Targeting mitochondria in EOC to improve immunity

Document Type

Article

Publication Date

1-28-2024

Publication Title

Cancer Letters

Abstract

Immunosuppressive myeloid cells (CD11b+Gr1+) are a major constituent of the epithelial ovarian cancer (EOC) microenvironment that confer immunosuppression and promote tumor growth. We recently showed that the EOC microenvironment can induce metabolic reprogramming in CD11b+Gr1+ cells by increasing oxidative phosphorylation via TCA cycle, resulting in increased immunosuppressive ability. Increased TCA cycle activity was due to glutamine anaplerosis, which was facilitated by the upregulation of DLST (dihydrolipoamide succinyl transferase), the E2 transferase subunit of α-KGDC (alpha-ketoglutarate dehydrogenase complex). We selected CPI-613 (Devimistat), an orphan metabolic drug, being actively tested in clinical trials to target the α-KGDC complex. We utilized the syngeneic ID8p53-/- model, a high grade serous ovarian cancer, to determine if CPI-613 may regulate CD11b+Gr1+ cell metabolism and immunosuppressive function and restore an antitumor immune response that inhibits EOC. One week after inducing tumors, mice were treated with CPI-613 (2.5mg/kg body weight) twice a week by IP injections or with vehicle (corn oil, control). CPI-613 treated mice showed significantly improved overall survival (median survival 75 days versus 48 days in control), decreased tumor progression and burden. CPI-613 decreased the number of CD11b+Gr1+ myeloid cells in ascites, and more importantly, reduced the intracellular immunosuppressive markers arginase 1 and IL-1β, indicating that the immunosuppressive potential was diminished, which was also validated by reversal of T cell suppression by CPI-613. The alleviation of immunosuppression was complemented by remarkable increase in CD8+ T effector cells. Further, combination of CPI-613 with anti-PD1 (100ug/mice, every 5th day for 4 weeks) significantly improved survival and potentiated the CD8+ mediated anti-tumor response. CPI-613 inhibited expression of DLST and immunosuppressive markers in the CD11b+Gr1+ myeloid cells, accompanied by decreased oxidative phosphorylation and decreased glutamine anaplerosis. Interestingly CPI-613 treatment also decreased the tumor associated macrophages, increased the M1 marker CD38 and decreased M2 marker EGR2, which reflected in increased M1/M2 macrophage ratio. Increased glutamine demand and addiction have been shown in variety of cancers, including EOC. We found that DLST expression correlates with worse progression free survival in the ovarian cancer TCGA dataset, implying that DLST is important in EOC cells. As a result, DLST targeting of aberrant glutamine metabolism will have the dual benefit of reducing CD11b+Gr1+ cell-mediated immunosuppression while also directly inhibiting tumor growth. Thus CPI-613 represents an attractive drug to target glutamine addiction and reduce immunosuppressive environment plaguing ovarian cancer. The authors have declared no conflicts of interest.

Volume

581

First Page

216563

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