Activation of Peroxisome Proliferator-Activated Receptors α and δ Synergizes with Inflammatory Signals to Enhance Adoptive Cell Therapy
| العنوان: | Activation of Peroxisome Proliferator-Activated Receptors α and δ Synergizes with Inflammatory Signals to Enhance Adoptive Cell Therapy |
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| المؤلفون: | Linh T. Nguyen, Dominic G. Roy, Pamela S. Ohashi, Kavita Israni-Winger, Samuel Saibil, Natasha Grimshaw, Alisha R. Elford, Carlos Garcia-Batres, Robert C. Laister, Celine Robert-Tissot, Russell G. Jones, Michael St. Paul |
| المصدر: | Cancer Research. 79:445-451 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, medicine.medical_treatment, Peroxisome proliferator-activated receptor, CD8-Positive T-Lymphocytes, Immunotherapy, Adoptive, GW501516, Cell therapy, Interferon-gamma, Mice, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, medicine, Animals, Humans, PPAR alpha, PPAR delta, Receptor, PPAR-beta, Inflammation, chemistry.chemical_classification, Effector, Chemistry, Fatty Acids, Immunotherapy, Lipid Metabolism, medicine.disease, Interleukin-12, Cell biology, Gene Expression Regulation, Neoplastic, Thiazoles, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Interleukin 12, Oxidation-Reduction, CD8 |
| الوصف: | Memory CD8+ T cells (Tmem) are superior mediators of adoptive cell therapy (ACT) compared with effector CD8+ T cells (Teff) due to increased persistence in vivo. Underpinning Tmem survival is a shift in cellular metabolism away from aerobic glycolysis towards fatty acid oxidation (FAO). Here we investigated the impact of the peroxisome proliferator-activated receptor (PPAR) agonist GW501516 (GW), an agent known to boost FAO in other tissues, on CD8+ T-cell metabolism, function, and efficacy in a murine ACT model. Via activation of both PPARα and PPARδ/β, GW treatment increased expression of carnitine palmitoyl transferase 1a, the rate-limiting enzyme of FAO, in activated CD8+ T cells. Using a metabolomics approach, we demonstrated that GW increased the abundance of multiple different acylcarnitines, consistent with enhanced FAO. T cells activated in the presence of GW and inflammatory signals, either mature dendritic cells or IL12, also demonstrated enhanced production of IFNγ and expression of T-bet. Despite high expression of T-bet, a characteristic of short-lived effector cells, GW-treated cells demonstrated enhanced persistence in vivo and superior efficacy in a model of ACT. Collectively, these data identify combined PPARα and PPARδ/β agonists as attractive candidates for further studies and rapid translation into clinical trials of ACT. Significance: Dual activation of peroxisome proliferator-activated receptors α and δ improves the efficacy of adoptive cell therapy by reprogramming T-cell metabolism and cytokine expression. |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::105e72eac11f1d876a9107b5bc006f07 https://doi.org/10.1158/0008-5472.can-17-3053 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....105e72eac11f1d876a9107b5bc006f07 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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