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IL-7 Promotes CXCR3 Ligand-Dependent T Cell Antitumor Reactivity in Lung Cancer¹

Åsa Andersson^*, Seok-Chul Yang, Min Huang^*,,, Li Zhu^*,,, Upendra K. Kar^*, Raj K. Batra^*,,, David Elashoff^*, Robert M. Strieter^¶, Steven M. Dubinett^*,, and Sherven Sharma^2,*,,

^* Department of Medicine, University of California Los Angeles Lung Cancer Research Program and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; Department of Medicine, Division of Pulmonary and Critical Care Medicine, Seoul National University Hospital, Seoul, Korea; Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073; and ^¶ Department of Medicine, Division of Cardiology and Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA 22903

We are evaluating the immune enhancing activities of cytokines for their optimum utility in augmenting cellular immune responses against lung cancer. In this study, we evaluated the mechanism of antitumor responses following IL-7 administration to mice bearing established Lewis lung cancer. IL-7 decreased tumor burden with concomitant increases in the frequency of CD4 and CD8 T lymphocyte subsets, T cell activation markers CXCR3, CD69, and CD127^low, effector memory T cells, and T cell cytolytic activity against parental tumor cells. Accompanying the antitumor responses were increases in IFN-, CXCL9, CXCL10, and IL-12. Individual neutralization of CD4, CD8 T lymphocytes, or the CXCR3 ligands CXCL9 and CXCL10 reversed the antitumor benefit of IL-7, indicating their importance for optimal responses in vivo. Furthermore, IL-7 decreased the tumor-induced apoptosis of T cells with subsequent decrease of the proapoptotic marker Bim. We assessed the impact of IL-7 treatment on regulatory T cells that negatively impact antitumor immune responses. IL-7 decreased regulatory T Foxp3 as well as cell suppressive activity with a reciprocal increase in SMAD7. These results indicate that IL-7 induces CXCR3 ligand-dependent T cell antitumor reactivity in lung cancer.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 CA85686 and R01 CA126944 and University of California Los Angeles Lung Cancer SPORE P50 CA90388, Department of Veteran Affairs Medical Research Funds, and Tobacco Related Disease Program Award Program of the University of California.

² Address correspondence and reprint requests to Dr. Sherven Sharma, Division of Pulmonary and Critical Care Medicine, University of California Los Angeles lung Cancer Program, 10833 Le Conte Avenue, Los Angeles, CA 90095-1690. E-mail address: ssharma{at}mednet.ucla.edu

³ Abbreviations used in this paper: LN, lymph node; Treg, regulatory T; QPCR, quantitative PCR.