Treatment with the PPARα agonist fenofibrate improves the efficacy of CD8+ T cell therapy for melanoma

• Published in: Molecular therapy. Oncolytics 2023-12, Vol.31, p.100744-100744, Article 100744
• Main Authors: Hasanpourghadi, Mohadeseh, Chekaoui, Arezki, Kurian, Sophia, Kurupati, Raj, Ambrose, Robert, Giles-Davis, Wynetta, Saha, Amara, Xiaowei, Xu, Ertl, Hildegund C.J.
• Format: Article
• Language: English
• Subjects: melanoma; PDX mouse model; PPARα agonist treatment; T cell metabolism; tumor antigen-specific T cells
• ISSN: 2372-7705; 2372-7705
• DOI: 10.1016/j.omto.2023.100744

Adoptive transfer of tumor antigen-specific CD8+ T cells can limit tumor progression but is hampered by the T cells’ rapid functional impairment within the tumor microenvironment (TME). This is in part caused by metabolic stress due to lack of oxygen and glucose. Here, we report that fenofibrate treatment of human ex vivo expanded tumor-infiltrating lymphocytes (TILs) improves their ability to limit melanoma progression in a patient-derived xenograft (PDX) mouse model. TILs treated with fenofibrate, a peroxisome proliferator receptor alpha (PPARα) agonist, switch from glycolysis to fatty acid oxidation (FAO) and increase the ability to slow the progression of autologous melanomas in mice with freshly transplanted human tumor fragments or injected with tumor cell lines established from the patients’ melanomas and ex vivo expanded TILs. [Display omitted] Transfer of tumor antigen-specific CD8+ T cells into melanoma patients is commonly ineffective as they lose functions due to glucose deprivation within tumors. Drug-induced changes in their metabolism toward fatty acid catabolism improve efficacy and may offer a remedy to improve the outcome of T cell transfer.