By analyzing RNAseq data for 22 human melanoma samples, Zappasodi et al. showed that an inverse correlation of markers of tumor glycolysis and tumor-infiltrating immune cells was mostly alleviated by anti-CTLA-4 therapy. In mice, tumors engineered to be defective in glycolysis responded better to anti-CTLA-4 therapy. Post treatment, mice exhibited CD8+ T cells that mediated enhanced specific primary and recall antitumor responses, along with intratumoral CD25lo and/or CTLA-4loFoxP3+ Tregs that produced IFNγ and TNFα. In vitro, direct CD28 signalling similarly altered Tregs and CTLA-4 blockade (but not PD-1 inhibition), reduced suppression by Tregs, and boosted glucose uptake by Tregs.
Contributed by Paula Hochman
ABSTRACT: Limiting the metabolic competition in the tumor microenvironment (TME) may increase the effectiveness of immunotherapy. Because of its critical role in glucose metabolism of activated T cells, CD28 signaling has been proposed as a T-cell metabolic biosensor(1). Conversely, CTLA-4 engagement has been shown to down-regulate T-cell glycolysis(1). Here, we investigated the impact of CTLA-4 blockade on the metabolic fitness of intra-tumor T cells in relationship to the tumor glycolytic capacity. We found that CTLA-4 blockade promotes immune cell infiltration and metabolic fitness especially in glycolysis-low tumors. Accordingly, anti-CTLA-4 achieved better therapeutic outcomes in mice bearing glycolysis-defective tumors. Intriguingly, tumor-specific CD8(+) T-cell responses correlated with phenotypic and functional destabilization of tumor-infiltrating regulatory T cells (Tregs) toward IFN-_- and TNF-_-producing cells in glycolysis-defective tumors. By mimicking the highly and poorly glycolytic TME in vitro, we show that the effect of CTLA-4 blockade to promote Treg destabilization is dependent on Treg glycolysis and CD28 signaling. These findings indicate that decreasing tumor competition for glucose may facilitate the therapeutic activity of CTLA-4 blockade, thus supporting its combination with inhibitors of tumor glycolysis. Moreover, these results reveal a new mechanism through which anti-CTLA-4 interferes with Treg function in the presence of glucose.
