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.
Author Info: (1) Ludwig Collaborative and Swim Across America Laboratory, MSK, New York, NY, USA. roz4002@med.cornell.edu. Parker Institute for Cancer Immunotherapy, MSK, New York, NY, USA. roz
Author Info: (1) Ludwig Collaborative and Swim Across America Laboratory, MSK, New York, NY, USA. roz4002@med.cornell.edu. Parker Institute for Cancer Immunotherapy, MSK, New York, NY, USA. roz4002@med.cornell.edu. Weill Cornell Medicine, New York, NY, USA. roz4002@med.cornell.edu. (2) Weill Cornell Medicine, New York, NY, USA. Department of Neurology, MSK, New York, NY, USA. (3) Department of Neurology, MSK, New York, NY, USA. Gerstner Sloan Kettering Graduate School of Biomedical Sciences, MSK, New York, NY, USA. (4) Department of Neurology, MSK, New York, NY, USA. (5) Department of Neurology, MSK, New York, NY, USA. (6) Ludwig Collaborative and Swim Across America Laboratory, MSK, New York, NY, USA. Department of Oncology Bioinformatics, Genentech, South San Francisco, CA, USA. (7) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (8) Department of Medical Physics, MSK, New York, NY, USA. (9) Ludwig Collaborative and Swim Across America Laboratory, MSK, New York, NY, USA. (10) Ludwig Collaborative and Swim Across America Laboratory, MSK, New York, NY, USA. (11) Department of Neurology, MSK, New York, NY, USA. (12) Department of Neurology, MSK, New York, NY, USA. (13) Department of Neurology, MSK, New York, NY, USA. (14) Ludwig Collaborative and Swim Across America Laboratory, MSK, New York, NY, USA. (15) Ludwig Collaborative and Swim Across America Laboratory, MSK, New York, NY, USA. (16) Ludwig Collaborative and Swim Across America Laboratory, MSK, New York, NY, USA. (17) Ludwig Collaborative and Swim Across America Laboratory, MSK, New York, NY, USA. (18) Department of Medical Physics, MSK, New York, NY, USA. (19) Department of Medical Physics, MSK, New York, NY, USA. (20) Department of Oncology, University of Lausanne, Geneva, Switzerland. Ludwig Institute for Cancer Research, University of Lausanne, Geneva, Switzerland. (21) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (22) Department of Neurology, MSK, New York, NY, USA. Molecular Pharmacology Program, MSK, New York, NY, USA. (23) Ludwig Collaborative and Swim Across America Laboratory, MSK, New York, NY, USA. wolchokj@mskcc.org. Parker Institute for Cancer Immunotherapy, MSK, New York, NY, USA. wolchokj@mskcc.org. Weill Cornell Medicine, New York, NY, USA. wolchokj@mskcc.org. Human Oncology and Pathogenesis Program, MSK, New York, NY, USA. wolchokj@mskcc.org. (24) Ludwig Collaborative and Swim Across America Laboratory, MSK, New York, NY, USA. merghout@mskcc.org. Parker Institute for Cancer Immunotherapy, MSK, New York, NY, USA. merghout@mskcc.org. Weill Cornell Medicine, New York, NY, USA. merghout@mskcc.org. Human Oncology and Pathogenesis Program, MSK, New York, NY, USA. merghout@mskcc.org.
