Autophagy promotes growth of tumors with high mutational burden by inhibiting a T-cell immune response.

TitleAutophagy promotes growth of tumors with high mutational burden by inhibiting a T-cell immune response.
Publication TypeJournal Article
Year of Publication2020
AuthorsPoillet-Perez, L, Sharp, DW, Yang, Y, Laddha, SV, Ibrahim, M, Bommareddy, PK, Hu, ZSherrie, Vieth, J, Haas, M, Bosenberg, MW, Rabinowitz, JD, Cao, J, Guan, J-L, Ganesan, S, Chan, CS, Mehnert, JM, Lattime, EC, White, E
JournalNat Cancer
Volume1
Issue9
Pagination923-934
Date Published2020/09/30
ISSN2662-1347
Abstract

Macroautophagy (hereafter autophagy) degrades and recycles intracellular components to sustain metabolism and survival during starvation. Host autophagy promotes tumor growth by providing essential tumor nutrients. Autophagy also regulates immune cell homeostasis and function and suppresses inflammation. Although host autophagy does not promote a T-cell anti-tumor immune response in tumors with low tumor mutational burden (TMB), whether this was the case in tumors with high TMB was not known. Here we show that autophagy, especially in the liver, promotes tumor immune tolerance by enabling regulatory T-cell function and limiting stimulator of interferon genes, T-cell response and interferon-γ, which enables growth of high-TMB tumors. We have designated this as hepatic autophagy immune tolerance. Autophagy thereby promotes tumor growth through both metabolic and immune mechanisms depending on mutational load and autophagy inhibition is an effective means to promote an antitumor T-cell response in high-TMB tumors.

DOI10.1038/s43018-020-00110-7
Alternate JournalNat Cancer
PubMed ID34476408
PubMed Central IDPMC8409526
Grant ListR01 CA163591 / CA / NCI NIH HHS / United States
R01 CA193970 / CA / NCI NIH HHS / United States
R01 CA243547 / CA / NCI NIH HHS / United States