title: c-Src Suppresses Dendritic Cell Antitumor Activity via T Cell Ig and Mucin Protein-3 Receptor.
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.
authors.affiliation: Division of Cell Biology and Immunology, Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Gujar
authors.affiliation: Division of Cell Biology and Immunology, Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Maurya
authors.affiliation: Division of Cell Biology and Immunology, Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and.
authors.forename: Vinod
authors.identifier: 0000-0003-0038-4617
authors.initials: V
authors.lastname: Yadav
authors.affiliation: Division of Cell Biology and Immunology, Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and.
authors.forename: Mamta
authors.initials: M
authors.lastname: Gupta
authors.affiliation: Division of Cell Biology and Immunology, Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Arora
authors.affiliation: Division of Animal Facility, Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Khatri
authors.affiliation: Division of Cell Biology and Immunology, Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and psen@imtech.res.in.
authors.forename: Pradip
authors.initials: P
authors.lastname: Sen
mesh_terms: D019264:Adoptive Transfer; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D016391:Genes, src; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C408982:CPG-oligonucleotide; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D009838:Oligodeoxyribonucleotides; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases