Presenting Author:
Principal Investigator:
Department:
Medicine
Keywords:
Pancreatic cancer Epigenetic bromodomains and extra-terminal (BET) proteins PD-L1
Location:
Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital
B46 - Basic Science
Combination of BET and Immune Checkpoint Inhibitors for Pancreatic Cancer
Single agent treatment with T-cell checkpoint inhibitors has not been effective in pancreatic ductal adenocarcinoma (PDAC) patients since the PDAC stroma, which can account for as much as 80-90% of the tumor mass, acts as a physical and an immunologic barrier to T-cell-mediated therapies. We recently published that targeting bromodomains and extra-terminal (BET) proteins can induce primary stellate cells isolated from human PDAC tumors to become quiescent and decrease fibrosis in vivo. We have now found that activated stellate cells express high levels of PD-L1, which can bind to PD-1 on T lymphocytes to suppress its anti-tumorigenic function. Significantly, BET inhibitors and BRD4 siRNA decrease PD-L1 expression in primary pancreatic stellate cells. We show that BET inhibitors block binding of BRD4 to the PD-L1 promoter in stellate cells. As c-MYC, a well-known target of BET inhibitors, was recently shown to regulate PD-L1 in cancer cells, we evaluated the role of c-MYC in mediating PD-L1 expression in stellate cells. We show that c-MYC does not regulate PD-L1 in stellate cells. CDK5 was also recently shown to regulate PD-L1 in cancer cells. While we show that BET inhibitors can repress CDK5 in stellate cells, we have found that CDK5 does not regulate PD-L1 expression in stellate. Instead, we show that IRF1 forms a complex with BRD4 to regulate PD-L1 expression in stellate cells. In our ongoing experiments we are evaluating the extent to which BET inhibitors enhance the effects of immune checkpoint inhibitors in syngeneic mouse models of pancreatic cancer.
