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c-Src Suppresses Dendritic Cell Antitumor Activity via T Cell Ig and Mucin Protein-3 Receptor
Ravindra Gujar1, Neeraj Maurya1, Vinod Yadav1
1Division of Cell Biology and Immunology, Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and.
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.
Insights
Researchers identified a new signaling pathway controlling TIM-3 expression on dendritic cells. Targeting c-Src may improve DNA vaccine efficacy against cancer by reducing TIM-3 levels.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- Tumor-associated dendritic cells (DCs) express T cell Ig and mucin protein-3 (TIM-3), which inhibits antitumor immune responses.
- Enhanced TIM-3 expression on DCs can limit the effectiveness of DNA vaccines and other immunotherapies.
Purpose of the Study:
- To elucidate the molecular mechanisms regulating TIM-3 expression on tumor-associated DCs.
- To identify potential therapeutic targets for enhancing anticancer immunity.
Main Methods:
- Investigated the signaling pathway controlling TIM-3 upregulation on DCs.
- Utilized in vitro and in vivo models, including gene silencing (knockdown) of key pathway components.
- Assessed the impact of modulating TIM-3 expression on DC function and antitumor responses in mice.
Main Results:
- Identified a novel signaling pathway: c-Src→Bruton's tyrosine kinase→Ets1/Ets2/USF1/USF2, crucial for TIM-3 upregulation.
- Demonstrated that IL-10 and TGF-β from the tumor microenvironment induce TIM-3 expression via this pathway.
- Showed that in vivo knockdown of c-Src reduces TIM-3 on tumor-associated DCs and enhances the efficacy of CpG DNA immunotherapy.
Conclusions:
- The c-Src signaling pathway is a key regulator of TIM-3 expression in DCs.
- Targeting c-Src offers a promising strategy to overcome TIM-3-mediated immunosuppression.
- Modulating c-Src and TIM-3 expression can improve the effectiveness of nucleic acid-based cancer therapies.
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