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Generation of Orthotopic Pancreatic Tumors and Ex vivo Characterization of Tumor-Infiltrating T Cell Cytotoxicity
Published on: December 7, 2019
Compartment-specific PPARδ activity controls the outcome of cancer-immune cell competition and immunotherapy efficacy
Paul Bunk1, Ilgin Ergin1, Timothy Maher1,2,3
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Abstract:
Most patients with solid tumors fail to sustain antitumor immunity, in part because immune cells cannot outcompete cancer cells inside the immunosuppressive tumor microenvironment. Here, we show the lipid-sensing transcription factor PPARδ is a compartment-specific determinant of cancer-immune fitness balance and immunotherapy efficacy. Activating PPARδ in cancer cells promotes their growth and impairs antitumor immunity, whereas activating it in immune cells drives tumor suppression and overrides tumor-promoting effects of cancer-intrinsic activation. Mechanistically, PPARδ enhances CD8+ T cell fitness against cancer through effector-associated chromatin remodeling and Cpt1a-mediated fatty acid oxidation. Therapeutically, PPARδ-activated CD8+ T cells sensitize immunotherapy-resistant microsatellite stable metastatic colorectal cancer to checkpoint blockade in mice, and pharmacological or genetic PPARδ activation enhances human chimeric antigen receptor T cell function. These findings identify compartment-specific PPARδ activity as a targetable driver of immune cell fitness that can be harnessed to improve outcomes in immunotherapy-resistant tumors.
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