Tumor cell oxidative metabolism triggers immune escape in advanced kidney cancer 2325

Abstract Description The cancer-intrinsic factors that reduce CD8 T cell responses in advanced tumors are unclear. Using a novel strategy to isolate tumor cells from 83 late stage ccRCC patients combined with genomic, transcriptomic and phenotypic analyses, we identified two developmentally related cancer subsets: ENPP3lo and an aggressive ENPP3hi cell. While ENPP3hi cells correlated with more invasive cancer, their presence alone did not dictate immune evasion. Instead, elevated oxidative phosphorylation (OXPHOS) within these cells associated with reduced CD8 T cell activity and increased rate of metastasis. Mechanistically, metabolomics on tumor interstitial fluids from mice and human revealed that high OXPHOS cancer cells create an immunosuppressive tumor microenvironment, preventing TCF1+ stem-like CD8 T cells from differentiating into anti-tumor effectors. Succinate was a key metabolite in this process, and knockout of its transporter, MCT1, within highly oxidative cancer cells restored the immune responses and improved tumor control. Furthermore, treating mice with an MCT1 inhibitor (AZD3965) rescued responsiveness to anti-PD-L1 therapy, identifying a novel clinical axis to bolster cancer treatments. In conclusion, this study uncovers a previously underappreciated role for cancer-oxidative metabolism in driving immune evasion and disease progression, identifies its underlying biological mechanisms, and proposes MCT1 inhibition as a promising therapeutic avenue for high risk ccRCC patients. Funding Sources Supported by NCI 1R01CA280069 and DOD W81XWH-20-1-0525 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)