Search for a command to run...
Activation and differentiation of adaptive and innate immune cells require metabolic reprogramming involving diverse metabolic processes. Understanding these processes affords the opportunity to influence and ultimately re-direct the function and fate of these cells. Here, we present data suggesting that exposure of newly activated human CD8+ T cells to a small molecule inhibitor (ERG245; 50-400 μM) of BCAT1 (the cytosolic isoform of the enzyme responsible for the first step in the catabolism of leucine, isoleucine, and valine) resulted in inhibition of T cell proliferation, inhibition of IFNγ and Granzyme B production, and upregulation of PD-1. The antiproliferative effect, as determined by CFSE dilution, required inhibition of BCAT1 during the first 24 hrs of T cell activation and it was reversible upon early withdrawal of the inhibitor. Early withdrawal of ERG245 reversed the observed immunosuppression, ultimately giving rise to CD8+ T cells with higher proliferative capacity and increased cytotoxicity compared to untreated control cells. Exposure of CD8+ T cells to ERG245 resulted in a distinct metabolic phenotype including reduced concentrations of α-ketoglutaric acid (αKG), and lower levels of trimethylation of the lysine 4 (K4) and lysine 27 (K27) sites of histone 3 (H3), which implies that BCAT1 inhibition has epigenetic effects on human CD8+ T cells by modulating αKG-dependent histone demethylases. Similar observations were made with CD8+ T cells, isolated from the spleens of Bcat1 KO mice. In vivo, ERG245 (given at 5 mg/kg ip, bid at days 0, 1 and 2 of treatment), dramatically increased the efficacy of an anti-PD-1 antibody (clone RMP1-14; given at 10 mg/kg at days 0, 4, 7, and 11 of treatment) in the CT26 colon cancer model. Specifically, the combination of ERG245 and anti-PD-1 eradicated established tumors within a week of treatment initiation (cure rate of >80%), whereas the monotherapies (ERG245 or anti-PD-1 alone) did not improve the disease outcome. The data suggest that the temporal exposure of moderately immunogenic tumors to BCAT1 inhibition sensitizes the tumors to checkpoint inhibition.Citation Format: Adonia E. Papathanassiu, Dong-Wook Kim, Kwon-Sik Park, Jeong Hun Ko, Jacques V. Behmoaras. Immunotuning CD8+ T cells with BCAT1 inhibition to increase the efficacy of anti-PD-1 therapy and to eradicate moderately immunogenic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3200.