Maggioni D, Negro A, Sanvito F, Ponzoni M, Valentinis B, Bregni M, Prinetti A, Steffensen K, Sonnino S, Gustafsson J, Doglioni C, Bordignon C, Traversari C, Russo V (2010) Tumor-mediated liver X receptor-alpha activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses. Nat Med 16:98–105

    PubMed  CAS  Google Scholar 

  54. Belkaid Y, Oldenhove G (2008) Tuning microenvironments: induction of regulatory T cells by dendritic cells. Immunity 29:362–371

    PubMed  CAS  Google Scholar 

  55. Gabrilovich D, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174

    PubMed  CAS  Google Scholar 

  56. Klages K, Mayer C, Lahl K, Loddenkemper C, Teng M, Ngiow S, Smyth M, Hamann A, Huehn J, Sparwasser T (2010) Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma. Cancer Res 70:7788–7799

    PubMed  CAS  Google Scholar 

  57. Kodumudi K, Woan K, Gilvary D, Sahakian E, Wei S, Djeu J (2010) A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin Cancer Res 16:4583–4594

    PubMed  CAS  Google Scholar 

  58. Li X, Kostareli E, Suffner J, Garbi N, Hämmerling G (2010) Efficient Treg depletion induces T-cell infiltration and rejection of large tumors. Eur J Immunol 40:3325–3335

    PubMed  CAS  Google Scholar 

  59. Vincent J, Mignot GG, Chalmin F, Ladoire S, Bruchard ML, Chevriaux AL, Martin FO, Apetoh L, RéBé CD, Ghiringhelli FO (2010) Five-fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T Cell–dependent antitumor immunity. Cancer Res 70:3052–3061

    PubMed  CAS  Google Scholar 

  60. Haynes NM, Van Der Most RG, Lake RA, Smyth MJ (2008) Immunogenic anti-cancer chemotherapy as an emerging concept. Curr Op Immunol 20:545–557

    CAS  Google Scholar 

  61. Aymeric L, Apetoh L, Ghiringhelli F, Tesniere A, Martins I, Kroemer G, Smyth M, Zitvogel L (2010) Tumor cell death and ATP release prime dendritic cells and efficient anticancer immunity. Cancer Res 70:855–858

    PubMed  CAS  Google Scholar 

  62. Nowak A, Lake R, Marzo A, Scott B, Heath W, Collins E, Frelinger J, Robinson B (2003) Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol 170:4905–4913

    PubMed  CAS  Google Scholar 

  63. 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 66:601–604

    PubMed  Google Scholar 

  64. Van Der Most RG, Currie AJ, Cleaver AL, Salmons J, Nowak AK, Mahendran S, Larma I, Prosser A, Robinson BWS, Smyth MJ, Scalzo AA, Degli-Esposti MA, Lake RA (2009) Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-Dependent CD8 T Cell-mediated immune attack resulting in suppression of tumor growth. PLoS ONE 4:e6982

    PubMed  Google Scholar 

  65. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G (2008) Immunological aspects of cancer chemotherapy. Nat Rev Immunol 8:59–73

    PubMed  CAS  Google Scholar 

  66. Zhang B, Bowerman N, Salama J, Schmidt H, Spiotto M, Schietinger A, Yu P, Fu Y, Weichselbaum R, Rowley D, Kranz D, Schreiber H (2007) Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. J Exp Med 204:49–55

    PubMed  CAS  Google Scholar 

  67. Mihich E (1969) Modification of tumor regression by immunologic means. Cancer Res 29:2345–2350

    PubMed  CAS  Google Scholar 

  68. Mihich E (1969) Combined effects of chemotherapy and immunity against leukemia L1210 in DBA-2 mice. Cancer Res 29:848–854

    PubMed  CAS  Google Scholar 

  69. Ferrer J, Mihich E (1967) Antitumor effects of kethoxal-bis(thiosemicarbazone) and 6-mercaptopurine in neonatally thymectomized mice. Proc Soc Exp Biol Med 124:939–944

    PubMed  CAS  Google Scholar 

  70. Schwartz H, Grindey G (1973) Adriamycin and daunorubicin: a comparison of antitumor activities and tissue uptake in mice following immunosuppression. Cancer Res 33:1837–1844

    PubMed  CAS  Google Scholar 

  71. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, Vermaelen K, Panaretakis T, Mignot G, Ullrich E, Perfettini J-L, Schlemmer F, Tasdemir E, Uhl M, Genin P, Civas A, Ryffel B, Kanellopoulos J, Tschopp J, Andre F, Lidereau R, Mclaughlin N, Haynes N, Smyth M, Kroemer G, Zitvogel L (2009) Activation of the NLRP3 inflammasome in dendritic cells induces IL-1[beta]-dependent adaptive immunity against tumors. Nat Med 15:1170–1178

    PubMed  CAS  Google Scholar 

  72. Casares N, Pequignot M, Tesniere A, Ghiringhelli F, Roux S, Chaput N, Schmitt E, Hamai A, Hervas-Stubbs S, Obeid M, Coutant F, Metivier D, Pichard E, Aucouturier P, Pierron G, Garrido C, Zitvogel L, Kroemer G (2005) Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med 202:1691–1701

    PubMed  CAS  Google Scholar 

  73. Le H, Graham L, Cha E, Morales J, Manjili Mh, Bear H (2009) Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4 T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. Int Immunopharm 9:900–909

    CAS  Google Scholar 

  74. Suzuki E, Sun J, Kapoor V, Jassar A, Albelda S (2007) Gemcitabine has significant immunomodulatory activity in murine tumor models independent of its cytotoxic effects. Cancer Biol Ther 6:880–885

    PubMed  CAS  Google Scholar 

  75. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri M, Ullrich E, Saulnier P, Yang H, Amigorena S, Ryffel B, Barrat F, Saftig P, Levi F, Lidereau R, Nogues C, Mira J-P, 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 13:1050–1059

    PubMed  CAS  Google Scholar 

  76. Obeid M, Tesniere A, Ghiringhelli F, Fimia G, Apetoh L, Perfettini J-L, 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 13:54–61

    PubMed  CAS  Google Scholar 

  77. Spisek R, Charalambous A, Mazumder A, Vesole Dh, Jagannath S, Dhodapkar M (2007) Bortezomib enhances dendritic cell (DC) mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. Blood 109:4839–4845

    PubMed  CAS  Google Scholar 

  78. Panaretakis T, Joza N, Modjtahedi N, Tesniere A, Vitale I, Durchschlag M, Fimia G, Kepp O, Piacentini M, Froehlich Ku, Van Endert P, Zitvogel L, Madeo F, Kroemer G (2008) The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell Death Differ 15:1499–1509

    PubMed  CAS  Google Scholar 

  79. Ma Y, Kepp O, Ghiringhelli F, Apetoh L, Aymeric L, Locher C, Tesniere A, Martins I, Ly A, Haynes N, Smyth M, Kroemer G, Zitvogel L (2010) Chemotherapy and radiotherapy: Cryptic anticancer vaccines. Sem Immun 22:113–124

    Google Scholar 

  80. Tesniere A, Schlemmer F, Boige V, Kepp O, Martins I, Ghiringhelli F, Aymeric L, Michaud M, Apetoh L, Barault L, Mendiboure J, Pignon J, Jooste V, Van Endert P, Ducreux M, Zitvogel L, Piard F, Kroemer G (2010) Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 29:482–491

    PubMed  CAS  Google Scholar 

  81. Hu D-E, Moore A, Thomsen L, Brindle K (2004) Uric acid promotes tumor immune rejection. Cancer Res 64:5059–5062

    PubMed  CAS  Google Scholar 

  82. Shi Y, Evans J, Rock K (2003) Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425:516–521

    PubMed  CAS  Google Scholar 

  83. Gasse P, Riteau N, Charron S, Girre S, Fick L, Petrilli V, Tschopp J, Lagente V, Quesniaux V, Ryffel B, Couillin I (2009) Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis. Am J Respir Crit Care Med 179:903–913

    PubMed  CAS  Google Scholar 

  84. Tanaka H, Matsushima H, Mizumoto N, Takashima A (2009) Classification of chemotherapeutic agents based on their differential in vitro effects on dendritic cells. Cancer Res 69:6978–6986

    PubMed  CAS  Google Scholar 

  85. Tanaka H, Matsushima H, Nishibu A, Clausen B, Takashima A (2009) Dual therapeutic efficacy of vinblastine as a unique chemotherapeutic agent capable of inducing dendritic cell maturation. Cancer Res 69:6987–6994

    PubMed  CAS  Google Scholar 

  86. Shurin G, Tourkova I, Kaneno R, Shurin M (2009) Chemotherapeutic agents in noncytotoxic concentrations increase antigen presentation by Dendritic Cells via an IL-12-dependent mechanism. J Immunol 183:137–144

    PubMed  CAS  Google Scholar 

  87. Kaneno R, Shurin G, Tourkova I, Shurin M (2009) Chemomodulation of human dendritic cell function by antineoplastic agents in low noncytotoxic concentrations. J Trans Med 7:58

    Google Scholar 

  88. Gattinoni L, Finkelstein S, Klebanoff C, Antony P, Palmer D, Spiess P, Hwang L, Yu Z, Wrzesinski C, Heimann D, Surh C, Rosenberg S, Restifo N (2005) Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med 202:907–912

    PubMed  CAS  Google Scholar 

  89. Turtle C, Swanson H, Fujii N, Estey Eh, Riddell S (2009) A distinct subset of self-renewing human memory CD8+ T cells survives cytotoxic chemotherapy. Immunity 31:834–844

    PubMed  CAS  Google Scholar 

  90. Rudge G, Barrett SP, Scott B, Van Driel IR (2007) Infiltration of a mesothelioma by IFN-gamma-producing cells and tumor rejection after depletion of regulatory T cells. J Immunol 178:4089–4096

    PubMed  CAS  Google Scholar 

  91. Teng M, Ngiow S, Von Scheidt B, Mclaughlin N, Sparwasser T, Smyth M (2010) Conditional regulatory T-cell depletion releases adaptive immunity preventing carcinogenesis and suppressing established tumor growth. Cancer Res 70:7800–7809

    PubMed  CAS  Google Scholar 

  92. Van Der Most R, Currie A, Mahendran S, Prosser A, Darabi A, Robinson B, Nowak A, Lake R (2009) Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy. Cancer Immunol Immunother 58:1219–1228

    PubMed  Google Scholar 

  93. Deng L, Zhang H, Luan Y, Zhang J, Xing Q, Dong S, Wu X, Liu M, Wang S (2010) Accumulation of foxp3+ T regulatory cells in draining lymph nodes correlates with disease progression and immune suppression in colorectal cancer patients. Clin Cancer Res 16:4105–4112

    PubMed  CAS  Google Scholar 

  94. Liyanage U, Moore T, Joo H, Tanaka Y, Herrmann V, Doherty G, Drebin J, Strasberg S, Eberlein T, Goedegebuure P, Linehan D (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169:2756–2761

    PubMed  CAS  Google Scholar 

  95. Shen L, Wang J, Shen D, Yuan X, Dong P, Li M, Xue J, Zhang F, Ge H, Xu D (2009) CD4(+)CD25(+)CD127(low/-) regulatory T cells express Foxp3 and suppress effector T cell proliferation and contribute to gastric cancers progression. Clin Immunol 131:109–118

    PubMed  CAS  Google Scholar 

  96. Wolf A, 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 9:606–612

    PubMed  Google Scholar 

  97. Kim J (2010) Molecular mechanisms of regulatory T cell development and suppressive function. Prog Mol Biol Transl Sci 92:279–314

    PubMed  CAS  Google Scholar 

  98. 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 34:336–344

    PubMed  CAS  Google Scholar 

  99. Ghiringhelli F, Menard C, Puig P, 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 56:641–648

    PubMed  CAS  Google Scholar 

  100. Schiavoni G, Mattei F, Di Pucchio T, Santini S, Bracci L, Belardelli F, Proietti E (2000) Cyclophosphamide induces type I interferon and augments the number of CD44hi T lymphocytes in mice: implications for strategies of chemoimmunotherapy of cancer. Blood 95:2024–2030

    PubMed  CAS  Google Scholar 

  101. Chen X, Subleski JJ, Kopf H, Howard OMZ, Mãnnel DN, Oppenheim JJ (2008) Cutting edge: expression of TNFR2 defines a maximally suppressive subset of mouse CD4+CD25+FoxP3+ T regulatory cells: applicability to tumor-infiltrating T regulatory cells. J Immunol 180:6467–6471

    PubMed  CAS  Google Scholar 

  102. Herman A, Freeman G, Mathis D, Benoist C (2004) CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med 199:1479–1489

    PubMed  CAS  Google Scholar 

  103. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D, Mathian A, Nakahata T, Yamaguchi T, Nomura T, Ono M, Amoura Z, Gorochov G, Sakaguchi S (2009) Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30:899–911

    PubMed  CAS  Google Scholar 

  104. Radojcic V, Bezak K, Skarica M, Pletneva M, Yoshimura K, Schulick R, Luznik L (2010) Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination. Cancer Immunol Immunother 59:137–148

    PubMed  CAS  Google Scholar 

  105. Lutsiak M, Semnani R, De Pascalis R, Kashmiri S, Schlom J, Sabzevari H (2005) Inhibition of CD4 + 25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105:2862–2868

    PubMed  CAS  Google Scholar 

  106. Loeffler M, KrãGer JRA, Reisfeld RA (2005) Immunostimulatory effects of low-dose cyclophosphamide are controlled by inducible nitric oxide synthase. Cancer Res 65:5027–5030

    PubMed  CAS  Google Scholar 

  107. Zhao J, Cao Y, Lei Z, Yang Z, Zhang B, Huang B (2010) Selective depletion of CD4+CD25 + Foxp3+ regulatory T cells by low-dose cyclophosphamide is explained by reduced intracellular ATP levels. Cancer Res 70:4850–4858

    PubMed  CAS  Google Scholar 

  108. Berd D, Mastrangelo M (1988) Effect of low dose cyclophosphamide on the immune system of cancer patients: depletion of CD4+, 2 H4+ suppressor-inducer T-cells. Cancer Res 48:1671–1675

    PubMed  CAS  Google Scholar 

  109. Hoon D, Foshag L, Nizze A, Bohman R, Morton D (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 50:5358–5364

    PubMed  CAS  Google Scholar 

  110. Livingston PO, Cunningham-Rundles S, Marfleet G, Gnecco C, Wong GY, Schiffman G, Enker WE, Hoffman MK (1987) Inhibition of suppressor-cell activity by Cyclophosphamide in patients with Malignant Melanoma. J Immunother 6:392–403

    CAS  Google Scholar 

  111. Berd D, Maguire H, Mastrangelo M (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 46:2572–2577

    PubMed  CAS  Google Scholar 

  112. Maclean G, Miles D, Rubens R, Reddish M, Longenecker B (1996) Enhancing the effect of THERATOPE STn-KLH cancer vaccine in patients with metastatic breast cancer by pretreatment with low-dose intravenous cyclophosphamide. J Immunother Emphasis Tumor Immunol 19:309–316

    PubMed  CAS  Google Scholar 

  113. Greten T, Ormandy L, Fikuart A, Hochst B, Henschen S, Horning M, Manns M, Korangy F (2010) Low-dose cyclophosphamide treatment impairs regulatory T cells and unmasks AFP-specific CD4+ T-cell responses in patients with advanced HCC. J Immunother 33:211–218

    PubMed  CAS  Google Scholar 

  114. Vicari A, Luu R, Zhang N, Patel S, Makinen S, Hanson D, Weeratna R, Krieg A (2009) Paclitaxel reduces regulatory T cell numbers and inhibitory function and enhances the anti-tumor effects of the TLR9 agonist PF-3512676 in the mouse. Cancer Immunol Immunother 58:615–628

    PubMed  CAS  Google Scholar 

  115. Zhang L, Dermawan K, Jin M, Liu R, Zheng H, Xu L, Zhang Y, Cai Y, Chu Y, Xiong S (2008) Differential impairment of regulatory T cells rather than effector T cells by paclitaxel-based chemotherapy. Clin Immunol 129:219–229

    PubMed  CAS  Google Scholar 

  116. Almand B, Clark J, Nikitina E, Van Beynen J, English N, Knight S, Carbone D, Gabrilovich D (2001) Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 166:678–689

    PubMed  CAS  Google Scholar 

  117. Diaz-Montero C, Salem M, Nishimura M, Garrett-Mayer E, Cole D, Montero A (2009) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 58:49–59

    PubMed  CAS  Google Scholar 

  118. Rodriguez P, Ochoa A (2008) Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev 222:180–191

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  120. Pan P, Ma G, Weber K, Ozao-Choy J, Wang G, Yin B, Divino C, Chen Sh (2010) Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res 70:99–108

    PubMed  CAS  Google Scholar 

  121. Yang R, Cai Z, Zhang Y, Yutzy W, Roby K, Roden R (2006) CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1 + CD11b+ myeloid cells. Cancer Res 66:6807–6815

    PubMed  CAS  Google Scholar 

  122. Huang B, Pan P, Li Q, Sato A, Levy D, Bromberg J, Divino C, Chen Sh (2006) Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res 66:1123–1131

    PubMed  CAS  Google Scholar 

  123. Fridlender Z, Sun J, Singhal S, Kapoor V, Cheng G, Suzuki E, Albelda S (2010) Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms. Mol Ther 18:1947–1959

    PubMed  CAS  Google Scholar 

  124. Ko H-J, Kim Y-J, Kim Y-S, Chang W-S, Ko S-Y, Chang S-Y, Sakaguchi S, Kang C-Y (2007) A Combination of Chemoimmunotherapies Can Efficiently Break Self-Tolerance and Induce Antitumor Immunity in a Tolerogenic Murine Tumor Model. Cancer Res 67:7477–7486

    PubMed  CAS  Google Scholar 

  125. Sinha P, Clements V, Bunt S, Albelda S, Ostrand-Rosenberg S (2007) Cross-Talk between Myeloid-Derived Suppressor Cells and Macrophages Subverts Tumor Immunity toward a Type 2 Response. J Immunol 179:977–983

    PubMed  CAS  Google Scholar 

  126. Suzuki E, Kapoor V, Jassar A, Kaiser L, Albelda S (2005) Gemcitabine Selectively Eliminates Splenic Gr-1+/CD11b+ Myeloid Suppressor Cells in Tumor-Bearing Animals and Enhances Antitumor Immune Activity. Clin Cancer Res 11:6713–6721

    PubMed  CAS  Google Scholar 

  127. Nowak A, Robinson B, Lake R (2003) Synergy between Chemotherapy and Immunotherapy in the Treatment of Established Murine Solid Tumors. Cancer Res 63:4490–4496

    PubMed  CAS  Google Scholar 

  128. Plate J, Plate A, Shott S, Bograd S, Harris J (2005) Effect of gemcitabine on immune cells in subjects with adenocarcinoma of the pancreas. Cancer Immunol Immunother 54:915–925

    PubMed  CAS  Google Scholar 

  129. Soeda A, Morita-Hoshi Y, Makiyama H, Morizane C, Ueno H, Ikeda M, Okusaka T, Yamagata S, Takahashi N, Hyodo I, Takaue Y, Heike Y (2009) Regular dose of gemcitabine induces an increase in CD14+ Monocytes and CD11c+ dendritic cells in patients with advanced pancreatic cancer. Jap J Clin Oncol 39:797–806

    Google Scholar 

  130. Ugel S, Delpozzo F, Desantis G, Papalini F, Simonato F, Sonda N, Zilio S, Bronte V (2009) Therapeutic targeting of myeloid-derived suppressor cells. Curr Opin Pharmacol 9:470–481

    PubMed  CAS  Google Scholar 

  131. Ko J, Zea Ah, Rini B, Ireland J, Elson P, Cohen P, Golshayan A, Rayman P, Wood L, Garcia J, Dreicer R, Bukowski R, Finke Jh (2009) Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 15:2148–2157

    PubMed  CAS  Google Scholar 

  132. Bellone G, Novarino A, Vizio B, Brondino G, Addeo A, Prati A, Giacobino A, Campra D, Fronda G, Ciuffreda L (2009) Impact of surgery and chemotherapy on cellular immunity in pancreatic carcinoma patients in view of an integration of standard cancer treatment with immunotherapy. Int J Oncol 34:1701–1715

    PubMed  CAS  Google Scholar 

  133. Coleman S, Clayton A, Mason M, Jasani B, Adams M, Tabi Z (2005) Recovery of CD8+ T-cell function during systemic chemotherapy in advanced ovarian cancer. Cancer Res 65:7000–7006

    PubMed  CAS  Google Scholar 

  134. Lissoni P, Brivio F, Fumagalli L, Messina G, Meregalli S, Porro G, Rovelli F, Vigore L, Tisi E, D’amico G (2009) Effects of the conventional antitumor therapies surgery, chemotherapy, radiotherapy and immunotherapy on regulatory T lymphocytes in cancer patients. Anticancer Res 29:1847–1852

    PubMed  CAS  Google Scholar 

  135. Wu X, Feng Q, Wang Y, Shi J, Ge H, Di W (2010) The immunologic aspects in advanced ovarian cancer patients treated with paclitaxel and carboplatin chemotherapy. Cancer Immunol Immunother 59:279–291

    PubMed  CAS  Google Scholar 

  136. Miller JD, Van Der Most RG, Akondy RS, Glidewell JT, Albott S, Masopust D, Murali-Krishna K, Mahar PL, Edupuganti S, Lalor S, Germon S, Del Rio C, Mulligan MJ, Staprans SI, Altman JD, Feinberg MB, Ahmed R (2008) Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. Immunity 28:710–722

    PubMed  CAS  Google Scholar 

  137. Kim P, Ahmed R (2010) Features of responding T cells in cancer and chronic infection. Curr Opin Immunol 22:223–230

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Richard A. Lake.

Additional information

This article is published as part of the Special Issue on “Prognostic Impact of Anti-Cancer Immune Responses”.

Rights and permissions

Reprints and permissions

About this article

Cite this article

McDonnell, A.M., Nowak, A.K. & Lake, R.A. Contribution of the immune system to the chemotherapeutic response. Semin Immunopathol 33, 353–367 (2011). https://doi.org/10.1007/s00281-011-0246-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-011-0246-z

Keywords

Navigation