Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 2414-2433 |
| Number of pages | 20 |
| Journal | Cancer Discovery |
| Volume | 12 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 1 2022 |
Bibliographical note
Publisher Copyright:© 2022 The Authors; Published by the American Association for Cancer Research.
Funding
L.M. Coussens reports personal fees from (P30) Koch Institute for Integrated Cancer Research, Massachusetts Institute of Technology, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, (P50) Dana-Farber Cancer Center Breast SPORE, (P30) Dana-Farber/Harvard Cancer Center, (P30) University of California, San Diego Moores Cancer Center, (P30) The Jackson Laboratory Cancer Center, (P01) Columbia University Medical Center, Prostate P01, (P50) MD Anderson Cancer Center Gastrointestinal SPORE, the Cancer Research Institute, the Lustgarten Foundation for Pancreatic Cancer Research, the Therapeutics Working Group, the NIH/NCI-Frederick National Laboratory Advisory Committee, AbbVie Inc., Shasqi, Inc., and the American Association for Cancer Research (AACR): Cancer Immunology Research, personal fees and nonfinancial support from Cell Signaling Technology, nonfinancial and other support from ZellBio, Inc. and Syndax Pharmaceuticals Inc., personal fees, nonfinancial, and other support from Hibercell, Inc., personal fees and other support from the Susan G. Komen Foundation, and other support from Pharmacyclics, Inc.: steering committee for PCYC-1137-CA, the AACR: Cancer Discovery, the AACR, Cancer Cell, the Prospect Creek Foundation, the Lustgarten Foundation for Pancreatic Cancer Research, Carisma Therapeutics Inc., CytomX Therapeutics, Inc., Kineta Inc., Alkermes, Inc., PDX Pharmaceuticals, Inc., Zymeworks, Inc., AstraZeneca Partner of Choice Network, Genenta Sciences, and Pio Therapeutics Pty Ltd during the conduct of the study. M.H. Sherman reports personal fees from Autobahn Labs outside the submitted work. No disclosures were reported by the other authors. Human Tumor Atlas Network Research Center (U2C CA233280), and the Prospect Creek Foundation to the OHSU SMMART (Serial Measurement of Molecular and Architectural Responses to Therapy) Program. P. Tontonoz acknowledges funding from the NIH (R01 DK126779). We thank members of the OHSU Histopathology Shared Resource, Medicinal Chemistry Core, Massively Parallel Sequencing Shared Resource, Bioinformatics and Biostatistics Core, KCVI Epigenetics Consortium, and Advanced Light Microscopy Shared Resource for supporting this study, as well as Dr. Drew Jones and Leonard Ash from the NYU Langone Health Metabolomics Laboratory. We thank all members of the Sherman lab as well as Drs. Sara Courtneidge, Kimberly Beatty, and Amy Moran for helpful discussion of this work. This study was supported by a postdoctoral fellowship from the OHSU Fellowship for Diversity in Research (to J. Abrego), a graduate student fellowship from the Knight Cancer Institute Cancer Center Support Grant P30 CA069533 (to H. San-ford-Crane), NIH grants R00 CA188259 and R01 CA229580 (to M.H. Sherman) including CA229580-S1 Research Supplement to Promote Diversity in Health-Related Research (awarded to M.H. Sherman in support of J. Abrego), American Cancer Society grant RSG-18-142-01-CSM (to M.H. Sherman), and an OHSU Faculty Innovation Fund Award (to M.H. Sherman). L.M. Coussens acknowledges funding from the NIH (1U01 CA224012, U2C CA233280, R01 CA223150, R01 CA226909, and R21 HD099367), the Knight Cancer Institute, and the Brenden-Colson Center for Pancreatic Care at OHSU. Development of analytical methods used for image analysis at OHSU were developed and carried out with major support from the NIH, the NCI
| Funders | Funder number |
|---|---|
| Brenden-Colson Center for Pancreatic Care | |
| Carisma Therapeutics Inc. | |
| Hibercell, Inc. | |
| Jackson Laboratory Cancer Center | P50 |
| Kineta Inc. | |
| NCI-Frederick National Laboratory Advisory Committee | |
| Pharmacyclics, Inc. | PCYC-1137-CA |
| Pio Therapeutics Pty Ltd | |
| Therapeutics Working Group | |
| University of California, San Diego Moores Cancer Center | |
| ZellBio, Inc. | |
| National Institutes of Health (NIH) | R01 DK126779, R01 CA229580, R00 CA188259 |
| American Association for Cancer Research | |
| American Cancer Society-Michigan Cancer Research Fund | R01 CA226909, R01 CA223150, RSG-18-142-01-CSM, U2C CA233280, 1U01 CA224012, R21 HD099367 |
| NIH National Institute of Child Health and Human Development National Center for Medical Rehabilitation Research | R21HD099367 |
| Children's Cancer Research Institute, Vienna | |
| Lustgarten Foundation | |
| AbbVie | |
| Oregon Health and Science University | |
| Massachusetts Institute of Technology | |
| Ludwig Center at Dana-Farber Harvard Cancer Center | |
| Susan G Komen Foundation | |
| Sidney Kimmel Comprehensive Cancer Center | |
| Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University | |
| Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology | |
| Prospect Creek Foundation | |
| Cytori Therapeutics | |
| Knight Cancer Institute, Oregon Health and Science University | P30 CA069533 |
| Syndax Pharmaceuticals |
ASJC Scopus subject areas
- Oncology
