Xia et al. made the seminal observation that naive T cells from blood and tumor tissue of ovarian cancer patients and tumor-bearing mice were prone to apoptosis. They traced the cause to tumor-derived lactate, which translationally inhibits the expression of FIP200, a protein required for autophagy, leading to impaired autophagy induction, overactivated mitochondria, high levels of reactive oxygen species, and disruption of Bcl-2 gene family expression.
Naive T cells are poorly studied in cancer patients. We report that naive T cells are prone to undergo apoptosis due to a selective loss of FAK family-interacting protein of 200 kDa (FIP200) in ovarian cancer patients and tumor-bearing mice. This results in poor antitumor immunity via autophagy deficiency, mitochondria overactivation, and high reactive oxygen species production in T cells. Mechanistically, loss of FIP200 disables the balance between proapoptotic and antiapoptotic Bcl-2 family members via enhanced argonaute 2 (Ago2) degradation, reduced Ago2 and microRNA1198-5p complex formation, less microRNA1198-5p maturation, and consequently abolished microRNA1198-5p-mediated repression on apoptotic gene Bak1 Bcl-2 overexpression and mitochondria complex I inhibition rescue T cell apoptosis and promoted tumor immunity. Tumor-derived lactate translationally inhibits FIP200 expression by down-regulating the nicotinamide adenine dinucleotide level while potentially up-regulating the inhibitory effect of adenylate-uridylate-rich elements within the 3' untranslated region of Fip200 mRNA. Thus, tumors metabolically target naive T cells to evade immunity.