Enhanced Antitumor Immunity by a Peptide Improving Mitochondrial Quality in Dendritic Cells 2258813

Abstract

Abstract Introduction Cancer is one of the leading causes of death worldwide and poses significant challenges in treatment. Although conventional immunotherapy mainly focuses on CD8+ T cells to eliminate cancer, targeting other immune cells is emerging as a strategy to overcome its limited efficacy. Dendritic cells (DCs), key regulators of antitumor T cell responses, rely on mitochondria to maintain their immunological function. However, within the tumor microenvironment, DCs exhibit functional impairment associated with mitochondrial dysfunction. Recent evidence highlights the therapeutic potential of regulating mitochondrial quality in immune cells; yet this approach remains largely unexplored in DCs. Therefore, we developed a mitochondria-modulating peptide (MMP) to enhance mitochondria function in DCs and antitumor immunity. Methods Vehicle- or MMP-treated BMDCs were analyzed in vitro using qRT-PCR, Seahorse assay, ELISA, and flow cytometry. BMDCs were then co-cultured with T cells in the presence of polarizing cytokines to assess DC-mediated effects on T cells. For in vivo study, B16F10 cells were injected subcutaneously into mice, followed by intraperitoneal MMP administration. Tumor-infiltrating lymphocytes were analyzed by flow cytometry. Results Treatment with MMP restored the mitochondrial function of BMDCs in vitro. Moreover, MMP-treated DCs exhibited antitumoral characteristics, including increased antigen uptake, reduced expression of PD-L1 and iNOS, and decreased pro-tumor cytokines production. Consistent with these changes, co-culture of T cells resulted in increased Th1 differentiation, reduced Foxp3+ Treg differentiation, and enhanced proliferation and cytotoxicity of CD8+ T cells. In vivo, MMP administration suppressed tumor progression in the B16F10 melanoma model. Conclusion Improving mitochondrial quality in DCs using a peptide-drug reinvigorates antitumor immune responses. These results suggest that targeting mitochondrial activity in DCs can be a promising strategy for cancer treatment. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)