PPARγ induces PD-L1 expression in MSS plus colorectal cancer cells

Only a small subset of colorectal cancer (CRC) patients benefits from immunotherapies, comprising blocking antibodies (Abs) against checkpoint receptor programmed-cell-death-1 (PD1) and its ligand (PD-L1), because most cases lack the required mutational burden and neo-antigen load caused by microsatellite instability (MSI) and/or an inflamed, immune cell-infiltrated PD-L1+ tumor microenvironment. Peroxisome proliferator-activated-receptor-gamma (PPAR gamma), a metabolic transcription factor stimulated by anti-diabetic drugs, has been previously implicated in pre/clinical responses to immunotherapy. We therefore raised the hypothesis that PPAR gamma induces PD-L1 on microsatellite stable (MSS) tumor cells to enhance Ab-target engagement and responsiveness to PD-L1 blockage. We found that PPAR gamma-agonists upregulate PD-L1 mRNA/protein expression in human gastrointestinal cancer cell lines and MSS+ patient-derived tumor organoids (PDOs). Mechanistically, PPAR gamma bound to and activated DNA-motifs similar to cognate PPAR gamma-responsive-elements (PPREs) in the proximal -2 kb promoter of the human PD-L1 gene. PPAR gamma-agonist reduced proliferation and viability of tumor cells in co-cultures with PD-L1 blocking Ab and lymphokine-activated killer cells (LAK) derived from the peripheral blood of CRC patients or healthy donors. Thus, metabolic modifiers improved the antitumoral response of immune checkpoint Ab, proposing novel therapeutic strategies for CRC.

Automated summary

The study revealed that PPAR gamma agonists can upregulate PD-L1 expression in colorectal cancer, enhancing responsiveness to PD-L1 blocking antibodies and improving anti-tumoral responses. This suggests novel therapeutic strategies for CRC involving metabolic modifiers to enhance immune checkpoint antibody responses.