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Clin Cancer Res. 2011 Jun 1;17(11):3660-72. doi: 10.1158/1078-0432.CCR-10-3346.

Role of CXCR3 ligands in IL-7/IL-7R alpha-Fc-mediated antitumor activity in lung cancer.

Author information

1
Department of Medicine, UCLA Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA , California, USA.

Abstract

PURPOSE:

We evaluated the utility of chimeric γc homeostatic cytokine, IL-7/IL-7Rα-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-7Rα-Fc. APC, T cell, cytokine analyses, neutralization of CXCL9, CXCL10, and IFNγ were carried out to evaluate the mechanistic differences in the antitumor activity of IL-7/IL-7Rα-Fc in comparison to controls.

RESULTS:

IL-7/IL-7Rα-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-7Rα-Fc treatment of tumor bearing mice led to increased: (i) levels of CXCL9, CXCL10, IFNγ, IL-12 but reduced IL-10 and TGFβ, (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-7Rα-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-7Rα-Fc-mediated antitumor activity. Neutralization of CXCL9, CXCL10, or IFNγ reduced CXCR3 expressing activated T cells infiltrating the tumor and abrogated IL-7/IL-7Rα-Fc-mediated tumor growth inhibition.

CONCLUSIONS:

Our findings show that IL-7/IL-7Rα-Fc promotes afferent and efferent antitumor responses in lung cancer.

PMID:
21636553
PMCID:
PMC3118413
DOI:
10.1158/1078-0432.CCR-10-3346
[Indexed for MEDLINE]
Free PMC Article
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