TY - JOUR
T1 - A Cancer Cell–Intrinsic GOT2–PPARδ Axis Suppresses Antitumor Immunity
AU - Abrego, Jaime
AU - Sanford-Crane, Hannah
AU - Oon, Chet
AU - Xiao, Xu
AU - Betts, Courtney B.
AU - Sun, Duanchen
AU - Nagarajan, Shanthi
AU - Diaz, Luis
AU - Sandborg, Holly
AU - Bhattacharyya, Sohinee
AU - Xia, Zheng
AU - Coussens, Lisa M.
AU - Tontonoz, Peter
AU - Sherman, Mara H.
N1 - Publisher Copyright:
© 2022 The Authors; Published by the American Association for Cancer Research.
PY - 2022/10/1
Y1 - 2022/10/1
N2 - Despite significant recent advances in precision medicine, pancreatic ductal adenocar-cinoma (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.
AB - Despite significant recent advances in precision medicine, pancreatic ductal adenocar-cinoma (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.
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U2 - 10.1158/2159-8290.CD-22-0661
DO - 10.1158/2159-8290.CD-22-0661
M3 - Article
C2 - 35894778
AN - SCOPUS:85138781406
SN - 2159-8274
VL - 12
SP - 2414
EP - 2433
JO - Cancer discovery
JF - Cancer discovery
IS - 10
ER -