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

Published

Journal Article

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.

Full Text

Cited Authors

  • Xia, H; Wang, W; Crespo, J; Kryczek, I; Li, W; Wei, S; Bian, Z; Maj, T; He, M; Liu, RJ; He, Y; Rattan, R; Munkarah, A; Guan, J-L; Zou, W

Published Date

  • November 2017

Published In

Volume / Issue

  • 2 / 17

PubMed ID

  • 29150439

Pubmed Central ID

  • 29150439

Electronic International Standard Serial Number (EISSN)

  • 2470-9468

International Standard Serial Number (ISSN)

  • 2470-9468

Digital Object Identifier (DOI)

  • 10.1126/sciimmunol.aan4631

Language

  • eng