Asian Pacific Journal of Cancer Prevention

  • 제15권1호
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  • Pages.265-271
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  • 2014
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  • 1513-7368(pISSN)
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  • 2476-762X(eISSN)
아시아태평양암예방학회 (Asian Pacific Journal of Cancer Prevention)
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Interleukin-7 Enhances the in Vivo Anti-tumor Activity of Tumor-reactive CD8+ T cells with Induction of IFN-gamma in a Murine Breast Cancer Model

  • Yuan, Chun-Hui (Department of Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University) ;
  • Yang, Xue-Qin (Medical School of Jingchu University of Technology) ;
  • Zhu, Cheng-Liang (Department of Laboratory Medicine, Renmin Hospital of Wuhan University) ;
  • Liu, Shao-Ping (Hubei Key Laboratory of Tumor Biological Behavior & Hubei Cancer Clinical Study Center) ;
  • Wang, Bi-Cheng (Department of Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University) ;
  • Wang, Fu-Bing (Department of Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University)
  • 발행 : 2014.01.15
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초록

Interleukin-7 (IL-7) is a potent anti-apoptotic cytokine that enhances immune effector cell functions and is essential for lymphocyte survival. While it known to induce differentiation and proliferation in some haematological malignancies, including certain types of leukaemias and lymphomas, little is known about its role in solid tumours, including breast cancer. In the current study, we investigated whether IL-7 could enhance the in vivo antitumor activity of tumor-reactive $CD8^+$ T cells with induction of IFN-${\gamma}$ in a murine breast cancer model. Human IL-7 cDNA was constructed into the eukaryotic expression plasmid pcDNA3.1, and then the recombinational pcDNA3.1-IL-7 was intratumorally injected in the TM40D BALB/C mouse graft model. Serum and intracellular IFN-${\gamma}$ levels were measured by ELISA and flow cytometry, respectively. $CD8^+$ T cell-mediated cytotoxicity was analyzed using the MTT method. Our results showed that IL-7 administration significantly inhibited tumor growth from day 15 after direct intratumoral injection of pcDNA3.1-IL-7. The anti-tumor effect correlated with a marked increase in the level of IFN-${\gamma}$ and breast cancer cells-specific CTL cytotoxicity. In vitro cytotoxicity assays showed that IL-7-treatment could augment cytolytic activity of $CD8^+$ T cells from tumor bearing mice, while anti-IFN-${\gamma}$ blocked the function of $CD8^+$ T cells, suggesting that IFN-${\gamma}$ mediated the cytolytic activity of $CD8^+$ T cells. Furthermore, in vivo neutralization of $CD8^+$ T lymphocytes by CD8 antibodies reversed the antitumor benefit of IL-7. Thus, we demonstrated that IL-7 exerts anti-tumor activity mainly through activating $CD8^+$ T cells and stimulating them to secrete IFN-${\gamma}$ in a murine breast tumor model. Based on these results, our study points to a potential novel way to treat breast cancer and may have important implications for clinical immunotherapy.

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참고문헌

  1. Anderson RJ, Schneider J (2007). Plasmid DNA and viral vector-based vaccines for the treatment of cancer. Vaccine, 25, B24-34. https://doi.org/10.1016/j.vaccine.2007.05.030
  2. Andersson A, Yang SC, Huang M, et al (2009). IL-7 promotes CXCR3 ligand-dependent T cell antitumor reactivity in lung cancer. J Immunol, 182, 6951-8. https://doi.org/10.4049/jimmunol.0803340
  3. Appasamy PM (1999). Biological and clinical implications of interleukin-7 and lymphopoiesis. Cytokines Cell Mol Ther, 5, 25-39.
  4. Ferrari G, King K, Rathbun K, et al (1995). IL-7 enhancement of antigen-driven activation/expansion of HIV-1-specific cytotoxic T lymphocyte precursors (CTLp). Clin Exp Immunol, 101, 239-48. https://doi.org/10.1111/j.1365-2249.1995.tb08345.x
  5. Finke S, Trojaneck B, Lefterova P, et al (1998). Increase of proliferation rate and enhancement of antitumor cytotoxicity of expanded human $CD3^+$ $CD56^+$ immunologic effector cells by receptor-mediated transfection with the interleukin-7 gene. Gene Ther, 5, 31-9. https://doi.org/10.1038/sj.gt.3300560
  6. Fry TJ, Mackall CL (2002). Interleukin-7: from bench to clinic. Blood, 99, 3892-904. https://doi.org/10.1182/blood.V99.11.3892
  7. Geiselhart LA, Humphries CA, Gregorio TA, et al (2001). IL-7 administration alters the CD4:CD8 ratio, increases T cell numbers, and increases T cell function in the absence of activation. J Immunol, 166, 3019-27. https://doi.org/10.4049/jimmunol.166.5.3019
  8. Jicha DL, Mule JJ, Rosenberg SA (1991). Interleukin-7 generates antitumor cytotoxic T lymphocytes against murine sarcomas with efficacy in cellular adoptive immunotherapy. J Exp Med, 174, 1511-5. https://doi.org/10.1084/jem.174.6.1511
  9. Klebanoff CA, Finkelstein SE, Surman DR, et al (2004). IL-15 enhances the in vivo antitumor activity of tumor-reactive $CD8^{+}$ T cells. PNAS, 101, 1969-74. https://doi.org/10.1073/pnas.0307298101
  10. Klebanoff CA, Gattinoni L, Restifo NP (2006). $CD8^+$ T-cell memory in tumor immunology and immunotherapy. Immunol Rev, 211, 214-24. https://doi.org/10.1111/j.0105-2896.2006.00391.x
  11. Krawczenko A, Kieda C and Duś D (2005). The biological role and potential therapeutic application of interleukin-7. Arch Immunol Ther Exp (Warsz), 53, 518-25.
  12. Lai L, Jin J, Goldschneider I (2011). In vivo antitumor activity of a recombinant IL-7/HGFbeta hybrid cytokine in mice. Cancer Res, 71, 61-7.
  13. Lee S, Margolin K (2011). Cytokines in cancer immunotherapy. Cancers, 3, 3856-93. https://doi.org/10.3390/cancers3043856
  14. Li B, VanRoey MJ, Jooss K (2007). Recombinant IL-7 enhances the potency of GM-CSF-secreting tumor cell immunotherapy. Clin Immunol, 123, 155-65. https://doi.org/10.1016/j.clim.2007.01.002
  15. Liu S, Lizee G, Lou Y, et al (2007). IL-21 synergizes with IL-7 to augment expansion and anti-tumor function of cytotoxic T cells. Int Immunol, 19, 1213-21. https://doi.org/10.1093/intimm/dxm093
  16. Lo CH, Lee SC, Wu PY, et al (2003). Antitumor and antimetastatic activity of IL-23. J Immunol, 171, 600-7. https://doi.org/10.4049/jimmunol.171.2.600
  17. Lundstrom W, Fewkes NM, Mackall CL (2012). IL-7 in human health and disease. Semin Immunol, 24, 218-24. https://doi.org/10.1016/j.smim.2012.02.005
  18. Lynch DH, Miller RE (1994). Interleukin-7 promotes long-term in vitro growth of antitumor cytotoxic T lymphocytes with immunotherapeutic efficacy in vivo. J Exp Med, 179, 31-42. https://doi.org/10.1084/jem.179.1.31
  19. Murphy WJ, Back TC, Conlon KC, et al (1993). Antitumor effects of interleukin-7 and adoptive immunotherapy on human colon carcinoma xenografts. J Clin Invest, 92, 1918-24. https://doi.org/10.1172/JCI116785
  20. Pellegrini M, Calzascia T, Elford AR, et al (2009). Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nat Med, 15, 528-36. https://doi.org/10.1038/nm.1953
  21. Pellegrini M, Calzascia T, Toe JG, et al (2011). IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell, 144, 601-13. https://doi.org/10.1016/j.cell.2011.01.011
  22. Pellegrini M, Mak TW (2010). Tumor immune therapy: lessons from infection and implications for cancer-can IL-7 help overcome immune inhibitory networks? Eur J Immunol, 40, 1852-61. https://doi.org/10.1002/eji.201040603
  23. Roato I, Brunetti G, Gorassini E, et al (2006). IL-7 up-regulates TNF-alpha-dependent osteoclastogenesis in patients affected by solid tumor. PLoS One, 1, e124. https://doi.org/10.1371/journal.pone.0000124
  24. Rosenberg SA, Sportes C, Ahmadzadeh M, et al (2006). IL-7 administration to humans leads to expansion of $CD4^+$ and $CD8^+$ cells but a relative decrease of $CD4^+$ T-regulatory cells. J Immunother, 29, 313-9. https://doi.org/10.1097/01.cji.0000210386.55951.c2
  25. Rubinstein MP, Lind NA, Purton JF, et al (2008). IL-7 and IL-15 differentially regulate $CD8^+$ T-cell subsets during contraction of the immune response. Blood, 112, 3704-12. https://doi.org/10.1182/blood-2008-06-160945
  26. Sharma S, Batra RK, Yang SC, et al (2003). Interleukin-7 genemodified dendritic cells reduce pulmonary tumor burden in spontaneous murine bronchoalveolar cell carcinoma. Hum Gene Ther, 14, 1511-24. https://doi.org/10.1089/104303403322495025
  27. Sharma S, Wang J, Huang M, et al (1996). Interleukin-7 gene transfer in non-small-cell lung cancer decreases tumor proliferation, modifies cell surface molecule expression, and enhances antitumor reactivity. Cancer Gene Ther, 3, 302-13.
  28. Strengell M, Matikainen S, Siren J, et al (2003). IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells. J Immunol, 170, 5464-9. https://doi.org/10.4049/jimmunol.170.11.5464
  29. Tanaka H, Yoshizawa H, Yamaguchi Y, et al (1999). Successful adoptive immunotherapy of murine poorly immunogenic tumor with specific effector cells generated from genemodified tumor-primed lymph node cells. J Immunol, 162, 3574-82.
  30. Terabe M, Park JM, Berzofsky JA (2004). Role of IL-13 in regulation of anti-tumor immunity and tumor growth. Cancer Immunol Immunother, 53, 79-85. https://doi.org/10.1007/s00262-003-0445-0
  31. Unsinger J, McGlynn M, Kasten KR, et al (2010). IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol, 184, 3768-79. https://doi.org/10.4049/jimmunol.0903151
  32. Verhoeyen E, Dardalhon V, Ducrey-Rundquist O, et al (2003). IL-7 surface-engineered lentiviral vectors promote survival and efficient gene transfer in resting primary T lymphocytes. Blood, 101, 2167-74. https://doi.org/10.1182/blood-2002-07-2224
  33. Vudattu NK, Magalhaes I, Schmidt M, et al (2007). Reduced numbers of IL-7 receptor (CD127) expressing immune cells and IL-7-signaling defects in peripheral blood from patients with breast cancer. Int J Cancer, 121, 1512-9. https://doi.org/10.1002/ijc.22854
  34. Wu B, Shen RN, Wang WX, et al (1993). Antitumor effect of interleukin 7 in combination with local hyperthermia in mice bearing B16a melanoma cells. Stem Cells, 11, 412-21. https://doi.org/10.1002/stem.5530110508
  35. Yang H, Spencer AU, Teitelbaum DH (2005). Interleukin-7 administration alters intestinal intraepithelial lymphocyte phenotype and function in vivo. Cytokine, 31, 419-28. https://doi.org/10.1016/j.cyto.2005.06.014
  36. Zaidi MR, Merlino G (2011). The two faces of interferon-gamma in cancer. Clin Cancer Res, 17, 6118-24. https://doi.org/10.1158/1078-0432.CCR-11-0482

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