Laboratory for Mucosal Immunity

Most chronic illnesses are caused by both genetic and environmental factors. Dietary changes associated with modern life drive systemic perturbations, from changes in the microbiome, to chronic inflammatory and degenerative diseases and cancers. Obesity is a risk factor for many types of cancers. Also, a history of obesity can have a lasting glycemic risk long after reverting to normal weight, by yet unknown mechanisms. We found that a transient exposure to HFD impairs anti-tumor immunity even 3 months after reversion to a normal diet. This was due to lasting metabolome changes that included enrichment in polyunsaturated fatty acids sensitive to peroxidation and depletion of antioxidants, such as glutathione and xanthine, affecting the survival and function of CD8+ T cells. We demonstrate that under oxidative stress, CD8 T cells utilize the xanthine salvage pathway via hypoxanthine phosphoribosyl transferase (HPRT1) and guanosine monophosphate synthetase (GMPS) to fuel the synthesis of guanosine triphosphate (GTP) (Figure). GTP via GTP cyclohydrolase 1 (GCH1) is used to boost the pool of tetrahydrobiopterin (BH4) and its oxidized form, dihydrobiopterin (BH2). In vitro, xanthine and biopterins rescue CD8 T cells from ferroptosis. In vivo, xanthine or BH2 administration reduces the lipid peroxidation in tumor draining lymph nodes and improves anti-tumor immunity in mice that have experienced HFD. Conversely, CD8 T cells deficient in Gch1, the rate limiting enzyme for BH4 synthesis from GTP, show an impaired ability to control the tumor growth unless supplemented with BH2. Our data indicate that in CD8 T cells, metabolic stress extends long after a balanced diet has been restored, manifesting as vulnerability to oxidative stress and ferroptosis, that can be mitigated by replenishing the pool of biopterins by xanthine and its salvage pathway.