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Different immune correlates associated with tumor progression and regression: implications for prevention and treatment of cancer

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Abstract

Observations show that humans and animals respond immunologically to most cancers. Why does the immune system then fail to control cancer? We argue from the literature that there is a commonality in the regulation of responses against most murine tumors, and that a major mechanism of escape may be deviation of an effective Th1, cytotoxic T lymphocyte response to a less effective response with a Th2 component. We examined this hypothesis with two well-studied murine tumors. We found, following primary tumor implantation, that resistance correlates with Th1 responses and IgG2a antibody production and progression with mixed Th1/Th2 responses and production of IgG1 and IgG2a antibodies. Resistance is associated with a modulation of the anti-tumor response towards the Th1 pole in both systems. We conclude that the immune responses against these two tumors are in accord with our hypothesis, and argue that this is likely to be true of many human and murine tumors. The correlation of IgG isotype of anti-tumor antibody with the Th1/Th2 nature of the anti-tumor response readily allows one to longitudinally monitor the changing nature of the anti-tumor response. We suggest that such monitoring can guide immunotherapy to maximize the effectiveness of the host’s immune response against cancer.

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Abbreviations

sc:

Subcutaneous

id:

Intradermal

References

  1. Assudani DP, Horton RB, Mathieu MG, McArdle SE, Rees RC (2007) The role of CD4+ T cell help in cancer immunity and the formulation of novel cancer vaccines. Cancer Immunol Immunother 56(1):70–80

    Article  PubMed  Google Scholar 

  2. Awwad M, North RJ (1989) Cyclophosphamide-induced immunologically mediated regression of a cyclophosphamide-resistant murine tumor: a consequence of eliminating precursor L3T4+ suppressor T-cells. Cancer Res 49(7):1649–1654

    PubMed  CAS  Google Scholar 

  3. Beyer M, Schultze JL (2006) Regulatory T cells in cancer. Blood 108(3):804–811

    Article  PubMed  CAS  Google Scholar 

  4. Biddison WE, Palmer JC (1977) Development of tumor cell resistance to syngeneic cell-mediated cytotoxicity during growth of ascitic mastocytoma P815Y. Proc Natl Acad Sci USA 74(1):329–333

    Article  PubMed  CAS  Google Scholar 

  5. Bogen B (1996) Peripheral T cell tolerance as a tumor escape mechanism: deletion of CD4+ T cells specific for a monoclonal immunoglobulin idiotype secreted by a plasmacytoma. Eur J Immunol 26(11):2671–2679

    Article  PubMed  CAS  Google Scholar 

  6. Boon T, Coulie PG, Van den Eynde BJ, van der Bruggen P (2006) Human T cell responses against melanoma. Annu Rev Immunol 24:175–208

    Article  PubMed  CAS  Google Scholar 

  7. Bretscher PA, Ismail N, Menon JN, Power CA, Uzonna J, Wei G (2001) Vaccination against and treatment of tuberculosis, the leishmaniases and AIDS: perspectives from basic immunology and immunity to chronic intracellular infections. Cell Mol Life Sci 58(12–13):1879–1896

    Article  CAS  Google Scholar 

  8. Bretscher PA, Wei G, Menon JN, H Bielefeldt-Ohmann (1992) Establishment of stable, cell-mediated immunity that makes “susceptible” mice resistant to Leishmania major. Science 257(5069):539–542

    Article  PubMed  CAS  Google Scholar 

  9. Burnet F (1957) Cancer a biological approach. BMJ 1:841–847

    PubMed  CAS  Google Scholar 

  10. Corthay A, Skovseth DK, Lundin KU, Rosjo E, Omholt H, Hofgaard PO, Haraldsen G, Bogen B (2005) Primary antitumor immune response mediated by CD4+ T cells. Immunity 22(3):371–383

    Article  PubMed  CAS  Google Scholar 

  11. De Plaen E, Lurquin C, Lethe B, van der Bruggen P, Brichard V, Renauld JC, Coulie P, Van Pel A, Boon T (1997) Identification of genes coding for tumor antigens recognized by cytolytic T lymphocytes. Methods 12(2):125–142

    Article  PubMed  Google Scholar 

  12. Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22:329–360

    Article  PubMed  CAS  Google Scholar 

  13. Ehrlich P (1909) Ueber den jetzigen Stand der Karzinomforschung. Ned Tijdschr Geneeskd 5:273

    Google Scholar 

  14. Gorelik E (1983) Concomitant tumor immunity and the resistance to a second tumor challenge. Adv Cancer Res 39:71–120

    PubMed  CAS  Google Scholar 

  15. Hahn H, Kaufmann SH, Miller TE, Mackaness GB (1979) Peritoneal exudate T lymphocytes with specificity to sheep red blood cells. I. Production and characterization as to function and phenotype. Immunology 36(4):691–698

    PubMed  CAS  Google Scholar 

  16. Hailu A, Menon JN, Berhe N, Gedamu L, Hassard TH, Kager PA, Olobo J, Bretscher PA (2001) Distinct immunity in patients with visceral leishmaniasis from that in subclinically infected and drug-cured people: implications for the mechanism underlying drug cure. J Infect Dis 184(1):112–115

    Article  PubMed  CAS  Google Scholar 

  17. Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D, Levitsky H (1998) The central role of CD4(+) T cells in the antitumor immune response. J Exp Med 188(12):2357–2368

    Article  PubMed  CAS  Google Scholar 

  18. Khong HT, Restifo NP (2002) Natural selection of tumor variants in the generation of “tumor escape” phenotypes. Nat Immunol 3(11):999–1005

    Article  PubMed  CAS  Google Scholar 

  19. Klein G (1968) Tumor-specific transplantation antigens: G.H.A. Clowes Memorial Lecture. Cancer Res 28:625–635

    PubMed  CAS  Google Scholar 

  20. Kuhn R, Rajewsky K, Muller W (1991) Generation and analysis of interleukin-4 deficient mice. Science 254(5032):707–710

    Article  PubMed  CAS  Google Scholar 

  21. Lagrange PH, Mackaness GB (1975) A stable form of delayed-type hypersensitivity. J Exp Med 141(1):82–96

    Article  PubMed  CAS  Google Scholar 

  22. Lagrange PH, Mackaness GB, Miller TE (1974) Influence of dose and route of antigen injection on the immunological induction of T cells. J Exp Med 139(3):528–542

    Article  PubMed  CAS  Google Scholar 

  23. Mackaness GB, Lagrange PH, Miller TE, Ishibashi T (1974) Feedback inhibition of specifically sensitized lymphocytes. J Exp Med 139(3):543–559

    Article  PubMed  CAS  Google Scholar 

  24. Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S (2000) Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 74:181–273

    PubMed  CAS  Google Scholar 

  25. Menon JN, Bretscher PA (1996) Characterization of the immunological memory state generated in mice susceptible to Leishmania major following exposure to low doses of L. major and resulting in resistance to a normally pathogenic challenge. Eur J Immunol 26(1):243–249

    Article  PubMed  CAS  Google Scholar 

  26. Menon JN, Bretscher PA (1998) Parasite dose determines the Th1/Th2 nature of the response to Leishmania major independently of infection route and strain of host or parasite. Eur J Immunol 28(12):4020–4028

    Article  PubMed  CAS  Google Scholar 

  27. Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145–173

    Article  PubMed  CAS  Google Scholar 

  28. Nishimura T, Iwakabe K, Sekimoto M, Ohmi Y, Yahata T, Nakui M, Sato T, Habu S, Tashiro H, Sato M, Ohta A (1999) Distinct role of antigen-specific T helper type 1 (Th1) and Th2 cells in tumor eradication in vivo. J Exp Med 190(5):617–627

    Article  PubMed  CAS  Google Scholar 

  29. North RJ (1985) Down-regulation of the antitumor immune response. Adv Cancer Res 45:1–43

    Article  PubMed  CAS  Google Scholar 

  30. North RJ (1986) Radiation-induced, immunologically mediated regression of an established tumor as an example of successful therapeutic immunomanipulation. Preferential elimination of suppressor T cells allows sustained production of effector T cells. J Exp Med 164(5):1652–1666

    Article  PubMed  CAS  Google Scholar 

  31. North RJ, Awwad M (1990) Elimination of cycling CD4+ suppressor T cells with an anti-mitotic drug releases non-cycling CD8+ T cells to cause regression of an advanced lymphoma. Immunology 71(1):90–95

    PubMed  CAS  Google Scholar 

  32. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E (1999) Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59(13):3128–3133

    PubMed  CAS  Google Scholar 

  33. Parish CR (1972) The relationship between humoral and cell-mediated immunity. Transplant Rev 13:35–66

    PubMed  CAS  Google Scholar 

  34. Paul WE, J Ohara (1987) B-cell stimulatory factor-1/interleukin 4. Annu Rev Immunol 5:429–459

    PubMed  CAS  Google Scholar 

  35. Power CA, Grand CL, Ismail N, Peters NC, Yurkowski DP, Bretscher PA (1999) A valid ELISPOT assay for enumeration of ex vivo, antigen-specific, IFNgamma-producing T cells. J Immunol Methods 227(1–2):99–107

    Article  PubMed  CAS  Google Scholar 

  36. Rabinovich GA, Gabrilovich D, Sotomayor EM (2007) Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25:267–296

    Article  PubMed  CAS  Google Scholar 

  37. Ramshaw IA, Bretscher PA, Parish CR (1976) Regulation of the immune response. I. Suppression of delayed-type hypersensitivity by T cells from mice expressing humoral immunity. Eur J Immunol 6(10):674–679

    Article  PubMed  CAS  Google Scholar 

  38. Ramshaw IA, Bretscher PA, Parish CR (1977a) Regulation of the immune response. II. Repressor T cells in cyclophosphamide-induced tolerant mice. Eur J Immunol 7(3):180–185

    Article  PubMed  CAS  Google Scholar 

  39. Ramshaw IA, McKenzie IF, Bretscher PA, Parish CR (1977b) Discrimination of suppressor T cells of humoral and cell-mediated immunity by anti-Ly and anti-Ia sera. Cell Immunol 31(2):364–369

    Article  PubMed  CAS  Google Scholar 

  40. Sahin U, Tureci O, Schmitt H, Cochlovius B, Johannes T, Schmits R, Stenner F, Luo G, Schobert I, Pfreundschuh M (1995) Human neoplasms elicit multiple specific immune responses in the autologous host. Proc Natl Acad Sci USA 92(25):11810–3

    Article  PubMed  CAS  Google Scholar 

  41. Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T (2001) Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 182:18–32

    Article  PubMed  CAS  Google Scholar 

  42. Salvin SB (1958) Occurrence of delayed hypersensitivity during the development of Arthus type hypersensitivity. J Exp Med 107(1):109–124

    Article  PubMed  CAS  Google Scholar 

  43. Severinson E, Fernandez C, Stavnezer J (1990) Induction of germ-line immunoglobulin heavy chain transcripts by mitogens and interleukins prior to switch recombination. Eur J Immunol 20(5):1079–1084

    Article  PubMed  CAS  Google Scholar 

  44. Sher A, Gazzinelli RT, Oswald IP, Clerici M, Kullberg M, Pearce EJ, Berzofsky JA, Mosmann TR, James SL, Morse HC 3rd (1992) Role of T-cell derived cytokines in the downregulation of immune responses in parasitic and retroviral infection. Immunol Rev 127:183–204

    Article  PubMed  CAS  Google Scholar 

  45. Snapper CM, Peschel C, Paul WE (1988) IFN-gamma stimulates IgG2a secretion by murine B cells stimulated with bacterial lipopolysaccharide. J Immunol 140(7):2121–2127

    PubMed  CAS  Google Scholar 

  46. Staveley-O’Carroll K, Sotomayor E, Montgomery J, Borrello I, Hwang L, Fein S, Pardoll D, Levitsky H (1998) Induction of antigen-specific T cell anergy: an early event in the course of tumor progression. Proc Natl Acad Sci USA 95(3):1178–1183

    Article  PubMed  CAS  Google Scholar 

  47. Uyttenhove C, Maryanski J, Boon T (1983) Escape of mouse mastocytoma P815 after nearly complete rejection is due to antigen-loss variants rather than immunosuppression. J Exp Med 157(3):1040–1052

    Article  PubMed  CAS  Google Scholar 

  48. Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 9(10):1269–1274

    Article  PubMed  CAS  Google Scholar 

  49. Uzonna JE, Bretscher PA (2001) Anti-IL-4 antibody therapy causes regression of chronic lesions caused by medium-dose Leishmania major infection in BALB/c mice. Eur J Immunol 31(11):3175–3184

    Article  PubMed  CAS  Google Scholar 

  50. Uzonna JE, Wei G, Yurkowski D, Bretscher P (2001) Immune elimination of Leishmania major in mice: implications for immune memory, vaccination, and reactivation disease. J Immunol 167(12):6967–6974

    PubMed  CAS  Google Scholar 

  51. Wolf ML, Weng WK, Stieglbauer KT, Shah N, LeBien TW (1993) Functional effect of IL-7-enhanced CD19 expression on human B cell precursors. J Immunol 151(1):138–148

    PubMed  CAS  Google Scholar 

  52. Yamaguchi T, Sakaguchi S (2006) Regulatory T cells in immune surveillance and treatment of cancer. Semin Cancer Biol 16(2):115–123

    Article  PubMed  CAS  Google Scholar 

  53. Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6(4):295–307

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from the Ralston Brothers’ Fund and from an NCIC-regional partnership program to Peter A. Bretscher. We thank Dr. C. Havele and G. Wei for help in the early phases of this work. The authors report no competing financial interests.

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Correspondence to Peter A. Bretscher.

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Hamilton, D.H., Bretscher, P.A. Different immune correlates associated with tumor progression and regression: implications for prevention and treatment of cancer. Cancer Immunol Immunother 57, 1125–1136 (2008). https://doi.org/10.1007/s00262-007-0442-9

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