Browse > Article
http://dx.doi.org/10.7314/APJCP.2014.15.1.265

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)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.15, no.1, 2014 , pp. 265-271 More about this Journal
Abstract
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.
Keywords
Interleukin-7; breast cancer; $CD8^+$ T cells; IFN-${\gamma}$; anti-tumor activity;
Citations & Related Records
연도 인용수 순위
  • Reference
1 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.   DOI
2 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.   DOI
3 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.   DOI
4 Yang H, Spencer AU, Teitelbaum DH (2005). Interleukin-7 administration alters intestinal intraepithelial lymphocyte phenotype and function in vivo. Cytokine, 31, 419-28.   DOI
5 Zaidi MR, Merlino G (2011). The two faces of interferon-gamma in cancer. Clin Cancer Res, 17, 6118-24.   DOI
6 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.   DOI
7 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.   DOI
8 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.   DOI
9 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.   DOI
10 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.
11 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.   DOI
12 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.   DOI
13 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.
14 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.   DOI   ScienceOn
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.   DOI
16 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.
17 Lee S, Margolin K (2011). Cytokines in cancer immunotherapy. Cancers, 3, 3856-93.   DOI   ScienceOn
18 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.   DOI
19 Lo CH, Lee SC, Wu PY, et al (2003). Antitumor and antimetastatic activity of IL-23. J Immunol, 171, 600-7.   DOI
20 Lundstrom W, Fewkes NM, Mackall CL (2012). IL-7 in human health and disease. Semin Immunol, 24, 218-24.   DOI
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.   DOI   ScienceOn
22 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.   DOI
23 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.   DOI
24 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.   DOI
25 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.   DOI
26 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.   DOI
27 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.   DOI
28 Appasamy PM (1999). Biological and clinical implications of interleukin-7 and lymphopoiesis. Cytokines Cell Mol Ther, 5, 25-39.
29 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.   DOI
30 Fry TJ, Mackall CL (2002). Interleukin-7: from bench to clinic. Blood, 99, 3892-904.   DOI   ScienceOn
31 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.   DOI
32 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.   DOI
33 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.   DOI
34 Klebanoff CA, Gattinoni L, Restifo NP (2006). $CD8^+$ T-cell memory in tumor immunology and immunotherapy. Immunol Rev, 211, 214-24.   DOI   ScienceOn
35 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.
36 Anderson RJ, Schneider J (2007). Plasmid DNA and viral vector-based vaccines for the treatment of cancer. Vaccine, 25, B24-34.   DOI