Year: 2022
Type: article
Abstract: Despite significant recent advances in precision medicine, pancreatic ductal adenocarcinoma (PDAC) remains near uniformly lethal. Although immune-modulatory therapies hold promise to meaningfully improve outcomes for patients with PDAC, the development of such therapies requires an improved understanding of the immune evasion mechanisms that characterize the PDAC microenvironment. Here, we show that cancer cell-intrinsic glutamic-oxaloacetic transaminase 2 (GOT2) shapes the immune microenvironment to suppress antitumor immunity. Mechanistically, we find that GOT2 functions beyond its established role in the malate-aspartate shuttle and promotes the transcriptional activity of nuclear receptor peroxisome proliferator-activated receptor delta (PPARδ), facilitated by direct fatty acid binding. Although GOT2 is dispensable for cancer cell proliferation in vivo, the GOT2-PPARδ axis promotes spatial restriction of both CD4+ and CD8+ T cells from the tumor microenvironment. Our results demonstrate a noncanonical function for an established mitochondrial enzyme in transcriptional regulation of immune evasion, which may be exploitable to promote a productive antitumor immune response. SIGNIFICANCE: Prior studies demonstrate the important moonlighting functions of metabolic enzymes in cancer. We find that the mitochondrial transaminase GOT2 binds directly to fatty acid ligands that regulate the nuclear receptor PPARδ, and this functional interaction critically regulates the immune microenvironment of pancreatic cancer to promote tumor progression. See related commentary by Nwosu and di Magliano, p. 2237.. This article is highlighted in the In This Issue feature, p. 2221.
Source: Cancer Discovery
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: American Association for Cancer Research, American Cancer Society, Susan G. Komen for the Cure, AstraZeneca, AbbVie, Oregon Health and Science University, Frederick National Laboratory for Cancer Research, Prospect Creek Foundation, Syndax Pharmaceuticals, National Institutes of Health, Pharmacyclics, Knight Cancer Institute, Oregon Health and Science University, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: The Nuclear Receptor-Aster Pathway in Enterohepatic Metabolism, G1581679921, G1797368095, G2364826267, G2529935051, G4302734783, G4860891374, In Situ characterization and manipulation of tumor immune cell metabolomics using implantable microdevices, G5591359705, G877816848, Therapeutic Targeting of Macrophage PI3Kgamma in HNSCC
OpenAlex ID: W4288067562