Deciphering the metabolic regulation of immunosuppressive CD11b+Gr1+ myeloid cells in epithelial ovarian cancer.

Immunosuppressive CD11b⁺Gr1⁺ myeloid cells are key drivers of immunosuppression and decrease immunotherapy efficacy in epithelial ovarian cancer (EOC). We showed that EOC enhances CD11b⁺Gr1⁺ myeloid cell immunosuppression capacity by upregulating αKGDC (ketoglutarate dehydrogenase complex) expression, resulting in increased TCA cycle- glutamine anaplerosis causing enhanced oxidative phosphorylation (OXPHOS), increased immunosuppression markers and T cell suppression. Inhibition of TCA-glutamine anaplerosis by CPI-613 decreased OXPHOS and CD11b⁺Gr1⁺ immunosuppressive ability resulting in restored anti-tumor T cell response and inhibition of EOC. Targeted metabolomics of CPI-613 treated CD11b⁺Gr1⁺ cells showed a profound decrease in TCA metabolite α-ketoglutarate (αKG). Among all TCA metabolites, only αKG supplementation reversed the OXPHOS inhibition, T cell immunosuppression by CPI-613 and increased immunosuppressive markers in ex-vivo conditions. In vivo treatment of αKG alone replicated the ex-vivo effect and enhanced CD11b⁺Gr1⁺ myeloid cell OXPHOS and immunosuppressive ability but did not affect survival. In combination with CPI-613, αKG was able to reverse the inhibitory effect of CPI-613 on immunosuppression, OXPHOS and decreased survival. Our study shows that αKG generated by TCA- glutamine anaplerosis is crucial for supporting an immunosuppressive phenotype of CD11b⁺Gr1⁺ myeloid cells in EOC, and targeting αKG may enhance anti-tumor immune responses.