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.
Author Info: (1) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. (2) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI
Author Info: (1) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. (2) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. Department of Immunology and Key Laboratory of Medical Immunology of Ministry of Public Health, Peking University Health Science Center, Beijing 100191, China. (3) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. (4) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. (5) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. (6) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. (7) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. Department of Environmental Health, Cincinnati University College of Medicine, Cincinnati, OH 45267, USA. (8) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. (9) Department of Immunology, School of Medicine, Duke University, Durham, NC 27710, USA. (10) Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. (11) Department of Immunology, School of Medicine, Duke University, Durham, NC 27710, USA. (12) Department of Women's Health Services, Henry Ford Health System, Detroit, MI 48202, USA. (13) Department of Women's Health Services, Henry Ford Health System, Detroit, MI 48202, USA. (14) Department of Cancer Biology, Cincinnati University College of Medicine, Cincinnati, OH 45267, USA. (15) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. wzou@med.umich.edu. Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. Graduate Program in Tumor Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. University of Michigan Comprehensive Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
