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Series GSE155556 Query DataSets for GSE155556
Status Public on Aug 03, 2020
Title Autophagy Promotes Growth of High Tumor Mutational Burden Tumors by Inhibiting a T Cell Immune Response [Exome-seq]
Organism Mus musculus
Experiment type Other
Summary 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
 
Overall design DNA was extracted from MB49, YUMM 1.1 and UV YUMM 1.1-9 cell lines using the QIAsymphony DSP DNA midi kit (937255, Qiagen). Mouse whole exome libraries were constructed using Agilent SureSelect Mouse All Exon kit according to the manufacturer’s protocol. The resulting sequencing libraries were analyzed using Agilent D1000 screentape and quantified using KAPA qPCR. Libraries were then normalized and pooled into one pool. The library pool was then clustered and sequenced on the Illumina NextSeq550 instrument using 2x151bp paired end reads to a mean death of 80X, following the manufacturer’s protocols
4 samples
Web link https://www.nature.com/articles/s43018-020-00110-7
 
Contributor(s) Laddha SV, Chan CS, Poillet-Perez L, White E
Citation(s) 34476408
Submission date Aug 03, 2020
Last update date Sep 08, 2021
Contact name SAURABH V LADDHA
E-mail(s) saurabhvladdha@gmail.com
Organization name Rutgers Cancer Institute of New Jersey
Department Center for Systems and Computational Biology
Street address 195 Little Albany Street
City New Brunswick
State/province NEW JERSEY
ZIP/Postal code 08901-1914
Country USA
 
Platforms (1)
GPL21626 NextSeq 550 (Mus musculus)
Samples (4)
GSM4706141 YUMM 1.1
GSM4706142 YUMM 1.3
GSM4706143 UV YUMM 1.1-9
This SubSeries is part of SuperSeries:
GSE155557 Autophagy Promotes Growth of High Tumor Mutational Burden Tumors by Inhibiting a T Cell Immune Response
Relations
BioProject PRJNA650292
SRA SRP275566

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Supplementary file Size Download File type/resource
GSE155556_Supplementary_table_3_4_5_6.xlsx 209.3 Kb (ftp)(http) XLSX
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Processed data are available on Series record

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