Researchers led by Ludwig Princeton’s Kellen Olszewski and Director Joshua Rabinowitz reported in a May publication in Cell Chemical Biology that tumor-infiltrating T lymphocytes (TILs), which can target cancer cells, favor the use of the de novo purine biosynthetic pathway, which requires copious 1-carbon units generated by folate metabolism. This contrasts with T cells in lymph nodes and in the spleen, which mainly rely on nucleoside salvage for purines, which are key DNA and RNA components. Like TILs, cancer cells too synthesize purines de novo. This sets up a competition for 1-carbon units between cancer cells and T cells in tumors. 1-carbon units can circulate in the body as formate. Supplementing 1-carbon units by infusing mice with formate—or orally administering low doses of methanol, which the researchers show boosts formate levels—drives purine biosynthesis in TILs. Further, methanol augments anti-PD-1 checkpoint blockade in a mouse model of colorectal cancer, tripling the incidence of durable tumor regressions. These findings align with a study reported last year, led by Ludwig Harvard’s Marcia Haigis and Arlene Sharpe, showing formate supplementation boosts T cell fitness and enhances PD-1 blockade in a mouse model of melanoma. All this suggests the availability of 1-carbon units is a limiting factor in T cell-mediated anti-tumor immunity. It further offers a readily testable strategy for improving responses to immunotherapy.
One-carbon unit supplementation fuels purine synthesis in tumor-infiltrating T cells and augments checkpoint blockade
Cell Chemical Biology, 2024 May 16