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

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.

SUBMITTER: Poillet-Perez L

PROVIDER: S-EPMC8409526 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Poillet-Perez Laura L Sharp Daniel W DW Yang Yang Y Laddha Saurabh V SV Ibrahim Maria M Bommareddy Praveen K PK Hu Zhixian Sherrie ZS Vieth Joshua J Haas Michael M Bosenberg Marcus W MW Rabinowitz Joshua D JD Cao Jian J Guan Jun-Lin JL Ganesan Shridar S Chan Chang S CS Mehnert Janice M JM Lattime Edmund C EC White Eileen E

Nature cancer 20200918 9

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. He ...[more]

PMID: 34476408

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Project description:Autophagy degrades and recycles intracellular components to sustain metabolism and survival during starvation. Tumor cells upregulate and require autophagy to support their metabolism and enhance their proliferation and malignancy, and host autophagy also promotes tumor growth by providing essential tumor nutrients such as arginine in the circulation or alanine in the local tumor microenvironment. In addition to its metabolic role, autophagy regulates immune cell homeostasis and function, and suppresses inflammation, which may also play a role in cancer. 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 in contrast to low TMB tumors, host-specific deletion of the essential autophagy gene Atg7 induces a pro-inflammatory cytokine response and limits the growth of high TMB tumors, which is rescued by T-cell depletion. Expression of immune-related genes is increased in tumors from Atg7Δ/Δ hosts in a T-cell dependent manner. Tumors from Atg7Δ/Δ hosts also have decreased T regulatory cells (Tregs), and depletion of Tregs phenocopies the reduced tumor growth observed in Atg7Δ/Δ hosts. Moreover, loss of Stimulator of interferon genes (Sting) or IFNg restores growth of high TMB tumors on Atg7Δ/Δ hosts. Finally, similar to whole-body loss of autophagy, specific loss of autophagy in the liver is sufficient to limit tumor growth. Thus, autophagy, especially in the liver, promotes tumor immune tolerance by limiting STING, T cells, and IFNg, which enables tumor growth. We have designated this: Hepatic Autophagy Immune Tolerance (HAIT). 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 anti-tumor T-cell response in high TMB tumors. Genomic DNA Profiling using Agilent SureSelect Mouse All Exon kit and sequencing using Illumina NextSeq550

Dataset Information

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

Publications

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

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