PPARα Agonist Fenofibrate Enhances Cancer Vaccine Efficacy

Abstract

Reducing metabolic stress within the tumor microenvironment (TME) could be essential for improving the efficacy of cancer immunotherapy. Using a mouse model of melanoma, we show here that appropriately timed treatment with the PPARα agonist fenofibrate improves the ability of a T cell–inducing cancer vaccine to delay tumor progression. Fenofibrate reduced the use of glucose by tumor and stromal cells in the TME and promoted the use of fatty acids for their metabolic needs. The glucose within the TME was in turn available for use by vaccine-induced tumor-infiltrating CD8+ T cells, which improved their ability to slow tumor progression. Early fenofibrate treatment 3 days after vaccination improved functions of circulating CD8+ T cells but failed to significantly affect tumor-infiltrating lymphocyte (TIL) metabolism or decrease tumor progression. In contrast, delaying treatment until day 5 after vaccination modified TIL metabolism and augmented the vaccine's ability to slow tumor progression. In summary, our findings reveal that a PPARα agonist can increase the efficacy of a cancer vaccine by reprogramming cells within tumors to increase fatty acid metabolism, providing T cells access to glucose in the TME. Significance: These findings suggest that metabolic manipulations using already approved drugs may offer an easy pathway to increase the efficacy of vaccines against solid tumors.

Identification of the shared gene signatures and pathways between polycystic ovary syndrome and endometrial cancer: An omics data based combined approach

“…A previous study reported that fenofibrate inhibited proliferation and induced apoptosis in Ishikawa endometrial cancer cells [ 49 ]. Moreover, it promotes metabolism of fatty acids over glucose for the metabolic needs in tumor microenvironment thus decreasing tumor progression [ 50 ]. In order to explore the therapeutic potential of fenofibrate, we started a preliminary validation through molecular docking, which can predict binding affinities between molecule and protein residues using binding free energy (ΔGbind) [ 51 ].…”

Prognostic Relevance of Nuclear Receptors in Relation to Peritumoral Inflammation and Tumor Infiltration by Lymphocytes in Breast Cancer

“…Altogether, this study is one of the first that describes the correlation between the expression of nuclear receptors (in particular PPARγ) and peritumoral inflammation or TIL levels in relation to prognosis in BC. Although some studies exist on PPARα in melanoma [ 62 , 63 , 64 ], PPARγ has, to our knowledge, never been investigated in relation to TILs and survival in any form of cancer. In our whole cohort of sporadic breast cancers, PPARγ expression in the cytoplasm of cancer cells was positively correlated with TIL levels and peritumoral inflammation.…”

Role of PPAR Receptor and Ligands in the Pathogenesis and Therapy of Hematologic Malignancies

“…A recent study discovered that in MC38-OT I cancer model, the tumor microenvironment produces immunological defective tumor-infiltrating DCs (TIDCs), which can suppress dendritic cells' anti-tumor regulatory function, and this impact is produced by PPARα activation [48]; however, an exciting study indicated that the PPARα agonist Fenofibrate could boost the ability of a T-cell-inducing melanoma vaccine to delay tumor progression [49], which appears to contradict the finding above. These findings suggested that PPARα plays a significant role in hematologic malignancies.…”