Skip to main content
NCBI home page
Cancer Science logoLink to Cancer Science
. 2005 Aug 19;94(10):924–928. doi: 10.1111/j.1349-7006.2003.tb01377.x

Critical role of the Th1/Tc1 circuit for the generation of tumor‐specific CTL during tumor eradication in vivo by Th1‐cell therapy

Kenji Chamoto 1, Akemi Kosaka 1, Takemasa Tsuji 1, Junko Matsuzaki 1, Takeshi Sato 1, Tsuguhide Takeshima 1, Kenji Iwakabe 1, Yuji Togashi 1, Toshiaki Koda 1, Takashi Nishimura 1,✉
PMCID: PMC11160164  PMID: 14556668

Abstract

Th1 and Th2 cells obtained from OVA‐specific T cell receptor transgenic mice completely eradicated the tumor mass when transferred into mice bearing A20‐OVA tumor cells expressing OVA as a model tumor antigen. To elucidate the role of Tc1 or Tc2 cells during tumor eradication by Th1‐ or Th2‐cell therapy, spleen cells obtained from mice cured of tumor by the therapy were restimulated with the model tumor antigen (OVA) for 4 days. Spleen cells obtained from mice cured by Th1‐cell therapy produced high levels of IFN‐γ, while spleen cells from mice cured by Th2‐cell therapy produced high levels of IL‐4. Intracellular staining analysis demonstrated that a high frequency of IFN‐γ‐producing Tc1 cells was induced in mice given Th1‐cell therapy. In contrast, IL‐4‐producing Tc2 cells were mainly induced in mice after Th2‐cell therapy. Moreover, Tc1, but not Tc2, exhibited a tumor‐specific cytotoxicity against A20‐OVA but not against CMS‐7 fibrosarcoma. Thus, immunological memory essential for CTL generation was induced by the Th1/Tc1 circuit, but not by the Th2/Tc2 circuit. We also demonstrated that Th1‐cell therapy is greatly augmented by combination therapy with cyclophosphamide treatment. This finding indicated that adoptive chemoimmuno‐therapy using Th1 cells should be applicable as a novel tool to enhance the Th1/Tc1 circuit, which is beneficial for inducing tumor eradication in vivo.

References

  • 1. Van der Bruggen P, Traversari C, Chomoes P, Lurquin C, De Plean E, Van den Eynde E, Knuth A, Boon T. A gene encoding an antigen recognized by cytotoxic T lymphocytes on a human melanoma. Science 1991; 254: 1643–7. [DOI] [PubMed] [Google Scholar]
  • 2. Lee K, Panelli MC, Kim CJ, Riker AL, Bettinotti MP, Roden MM, Fetsch P, Abati A, Rosenberg SA, Marincola FM. Functional dissociation between local and systemic immune response during anti‐melanoma peptide vaccination. J Immunol 1998; 161: 4183–94. [PubMed] [Google Scholar]
  • 3. Wang RF, Rosenberg SA. Human tumor antigens for cancer vaccine development. Immunol Rev 1999; 170: 85–100. [DOI] [PubMed] [Google Scholar]
  • 4. Celis E. Getting peptide vaccines to work: just a matter of quality control J Clin Invest 2002; 110: 1765–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Brossart P, Wirths S, Stuhler G, Reichardt VL, Kanz L, Brugger W. Induction of cytotoxic T‐lymphocyte responses in vivo after vaccinations with peptide‐pulsed dendritic cells. Blood 2000; 96: 3102–8. [PubMed] [Google Scholar]
  • 6. He L, Feng H, Raymond A, Kreeger M, Zeng Y, Graner M, Whitesell L, Katsanis E. Dendritic‐cell‐peptide immunization provides immunoprotection against bcr‐abl‐positive leukemia in mice. Cancer Immunol Immunother 2001; 50: 31–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Lee K, Wang E, Nielsen E, Wunderlich J, Migueles S, Connors M, Steinberg SM, Rosenberg SA, Marincola FM. Increased vaccine‐specific T cell frequency after peptide‐based vaccination correlates with increased susceptibility to in vitro stimulation but does not lead to tumor regression. J Immunol 1999; 163: 6292–300. [PubMed] [Google Scholar]
  • 8. Sakaguchi S, Sahaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 2001; 182: 18–32. [DOI] [PubMed] [Google Scholar]
  • 9. Whiteside TL. Signaling defects in T lymphocytes of patients with malignancy. Cancer Immunol Immunother 1999; 48: 346–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Kageshita T, Hirai S, Ono T, Hicklin DJ, Ferrone S. Down‐regulation of HLA class I antigen‐processing molecules in malignant melanoma: association with disease progression. Am J Pathol 1999; 154: 745–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Steinman RM, Dhodapkar M. Active immunization against cancer with dendric cells: the near future. Int J Cancer 2001; 94: 459–73. [DOI] [PubMed] [Google Scholar]
  • 12. Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S, Iwakura Y, Yagita H, Okumura K. Involvement of tumor‐necrosis factor‐related apoptosis‐inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med 2001; 7: 94–100. [DOI] [PubMed] [Google Scholar]
  • 13. Nishimura T, Kitamura H, Iwakabe K, Yahata T, Ohta A, Sato M, Takeda K, Okumura K, Van LK, Kawano T, Taniguchi M, Nakui M. The interface between innate and acquired immunity: glycolipid antigen presentation by CD1d‐expressing dendritic cells to NKT cells induces the differentiation of antigen‐specific cytotoxic T lymphocytes. Int Immunol 2000; 12: 987–94. [DOI] [PubMed] [Google Scholar]
  • 14. Nishimura T, Nakui M, Sato M, Iwakabe K, Kitamura H, Sekimoto M, Ohta A, Koda T, Nishimura T. The critical role of Th1‐dominant immunity in tumor immunology. Cancer Chemother Pharmacol. 2000; 46: S52–61. [DOI] [PubMed] [Google Scholar]
  • 15. Medema JP, Schuurhuis DH, Rea D, van Tongeren J, de Jong J, Schumacher TNM, Toes REM, Toebes M, Schumacher TNM, Bladergroen BA, Ossendorp F, Kummer JA, Melief CJM, Offringa R. Expression of the serpin serine protease inhibition 6 protects dendritic cells from cytotoxic T lymphocyte‐induced apoptosis: differential modulation by T helper type 1 and type 2 cells. J Exp Med 2001; 194: 657–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Shimizu K, Thomas EK, Giedlin M, Mule JJ. Enhancement of tumor lysate‐and peptide‐pulsed dendritic cell‐based vaccines by the addition of foreign helper protein. Cancer Res 2001; 61: 2618–24. [PubMed] [Google Scholar]
  • 17. John M, Timmerman JM, Levy R. Linkage of foreign carrier protein to a self‐tumor antigen enhances the immunogenicity of a pulsed dendritic cell vaccine. J Immunol 2000; 164: 4797–803. [DOI] [PubMed] [Google Scholar]
  • 18. Dobrzanski MJ, Reome JB, Dutton RW. Therapeutic effect of tumor‐reactive type 1 and type 2 CD8+ T cell subpopulations in established pulmonary metastases. J Immunol 1999; 162: 6671–80. [PubMed] [Google Scholar]
  • 19. Dobrzanski MJ, Reome JB, Dutton RW. Type 1 and type 2 CD8+ effector T cell subpopulations promote long‐term tumor immunity and protection to progressively growing tumor. J Immunol 2000; 162: 916–25. [DOI] [PubMed] [Google Scholar]
  • 20. Dobrzanski MJ, Reome JB, Dutton RW. Role of effector cell‐derived IL‐4, IL‐5, and perforin in early and late stages of type 2 CD8 effector cell‐mediated tumor rejection. J Immunol 2001; 167: 424–34. [DOI] [PubMed] [Google Scholar]
  • 21. Murphy KM, Reiner SL. The lineage decisions of helper T cells. Nat Rev Immunol 2002; 2: 933–44. [DOI] [PubMed] [Google Scholar]
  • 22. Nishimura T, Ohta A. A critical role for antigen‐specific Th1 cells in acute liver injury in mice. J Immunol 1999; 162: 6503–9. [PubMed] [Google Scholar]
  • 23. Takaoka A, Tanaka Y, Tsuji T, Jinushi T, Hoshino A, Asakura Y, Mita Y, Watanabe K, Nakaike S, Togashi Y, Koda T, Matsushima T, Nishimura T. A critical role for mouse CXC chemokine(s) in pulmonary neutrophilia during Th type 1‐dependent airway inflammation. J Immunol 2001; 167: 2349–53. [DOI] [PubMed] [Google Scholar]
  • 24. Cerwenka A, Carter LL, Reome JB, Swain SL, Dutton RW. In vivo persistence of CD8 polarized T cell subsets producing Type 1 or Type 2 cytokines. J Immunol 1998; 161: 97–105. [PubMed] [Google Scholar]
  • 25. Nishimura T, Iwakabe K, Sekimoto M, Ohmi Y, Yahata T, Nakui M, Sato T, Habu S, Tashiro H, Ohta A. Distinct role of antigen‐specific T helper type 1 (Th1) and Th2 cells in tumor eradication in vivo . J Exp Med 1999; 190: 617–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Nishimura T, Togashi Y, Goto M, Yagi H, Uchiyama Y, Hashimoto H. Augmentation of the therapeutic efficacy of adoptive tumor immunotherapy by in vivo administration of slowly released recombinant interleukin 2. Cancer Immunol Immunother 1986; 21: 12–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Nishimura T, Burakoff SJ, Herrmann SH. Protein kinase C required for cytotoxic T lymphocyte triggering. J Immunol 1987; 139: 2888–91. [PubMed] [Google Scholar]
  • 28. Pernis A, Gupta S, Gollob KJ, Garfein E, Coffman RL, Schindler C, Rothman P. Lack of interferon gamma receptor beta chain and the prevention of interferon gamma signaling in TH1 cells. Science 1995; 269: 245–7. [DOI] [PubMed] [Google Scholar]
  • 29. Mattes J, Hulett M, Xie W, Hogan S, Rothenberg ME, Foster P, Parish C. Immunotherapy of cytotoxic T cell‐resistant tumors by T helper 2 cells: an eotaxin and STAT6‐dependent process. J Exp Med 2003; 197: 387–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Rodolfo M, Melani C, Zilocchi C, Cappetti B, Luison E, Arioli I, Parenza M, Canevari S, Colombo MP. IgG2a induced by interleukin (IL) 12‐producing tumor cell vaccines but not IgG1 induced by IL‐4 vaccine is associated with the eradication of experimental metastases. Cancer Res 1998; 58: 5812–7. [PubMed] [Google Scholar]
  • 31. Trinchieri, G. Interleukin‐12: a cytokine produced by antigen‐presenting cells with immunoregulatory functions in the generation of T‐helper cells type 1 and cytotoxic lymphocytes. Blood 1995; 84: 4008–27. [PubMed] [Google Scholar]
  • 32. Bellon M, Cantarella D, Castiglioni P, Crosti MC, Ronchetti A, Moro M, Garancini MP, Casorati G, Dellabona P. Relevance of the tumor antigen in the validation of the vaccination strategies for melanoma. J Immunol 2000; 165: 2651–6. [DOI] [PubMed] [Google Scholar]
  • 33. Soares MM, Mehta V, Finn OJ. Three different vaccines based on the 140‐amino acid MUC1 peptide with seven tandemly repeated tumor‐specific epitopes elicit distinct immune effector mechanisms in wild‐type versus MUC1‐transgenic mice with different potential for tumor rejection. J Immunol 2001; 166: 6555–63. [DOI] [PubMed] [Google Scholar]
  • 34. Sato M, Chamoto K, Nishimura T. A novel tumor‐vaccine cell therapy using bone marrow‐derived dendritic cell type 1 and antigen‐specific T helper type 1 cells. Int Immunol 2003; 15: 837–43. [DOI] [PubMed] [Google Scholar]
  • 35. Tong Y, Song W, Crystal RG. Combined intratumoral injection of bone marrow‐derived dendritic cells and systemic chemotherapy to treat pre‐existing tumors. Cancer Res 2001; 61: 7530–5. [PubMed] [Google Scholar]
  • 36. Proietti E, Greco G, Garrone B, Baccarini Sara Maui C, Venditti M, Carlei D, Belardelli F. Importance of cyclophosphamide‐induced bystander effect on T cells for a successful tumor eradication in response to adoptive immunotherapy in mice. J Clin Invest 1998; 100: 429–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Matar P, Rozados VR, Gervasoni SI, Schaarovsky OG. Down regulation of T‐cell‐derived IL‐10 production by low‐dose cyclophosphamide treatment in tumor‐bearing rats restores in vitro normal lymphoproliferative response. Int Immunopharmacol 2001; 1: 307–19. [DOI] [PubMed] [Google Scholar]
  • 38. Ibe S, Qin Z, Schuler T, Press S, Blankenstein T. Tumor rejection by disturbing tumor stroma cell interactions. J Exp Med 2001; 194: 1549–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Dudley M, Wunderlich JR, Robbins P, Yang JC, Hwu P, Schwartzentruber DJ, Topalian S, Scherry R, Restifo N, Hubicki AM, Robinson MR, Raffeld M, Duray P, Sepp CA, Rogers‐Feezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2003; 298: 850–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Gomez GG, Hutchison RB, Kruse CA. Chemo‐immunotherapy and chemo‐adoptive immunotherapy of cancer. Cancer Treat Rev 2001; 27: 375–402. [DOI] [PubMed] [Google Scholar]

Articles from Cancer Science are provided here courtesy of Wiley

RESOURCES