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

Mohadeseh Hasanpourghadi; Arezki Chekaoui; Sophia Kurian; Raj Kurupati; Robert Ambrose; Wynetta Giles-Davis; Amara Saha; Xu Xiaowei; Hildegund C J Ertl

doi:10.1016/j.omto.2023.100744

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

Mol Ther Oncolytics. 2023 Nov 3:31:100744. doi: 10.1016/j.omto.2023.100744. eCollection 2023 Dec 19.

Authors

Mohadeseh Hasanpourghadi¹, Arezki Chekaoui¹, Sophia Kurian¹, Raj Kurupati^{1

2}, Robert Ambrose¹, Wynetta Giles-Davis¹, Amara Saha¹, Xu Xiaowei³, Hildegund C J Ertl¹

Affiliations

¹ The Wistar Institute, Philadelphia, PA 19104, USA.
² The Janssen Pharmaceutical Companies of Johnson & Johnson, New Brunswick, NJ, USA.
³ Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

Abstract

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.

Keywords: PDX mouse model; PPARα agonist treatment; T cell metabolism; melanoma; tumor antigen-specific T cells.

Grants and funding

R41 CA180191/CA/NCI NIH HHS/United States