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IL-7 + IL-15 are superior to IL-2 for the ex vivo expansion of 4T1 mammary carcinoma-specific T cells with greater efficacy against tumors in vivo

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Abstract

Regression of established tumors can be induced by adoptive immunotherapy (AIT) with tumor draining lymph node (DLN) lymphocytes activated with bryostatin and ionomycin (B/I). Tumor antigen-sensitized DLN lymphocytes from BALB/c mice with 10-day 4T1 mammary carcinomas were harvested, activated with B/I, and expanded in culture with either interleukin-2 (IL-2) or IL-7 + IL-15. Cell yields, proliferation, phenotypes, and in vitro responses to tumor antigen were compared for cells grown in different cytokines. These T cells were also tested for antitumor activity against established 4T1 mammary carcinomas after inoculation of tumor cells subcutaneously (s.c.). IL-7/15 resulted in much faster and more prolonged proliferation of B/I-activated T cells than culturing the same cells in IL-2. This resulted in approximately 5–10-fold greater yields of viable cells. Culture in IL-7/15 yielded higher proportions of CD8+ T cells and a higher proportion of cells with a central memory phenotype. T cells grown in IL-2 had higher interferon-gamma (IFN-γ) release responses to tumor antigen than cells grown in IL-7/15. Adoptive transfer of B/I-activated T cells grown in IL-7/15 demonstrated much greater efficacy against 4T1 tumors in vivo. Activation of tumor antigen-sensitized T cells with B/I and culture in IL-7 + IL-15 is a promising modification of standard regimens for production of T cells for use in AIT of cancer.

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References

  1. Chang AE, Li Q, Jiang G, Sayre DM, Braun TM, Redman BG (2003) Phase II trial of autologous tumor vaccination, anti-CD3-activated vaccine-primed lymphocytes, and interleukin-2 in stage IV renal cell cancer. J Clin Oncol 21:884–890

    Article  CAS  PubMed  Google Scholar 

  2. Nijhuis EWP, Wiel-van Kemenade EVD, Figdor CG, Van Lier RAW (1990) Activation and expansion of tumour-infiltrating lymphocytes by anti-CD3 and anti-CD28 monoclonal antibodies. Cancer Immunol Immunother 32:245–250

    Article  CAS  PubMed  Google Scholar 

  3. Alexander JP, Kudoh S, Melsop KA, Hamilton TA, Edinger MG, Tubbs RR, Sica D, Tuason L, Klein E, Bukowski RM, Finke JH (1993) T-cells infiltrating renal cell carcinoma display a poor proliferative response even though they can produce interleukin 2 and express interleukin 2 receptors. Cancer Res 53:1380–1387

    CAS  PubMed  Google Scholar 

  4. Correa MR, Ochoa AC, Ghosh P, Mizoguchi H, Harvey L, Longo DL (1997) Sequential development of structural and functional alterations in T cells from tumor-bearing mice. J Immunol 158:5292–5296

    CAS  PubMed  Google Scholar 

  5. Danna EA, Sinha P, Gilbert M, Clements VK, Pulaski BA, Ostrand-Rosenberg S (2004) Surgical removal of primary tumor reverses tumor-induced immunosuppression despite the presence of metastatic disease. Cancer Res 64:2205–2211

    Article  CAS  PubMed  Google Scholar 

  6. Morse MA, Clay TM, Lyerly HK (2002) Current status of adoptive immunotherapy of malignancies. Expert Opin Biol Ther 2:237–247

    Article  CAS  PubMed  Google Scholar 

  7. Tuttle TM, Inge TH, Bethke KP, McCrady CW, Pettit GR, Bear HD (1992) Activation and growth of murine tumor-specific T-cells which have in vivo activity with bryostatin 1. Cancer Res 52:548–553

    CAS  PubMed  Google Scholar 

  8. Tuttle TM, Bethke KP, Inge TH, McCrady CW, Pettit GR, Bear HD (1992) Bryostatin 1-activated T cells can traffic and mediate tumor regression. J Surg Res 52:543–548

    Article  CAS  PubMed  Google Scholar 

  9. Tuttle TM, McCrady CW, Inge TH, Salour M, Bear HD (1993) γ-interferon plays a key role in T-cell-induced tumor regression. Cancer Res 53:833–839

    CAS  PubMed  Google Scholar 

  10. Tuttle TM, Fleming MF, Hogg PS, Inge TH, Bear HD (1994) Low-dose cyclophosphamide overcomes metastasis-induced immunosuppression. Ann Surg Oncol 1:53–58

    Article  CAS  PubMed  Google Scholar 

  11. Yee C (2003) Adoptive T cell therapy—immune monitoring and MHC multimers. Clin Immunol 106:5–9

    Article  CAS  PubMed  Google Scholar 

  12. Chin CS, Miller CH, Graham L, Parviz M, Zacur S, Patel B, Duong A, Bear HD (2004) Bryostatin 1/ionomycin (B/I) ex vivo stimulation preferentially activates L-selectinlow tumor-sensitized lymphocytes. Int Immunol 16:1283–1294

    Article  CAS  PubMed  Google Scholar 

  13. Cantrell D (1996) T cell antigen receptor signal transduction pathways. Annu Rev Immunol 14:259–274

    Article  CAS  PubMed  Google Scholar 

  14. Kazanietz MG, Lewin NE, Gao F, Pettit GR, Blumberg PM (1994) Binding of [26-3H]bryostatin 1 and analogs to calcium-dependent and calcium-independent protein kinase C isozymes. Mol Pharmacol 46:374–379

    CAS  PubMed  Google Scholar 

  15. Pettit GR, Herald SL, Doubek DL, Arnold E, Clardy J (1982) Isolation and structure of bryostatin 1. J Am Chem Soc 104:6846–6848

    Article  CAS  Google Scholar 

  16. Chatila T, Silverman L, Miller R, Geha R (1989) Mechanisms of T cell activation by the calcium ionophore ionomycin. J Immunol 143:1283–1289

    CAS  PubMed  Google Scholar 

  17. Le HK, Graham L, Miller CH, Kmieciak M, Manjili MH, Bear HD (2009) Incubation of antigen-sensitized T lymphocytes activated with bryostatin 1 + ionomycin in IL-7 + IL-15 increases yield of cells capable of inducing regression of melanoma metastases compared to culture in IL-2. Cancer Immunol Immunother 58:1565–1576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6:1142–1151

    Article  CAS  PubMed  Google Scholar 

  19. Fontenot JD, Rudensky AY (2005) A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol 6:331–337

    Article  CAS  PubMed  Google Scholar 

  20. Oh S, Berzofsky JA, Burke DS, Waldmann TA, Perera LP (2003) Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity. Proc Natl Acad Sci USA 100:3392–3397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Waldmann TA (2006) The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 6:595–601

    Article  CAS  PubMed  Google Scholar 

  22. Waldmann TA, Dubois S, Tagaya Y (2001) Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity 14:105–110

    CAS  PubMed  Google Scholar 

  23. Refaeli Y, Van Parijs L, London CA, Tschopp J, Abbas AK (1998) Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity 8:615–623

    Article  CAS  PubMed  Google Scholar 

  24. Haux J, Johnsen AC, Steinkjer B, Egeberg K, Sundan A, Espevik T (1999) The role of interleukin-2 in regulating the sensitivity of natural killer cells for Fas-mediated apoptosis. Cancer Immunol Immunother 48:139–146

    Article  CAS  PubMed  Google Scholar 

  25. Klebanoff CA, Finkelstein SE, Surman DR, Lichtman MK, Gattinoni L, Theoret MR, Grewal N, Spiess PJ, Antony PA, Palmer DC, Tagaya Y, Rosenberg SA, Waldmann TA, Restifo NP (2004) IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc Natl Acad Sci USA 101:1969–1974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Klebanoff CA, Gattinoni L, Torabi-Parizi P, Kerstann K, Cardones AR, Finkelstein SE, Palmer DC, Antony PA, Hwang ST, Rosenberg SA, Waldmann TA, Restifo NP (2005) Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci USA 102:9571–9576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Melchionda F, Fry TJ, Milliron MJ, McKirdy MA, Tagaya Y, Mackall CL (2005) Adjuvant IL-7 or IL-15 overcomes immunodominance and improves survival of the CD8+ memory cell pool. J Clin Invest 115:1177–1187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gattinoni L, Klebanoff CA, Palmer DC, Wrzesinski C, Kerstann K, Yu Z, Finkelstein SE, Theoret MR, Rosenberg SA, Restifo NP (2005) Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8(+) T cells. J Clin Invest 115:1616–1626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Oh S, Perera LP, Burke DS, Waldmann TA, Berzofsky JA (2004) IL-15/IL-15Rα-mediated avidity maturation of memory CD8+ T cells. Proc Natl Acad Sci USA 101:15154–15159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chin CS, Graham LJ, Hamad GG, George KR, Bear HD (2001) Bryostatin/ionomycin-activated T cells mediate regression of established tumors. J Surg Res 98:108–115

    Article  CAS  PubMed  Google Scholar 

  31. Parviz M, Chin CS, Graham LJ, Miller C, Lee C, George K, Bear HD (2003) Successful adoptive immunotherapy with vaccine-sensitized T cells, despite no effect with vaccination alone in a weakly immunogenic tumor model. Cancer Immunol Immunother 52:739–750

    Article  CAS  PubMed  Google Scholar 

  32. Joshi NS, Kaech SM (2008) Effector CD8 T cell development: a balancing act between memory cell potential and terminal differentiation. J Immunol 180:1309–1315

    Article  CAS  PubMed  Google Scholar 

  33. Carrio R, Bathe OF, Malek TR (2004) Initial antigen encounter programs CD8+ T cells competent to develop into memory cells that are activated in an antigen-free, IL-7- and IL-15-rich environment. J Immunol 172:7315–7323

    Article  CAS  PubMed  Google Scholar 

  34. Gett AV, Sallusto F, Lanzavecchia A, Geginat J (2003) T cell fitness determined by signal strength. Nat Immunol 4:355–360

    Article  CAS  PubMed  Google Scholar 

  35. Lanzavecchia A, Sallusto F (2005) Understanding the generation and function of memory T cell subsets. Curr Opin Immunol 17:326–332

    Article  CAS  PubMed  Google Scholar 

  36. Keller AM, Borst J (2006) Control of peripheral T cell survival: a delicate division of labor between cytokines and costimulatory molecules. Hum Immunol 67:469–477

    Article  CAS  PubMed  Google Scholar 

  37. Sprent J, Cho JH, Boyman O, Surh CD (2008) T cell homeostasis. Immunol Cell Biol 86:312–319

    Article  CAS  PubMed  Google Scholar 

  38. Boyman O, Purton JF, Surh CD, Sprent J (2007) Cytokines and T-cell homeostasis. Curr Opin Immunol 19:320–326

    Article  CAS  PubMed  Google Scholar 

  39. Roychowdhury S, May KF Jr, Tzou KS, Lin T, Bhatt D, Freud AG, Guimond M, Ferketich AK, Liu Y, Caligiuri MA (2004) Failed adoptive immunotherapy with tumor-specific T cells: reversal with low-dose interleukin 15 but not low-dose interleukin 2. Cancer Res 64:8062–8067

    Article  CAS  PubMed  Google Scholar 

  40. Van PL, Refaeli Y, Lord JD, Nelson BH, Abbas AK, Baltimore D (1999) Uncoupling IL-2 signals that regulate T cell proliferation, survival, and Fas-mediated activation-induced cell death. Immunity 11:281–288

    Article  Google Scholar 

  41. Rolle CE, Carrio R, Malek TR (2008) Modeling the CD8+ T effector to memory transition in adoptive T-cell antitumor immunotherapy. Cancer Res 68:2984–2992

    Article  CAS  PubMed  Google Scholar 

  42. Liu S, Riley J, Rosenberg S, Parkhurst M (2006) Comparison of common gamma-chain cytokines, interleukin-2, interleukin-7, and interleukin-15 for the in vitro generation of human tumor-reactive T lymphocytes for adoptive cell transfer therapy. J Immunother 29:284–293

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Physiology and Biophysics, Virginia Commonwealth University’s Medical College of Virginia, Richmond, VA, USA

    Esther Cha

  2. Division of Surgical Oncology, Department of Surgery and the Massey Cancer Center, Virginia Commonwealth University’s Medical College of Virginia, Richmond, VA, USA

    Laura Graham

  3. Department of Microbiology and Immunology and the Massey Cancer Center, Virginia Commonwealth University’s Medical College of Virginia and the Massey Cancer Center, Richmond, VA, USA

    Masoud H. Manjili

  4. Division of Surgical Oncology, Department of Surgery and the Massey Cancer Center, Virginia Commonwealth University’s Medical College of Virginia, Box 980011, Richmond, VA, 23298-0011, USA

    Harry D. Bear

Authors
  1. Esther Cha
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  4. Harry D. Bear
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Correspondence to Harry D. Bear.

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Cha, E., Graham, L., Manjili, M.H. et al. IL-7 + IL-15 are superior to IL-2 for the ex vivo expansion of 4T1 mammary carcinoma-specific T cells with greater efficacy against tumors in vivo. Breast Cancer Res Treat 122, 359–369 (2010). https://doi.org/10.1007/s10549-009-0573-0

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  • DOI: https://doi.org/10.1007/s10549-009-0573-0

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