Role of CXCR3 Ligands in IL-7/IL-7Rα-Fc-Mediated Antitumor Activity in Lung Cancer

Purpose: We evaluated the utility of chimeric gamma c homeostatic cytokine, IL-7/IL-7R alpha-Fc, to restore host APC (antigen presenting cell) and T cell activities in lung cancer. Experimental Design: Utilizing murine lung cancer models we determined the antitumor efficacy of IL-7/IL-7R alpha-Fc. APC, T cell, cytokine analyses, neutralization of CXCL9, CXCL10, and IFN gamma were carried out to evaluate the mechanistic differences in the antitumor activity of IL-7/IL-7R alpha-Fc in comparison to controls. Results: IL-7/IL-7R alpha-Fc administration inhibited tumor growth and increased survival in lung cancer. Accompanying the tumor growth inhibition were increases in APC and T cell activities. In comparison to controls, IL-7/IL-7R alpha-Fc treatment of tumor bearing mice led to increased: (i) levels of CXCL9, CXCL10, IFN gamma, IL-12 but reduced IL-10 and TGF beta, (ii) tumor macrophage infiltrates characteristic of M1 phenotype with increased IL-12, iNOS but reduced IL-10 and arginase, (iii) frequencies of T and NK cells, (iv) T cell activation markers CXCR3, CD69 and CD127(low), (v) effector memory T cells, and (vi) T cell cytolytic activity against parental tumor cells. IL-7/IL-7R alpha-Fc treatment abrogated the tumor induced reduction in splenic functional APC activity to T responder cells. The CXCR3 ligands played an important role in IL-7/IL-7R alpha-Fc-mediated antitumor activity. Neutralization of CXCL9, CXCL10, or IFN gamma reduced CXCR3 expressing activated T cells infiltrating the tumor and abrogated IL-7/IL-7R alpha-Fc-mediated tumor growth inhibition. Conclusions: Our findings show that IL-7/IL-7R alpha-Fc promotes afferent and efferent antitumor responses in lung cancer. Clin Cancer Res; 17(11); 3660-72. (C)2011 AACR.