c-Src Suppresses Dendritic Cell Antitumor Activity via T Cell Ig and Mucin Protein-3 Receptor.

Gujar, Ravindra and Maurya, Neeraj and Yadav, Vinod and Gupta, Mamta and Arora, Saurabh and Khatri, Neeraj and Sen, Pradip (2016) c-Src Suppresses Dendritic Cell Antitumor Activity via T Cell Ig and Mucin Protein-3 Receptor. Journal of immunology (Baltimore, Md. : 1950), 197 (5). pp. 1650-62. ISSN 1550-6606

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Abstract

The enhanced expression of T cell Ig and mucin protein-3 (TIM-3) on tumor-associated dendritic cells (DCs) attenuates antitumor effects of DNA vaccines. To identify a potential target (or targets) for reducing TIM-3 expression on tumor-associated DCs, we explored the molecular mechanisms regulating TIM-3 expression. In this study, we have identified a novel signaling pathway (c-Src→Bruton's tyrosine kinase→transcription factors Ets1, Ets2, USF1, and USF2) necessary for TIM-3 upregulation on DCs. Both IL-10 and TGF-β, which are produced in the tumor microenvironment, upregulated TIM-3 expression on DCs via this pathway. Suppressed expression of c-Src or downstream Bruton's tyrosine kinase, Ets1, Ets2, USF1, or USF2 blocked IL-10- and TGF-β-induced TIM-3 upregulation on DCs. Notably, in vivo knockdown of c-Src in mice reduced TIM-3 expression on tumor-associated DCs. Furthermore, adoptive transfer of c-Src-silenced DCs in mouse tumors enhanced the in vivo antitumor effects of immunostimulatory CpG DNA; however, TIM-3 overexpression in c-Src-silenced DCs blocked this effect. Collectively, our data reveal the molecular mechanism regulating TIM-3 expression in DCs and identify c-Src as a target for improving the efficacy of nucleic acid-mediated anticancer therapy.

Item Type:	Article
Additional Information:	Copyright of this article belongs to American Association of Immunologists.
Subjects:	Q Science > QR Microbiology > QR180 Immunology
Depositing User:	Dr. K.P.S.Sengar
Date Deposited:	29 Sep 2016 10:40
Last Modified:	29 Sep 2016 10:40
URI:	http://crdd.osdd.net/open/id/eprint/1868

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