PPARγ agonist pioglitazone enhances colorectal cancer immunotherapy by inducing PD-L1 autophagic degradation

Abstract

Blockade of PD-1/PD-L1 immune checkpoint could be an effective antitumor strategy for multiple types of cancer, but it is low response rate for colorectal cancer patients with unclear mechanism. Here we found that PPARγ agonist pioglitazone could reduce PD-L1 protein levels without effect on its gene expression. Further analysis showed that pioglitazone induced PD-L1 autophagic degradation in a PPARγ-dependent manner. Pioglitazone promoted PD-L1 translocation to lysosome by immunofluorescence analysis, which was associated with the increased binding of PPARγ to PD-L1. Moreover the combined pioglitazone with PD-1 antibody enhanced colorectal tumor immunotherapy, which was involved in reduced PD-L1 levels and increased CD8⁺ T cells. These findings suggest that PPARγ agonist could induce PD-L1 autophagic degradation resulting in increased colorectal tumor immunotherapy.

Keywords: Autophagic degradation; Colorectal tumor immunotherapy; PD-L1; Pioglitazone.