Victor Moreno, Director of Clinical Research at START Madrid FJD, shared on LinkedIn:
“Can the same target both promote and suppress cancer? And more intriguing, can this explain why some patients present ‘hyperprogression’ to immunotherapy?
A new Nature Immunology study shows why cellular context matters.
Activating PPARδ in cancer cells promoted tumor growth and impaired antitumor immunity. Yet activating the same pathway in immune cells improved CD8 T-cell fitness through chromatin remodeling and CPT1A-dependent fatty-acid oxidation.
In preclinical models, PPARδ-activated CD8 T cells sensitized immunotherapy-resistant MSS colorectal cancer to checkpoint blockade and enhanced human CAR-T-cell function.
This is promising – but still preclinical.
The translational challenge is not simply whether PPARδ should be activated or inhibited, but in which compartment.
Systemic modulation could produce opposing effects.
Cell-specific engineering or targeted delivery may therefore be essential to convert this biology into therapy.”
A more comprehensive analysis of the study results.
- Immune-intrinsic PPARδ overrides cancer PPARδ in tumor outcome: Activating PPARδ in immune cells suppressed tumor growth and counteracted the tumor-promoting and immunosuppressive effects of PPARδ activation in cancer cells.
- PPARδ activity enhances function and abundance of tumor CD8⁺ T cells: PPARδ activation increased CD8⁺ T-cell infiltration and enhanced their cancer-killing activity, inflammatory signaling and functional capacity within tumors.
- PPARδ reprograms CD8⁺ T-cell metabolism through Cpt1a: PPARδ enhanced fatty acid oxidation and promoted metabolic and chromatin changes associated with stronger T-cell function against cancer.
- PPARδ-activated CD8⁺ T cells sensitize MSS CRC to immunotherapy: In mouse models of immunotherapy-resistant, microsatellite-stable metastatic colorectal cancer, PPARδ-activated T cells improved responses to anti-PD-1 treatment, reduced tumor growth and metastasis, and enabled complete tumor rejection in some mice.
Title: Compartment-specific PPARδ activity controls the outcome of cancer-immune cell competition and immunotherapy efficacy
Authors: Paul Bunk, Ilgin Ergin, Timothy Maher, Vyom Shah, Julia R. Bonney, Lokesh B. S. S. Kumar, Charlie Chung, Nils Wellhausen, Philip Moresco, Sarah Shao, Jill Habel, Vinay Mandati, Rachel Rubino, David E. Rivadeneira, John E. Wilkinson, Laura Herrero, Peter M. K. Westcott, Samuel E. Weinberg, Saar I. Gill, Nathalie Y. R. Agar, Semir Beyaz
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