免疫系统
肿瘤微环境
生物
癌症研究
胰腺癌
过氧化物酶体
癌症
免疫
癌细胞
细胞生物学
受体
免疫学
生物化学
遗传学
作者
Jaime Abrego,Hannah Sanford-Crane,Chet Oon,Xiao Xu,Courtney B. Betts,Duanchen Sun,Shanthi Nagarajan,Luis Diaz,Holly Sandborg,Sohinee Bhattacharyya,Zheng Xia,Lisa M. Coussens,Peter Tontonoz,Mara H. Sherman
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2022-07-27
卷期号:12 (10): 2414-2433
被引量:20
标识
DOI:10.1158/2159-8290.cd-22-0661
摘要
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.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.
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