Research ArticleTUMOR IMMUNOLOGY

Suppression of FIP200 and autophagy by tumor-derived lactate promotes naïve T cell apoptosis and affects tumor immunity

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Science Immunology  17 Nov 2017:
Vol. 2, Issue 17, eaan4631
DOI: 10.1126/sciimmunol.aan4631

Tumor immunity flounders without FIP200

The tumor microenvironment impairs the function of effector and memory T cells, but its effect on naïve T cells is not well understood. Xia et al. show that the autophagy component FAK family–interacting protein of 200 kDa (FIP200) is critical for promoting antitumor responses mediated by T cells. Ovarian cancer patients and mouse tumor models had significantly higher rates of apoptosis and impaired autophagy in naïve T cells, as well as the selective loss of FIP200, which disrupted the balance of pro- and antiapoptotic factors. Tumor-derived lactate was shown to suppress FIP200 expression, thus causing enhanced apoptosis and attenuated antitumor responses.

Abstract

Naïve T cells are poorly studied in cancer patients. We report that naïve 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 naïve T cells to evade immunity.

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