Friday, April 4, 2025
4/4/2025
Metabolic reprogramming to boost the fitness of anti-tumor immunity against metastatic colon cancer - Abstract The primary goal of this project is to enhance the efficacy of immunotherapy against metastatic colorectal cancer (mCRC) by activating the peroxisome proliferator-activated receptor delta (PPARδ)-Carnitine palmitoyltransferase 1a (Cpt1a) axis in CD8+ T cells. Colorectal cancer (CRC) is among the deadliest cancers worldwide, with rising incidence and mortality in younger populations. Particularly, mCRC patients, predominantly of the microsatellite stable (MSS) subtype, show poor responsiveness to current immunotherapies due to the immunosuppressive tumor microenvironment and low mutation burden that associates with limited immunogenicity. This creates an urgent need for innovative approaches to boost the immunogenicity and improve treatment outcomes. Our preliminary studies highlight the role of PPARδ, a lipid-sensing transcription factor, in modulating the metabolic fitness of CD8+ T cells within the tumor microenvironment, thereby enhancing their immunogenic potential against mCRC. We found that by promoting mitochondrial fatty acid oxidation (FAO) through the PPARδ-Cpt1a axis, we could significantly augment the efficacy of existing immunotherapies. The roles of PPARδ and FAO in tumorigenesis and immunity are controversial due to lack of cell type-specific genetic loss-of-function and gain-of-function models. We hypothesize that the metabolic competition between cancer cells and the immune system is a critical determinant of immune cell fitness against cancer. By activating PPARδ in CD8+ T cells, we aim to tip this balance to enhance immune cell function and thus improve the anti-tumor efficacy of immunotherapies in mCRC. To achieve our goal, we propose three synergistic aims. First, we will delineate the specific mechanisms by which PPARδ activation enhances the anti-tumor activity of CD8+ T cells in the context of MSS mCRC, focusing on their anti-metastatic function and the underlying epigenetic alterations. Second, we will elucidate the role of Cpt1a-mediated fatty acid oxidation in the context of PPARδ-induced modifications in CD8+ T cells, assessing how these metabolic changes impact their effectiveness against cancer. Finally, we will evaluate the therapeutic potential of enhancing the PPARδ-Cpt1a axis within CD8+ T cells on the efficacy of immunotherapeutic approaches against mCRC, using both murine models and human patient-derived organoids to ensure clinical relevance. Collectively, this project is poised to transform mCRC treatment by demonstrating that modulating the metabolic dynamics within the tumor microenvironment can substantially improve immunotherapeutic outcomes. Successfully harnessing the PPARδ-Cpt1a axis in immune cells holds the promise of developing new therapeutic modalities that significantly extend survival and enhance the quality of life for mCRC patients, who suffer from lack of effective treatment options.
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