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

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.

• Authors: Asa Andersson, Minu K Srivastava, Marni Harris-White, Min Huang, Li Zhu, David Elashoff, Robert M Strieter, Steven M Dubinett, Sherven Sharma
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 11 Pg. 3660-72 (Jun 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21636553 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2011 AACR.

Chemical References

• Chemokine CXCL10
• Chemokine CXCL9
• Cxcl10 protein, mouse
• Cxcl9 protein, mouse
• Cxcr3 protein, mouse
• Immunoglobulin Fc Fragments
• Interleukin-7
• Receptors, CXCR3
• Receptors, Interleukin-7
• interleukin-7 receptor, alpha chain
• Interferon-gamma

Topics

• Animals
• Antigen-Presenting Cells (immunology)
• Cell Line, Tumor
• Cell Proliferation
• Chemokine CXCL10 (antagonists & inhibitors, biosynthesis)
• Chemokine CXCL9 (antagonists & inhibitors, biosynthesis)
• Immunoglobulin Fc Fragments (immunology)
• Interferon-gamma (antagonists & inhibitors, biosynthesis)
• Interleukin-7 (metabolism)
• Lung Neoplasms (immunology, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Receptors, CXCR3 (metabolism)
• Receptors, Interleukin-7 (metabolism)
• Signal Transduction (immunology)
• T-Lymphocytes (immunology)