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

Laura Poillet-Perez, Daniel W. Sharp, Yang Yang, Saurabh V. Laddha, Maria Ibrahim, Praveen K. Bommareddy, Zhixian Sherrie Hu, Joshua Vieth, Michael Haas, Marcus W. Bosenberg, Joshua D. Rabinowitz, Jian Cao, Jun Lin Guan, Shridar Ganesan, Chang S. Chan, Janice M. Mehnert, Edmund C. Lattime, Eileen White

Research output: Contribution to journalArticlepeer-review

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 antitumor 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.

Original languageEnglish (US)
Pages (from-to)923-934
Number of pages12
JournalNature Cancer
Volume1
Issue number9
DOIs
StatePublished - Sep 1 2020

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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