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Eliciting protective immune responses against murine myeloma challenge in lymphopenia mice through adoptive transfer of tumor antigen-specific lymphocytes and immunization of tumor vaccine secreting mIL-21

Abstract

Previous studies have indicated that the cytokine interleukin (IL)-21 may induce both innate and adaptive immune responses against tumors. The goal of this study was to evaluate a new adoptive immunotherapy strategy that combined lymphocytes from mice immunized with a murine myeloma vaccine secreting murine IL-21 (mIL-21-Sp2/0) in lymphopenic mice induced by cyclophosphamide. The data indicate that effective antitumor immunity was induced in mice receiving syngeneic murine lymphocytes from the mice immunized with the mIL-21-Sp2/0. More importantly, the efficacy against the Sp2/0 cell challenge was enhanced after the lymphocytes were activated and proliferated ex vivo before administration into the lymphopenic mice. We conclude that the adoptive transfer of tumor antigen-specific lymphocytes into mice immunized with mIL-21-Sp2/0 induced protective immune responses against myeloma challenge.

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References

  1. Butler MO, Lee JS, Ansen S, Neuberg D, Hodi FS, Murray AP et al. Long-lived antitumor CD8+ lymphocytes for adoptive therapy generated using an artificial antigen-presenting cell. Clin Cancer Res 2007; 13: 1857–1867.

    Article  CAS  Google Scholar 

  2. Li J, Mookerjee B, Wagner J . Purification of melanoma reactive T cell by using a monocyte-based solid phase T-cell selection system for adoptive therapy. J Immunother 2008; 31: 81–88.

    Article  Google Scholar 

  3. Powell DJ, Dudley ME, Hogan KA, Wunderlich JR, Rosenberg SA . Adoptive transfer of vaccine-induced peripheral blood mononuclear cells to patients with metastatic melanoma following lymphodepletion. J Immunol 2006; 177: 6527–6539.

    Article  CAS  Google Scholar 

  4. Goldrath AW, Bogatzki LY, Bevan MJ . Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J Exp Med 2000; 192: 557–564.

    Article  CAS  Google Scholar 

  5. Cho BK, Rao VP, Ge Q, Eisen HN, Chen J . Homeostasis stimulated proliferation drives naive T cells to differentiate directly into memory T cells. J Exp Med 2000; 192: 549–556.

    Article  CAS  Google Scholar 

  6. Prlic M, Blazar BR, Khoruts A, Zell T, Jameson SC . Homeostatic expansion occurs independently of costimulatory signals. J Immunol 2001; 167: 5664–5668.

    Article  CAS  Google Scholar 

  7. Wang LX, Jorgen K, Peter A, Shu S, Plautz GE . Memory T cells originate from adoptively transferred effectors and reconstituting host cells after sequential lymphodepletion and adoptive immunotherapy. J Immunol 2004; 172: 3462–3468.

    Article  CAS  Google Scholar 

  8. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006; 314: 126–129.

    Article  CAS  Google Scholar 

  9. Wilde VD, Benghiat FS, Novalrivas M, Lebrun JF, Kubjak C, Oldenhove G et al. Endotoxin hyperresponsiveness upon CD4+ T cell reconstitution in lymphopenic mice: control by natural regulatory T cells. Eur J Immunol 2008; 38: 48–53.

    Article  Google Scholar 

  10. Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 2000; 408: 57–63.

    Article  CAS  Google Scholar 

  11. Ettinger R, Sims GP, Fairhurst AM, Robbins R, da Silva YS, Spolski R et al. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. J Immunol 2005; 175: 7867–7879.

    Article  CAS  Google Scholar 

  12. Nutt SL, Brady J, Hayakawa Y, Smyth MJ . Interleukin 21: a key player in lymphocyte maturation. Crit Rev Immunol 2004; 24: 239–245.

    Article  CAS  Google Scholar 

  13. Dou J, Lili C, Fengshu Z, Tang Q, Zhang AF, Zhang LF et al. Study of immunotherapy of murine myeloma by an IL-21-based tumor vaccine in BALB/C mice. Cancer Biol Ther 2007; 6: 1871–1879.

    Article  CAS  Google Scholar 

  14. Dou J, Guobin C, Jing W, Fengshu Z, Junsong C, Xuesong F et al. Preliminary study on mouse interleukin 21 application in tumor gene therapy. Cellular Mol Immunol 2004; 1: 388–396.

    Google Scholar 

  15. Li Y, Yee C . IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes. Blood 2004; 111: 229–235.

    Article  Google Scholar 

  16. Iuchi T, Teitz-Tennenbaum S, Huang J, Redman BG, Hughes SD, Li M et al. Interleukin-21 augments the efficacy of T-cell therapy by eliciting concurrent cellular and humoral responses. Cancer Res 2008; 68: 4431–4441.

    Article  CAS  Google Scholar 

  17. Li Y, Bleakley M, Yee C . IL-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8T cell response. J Immunol 2005; 175: 2261–2269.

    Article  CAS  Google Scholar 

  18. Fina D, Fantini MC, Pallon F, Monteleone G . Role of interleukin-21 in inflammation and allergy. Inflamm Allergy Drug Targets 2007; 6: 63–68.

    Article  CAS  Google Scholar 

  19. Bracci L, Moschella F, Sestili P, La Sorsa V, Valentini M, Canini I et al. Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clin Cancer Res 2007; 13: 644–653.

    Article  CAS  Google Scholar 

  20. Julien T, Nathalie C, Noel S, Roux S, Novault S, Menard C et al. Chemoimmunotherapy of tumors: cyclophosphamide synergizes with exosome based vaccines. J Immunol 2006; 176: 2722–2729.

    Article  Google Scholar 

  21. Pawel M, Andrea B, Claudia W, Citrin DE, Rosenberg SA, Childs R et al. Increased intensity lymphodepletion and adoptive immunotherapy—how far can we go? Nat Clin Pract Oncol 2006; 3: 668–681.

    Google Scholar 

  22. Sara EH, Monika CW, Stephen P, Jameson SC . The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+ T cells. Nat Immunol 2006; 7: 475–481.

    Article  Google Scholar 

  23. Dou J, Xiaowu H, Fengshu Z, Wang J, Chen JS, Chen GB . Investigation of GM-CSF immune accessory effects in tumor-bearing mice by direct gene immunization. Immunol Invest 2006; 35: 227–237.

    Article  CAS  Google Scholar 

  24. Rutigliano JA, Johnson TR, Hollinger TN, Fischer JE, Aung S, Graham BS . Treatment with anti-LFA-1 delays the CD8+ cytotoxic T-lymphocyte response and viral clearance in mice with primary respiratory syncytial virus infection. J Virol 2004; 78: 3014–3023.

    Article  CAS  Google Scholar 

  25. Naeem K, Donna B, Rachel B, Nayak L, Rickinson AB, Moss PA . T cell recognition patterns of immunodominant cytomegalovirus antigens in primary and persistent infection. J Immunol 2007; 178: 4455–4465.

    Article  Google Scholar 

  26. Rosenberg SA, Sherry RM, Morton KE, Scharfman WJ, Yang JC, Topalian SL et al. Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma. J Immunol 2005; 175: 6169–6176.

    Article  CAS  Google Scholar 

  27. Martin B, Fae T, Jin L, Hesse M . Naturally occurring CD4+Foxp3+ regulatory T cells are an essential, IL-10-independent part of the immunoregulatory network in Schistosoma mansoni egg-induced inflammation. J Immunol 2006; 176: 5374–5387.

    Article  Google Scholar 

  28. Plas E, Carroll VA, Jilch R, Simak R, Mihaly J, Melchior S et al. Variations of components of the plasminogen activation system with the cell cycle in benign prostate tissue and prostate cancer. Cytometry 2001; 46: 184–189.

    Article  CAS  Google Scholar 

  29. Herve L, Michele F, Riviere Y, Gougeon ML . A novel flow cytometric assay for quantitation and multiparametric characterization of cell-mediated cytotoxicity. J Immunol Methods 2001; 253: 177–187.

    Article  Google Scholar 

  30. Turk MJ, Guevara-Patino JA, Rizzuto GA, Engelhorn ME, Sakaguchi S, Houghton AN et al. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med 2004; 20: 771–782.

    Article  Google Scholar 

  31. Smyth MJ, Teng MW, Sharkey J, Westwood JA, Haynes NM, Yagita H et al. Interleukin 21 enhances antibody-mediated tumor rejection. Cancer Res 2008; 68: 3019–3025.

    Article  CAS  Google Scholar 

  32. Hinrichs CS, Spolski R, Paulous CM, Gattinoni L, Kerstann KW, Palmer DC et al. IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood 2008; 111: 5326–5333.

    Article  CAS  Google Scholar 

  33. Deepe GS, Gibbons RS . TNF-alpha antagonism generates a population of antigen-specific CD4+CD25+ T cells that inhibit protective immunity in murine histoplasmosis. J mmunol 2008; 180: 1088–1097.

    Article  CAS  Google Scholar 

  34. Ohmura Y, Yoshikawa K, Saga S, Ueda R, Kazaoka Y, Yamada S et al. Combinations of tumor-specific CD8+ CTLs and anti-CD25mAb provide improved immunotherapy. Oncol Rep 2008; 19: 1265–1270.

    CAS  PubMed  Google Scholar 

  35. Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+T cells. JEM 2005; 202: 907–912.

    Article  CAS  Google Scholar 

  36. Tuettenberg A, Schmitt E, Knop J, Jonuleit H . Dendritic cell-based immunotherapy of malignant melanoma: success and limitations. J Dtsch Dermatol Ges 2007; 3: 190–196.

    Article  Google Scholar 

  37. Hill JA, Hall JA, Sun CM, Cai Q, Ghyselinck N, Chambon P et al. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4CD44hi cells. Immunity 2008; 29: 758–770.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr Aifeng Zhang for the assistance in histological section and analysis, and Dr Rod Donlan (Centers for Disease Control and Prevention in Atlanta, GA, USA) for kindly reviewing the article. This work was supported in part by the Program for the Top Researchers in Six Fields of Jiangsu Province, China (no. D14) and in part by the 973 Program of China (no. 2006CB933206).

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Correspondence to J Dou or N Gu.

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Dou, J., Wu, Y., Wang, J. et al. Eliciting protective immune responses against murine myeloma challenge in lymphopenia mice through adoptive transfer of tumor antigen-specific lymphocytes and immunization of tumor vaccine secreting mIL-21. Cancer Gene Ther 17, 675–683 (2010). https://doi.org/10.1038/cgt.2010.23

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