MEIS2 Modulates Oxidative Phosphorylation and ROS Generation to Affect CD8 T Cell Antitumor Immunity in Prostate Cancer.

[BACKGROUND] The response of prostate cancer (PCa) to immunotherapy remains suboptimal. Although MEIS homeobox 2 (MEIS2) has been shown to delay the malignant progression of PCa by inhibiting cancer cell proliferation, promoting DNA damage, and affecting CD8 T cell immune surveillance, its role in immune regulation and the underlying mechanisms remain elusive.

[METHODS] MEIS2 expression in PCa and its correlation with CD8 T cells were characterized using bioinformatics analysis and cell experiments. Using qPCR, flow cytometry, and ELISA, the impact of MEIS2 on CD8 T cell antitumor immunity was assessed. To delineate the role of MEIS2 in oxidative phosphorylation and ROS generation, OCR, ATP, and ROS measurements were collected. Finally, the oxidative phosphorylation inhibitor MCH32 was introduced and rescue experiments were conducted to elucidate the mechanism by which MEIS2 regulated CD8 T cell cytotoxicity.

[RESULTS] MEIS2 expression in PCa was found to be downregulated, positively correlating with CD8 T cell infiltration. Functionally, MEIS2 overexpression enhanced the cytotoxicity of CD8 T cells. Mechanistically, MEIS2 was notably enriched in oxidative phosphorylation and ROS pathways. Knockdown of MEIS2 in cancer cells stimulated oxidative phosphorylation and ROS production, which impaired CD8 T cell antitumor immunity. Treatment with the oxidative phosphorylation inhibitor MCH32 reversed these effects induced by MEIS2 knockdown.

[CONCLUSION] Targeting MEIS2 could represent a clinically relevant approach to enhancing CD8 T cell antitumor efficacy in PCa, our findings indicate.