Activation of peroxisome proliferator-activated receptors {alpha} and {delta} synergizes with inflammatory signals to enhance adoptive cell therapy

Memory CD8+ T cells (Tmem) are superior mediators of adoptive cell therapy (ACT) compared to 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 (CPT1a), 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 (DC) or IL-12, also demonstrated enhanced production of interferon-γ 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.

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