The aryl hydrocarbon receptor inhibits antigen presentation to promote progression of pancreatic ductal adenocarcinoma.

[BACKGROUND] The aryl hydrocarbon receptor (AhR) plays a pivotal role in modulating immune responses and influencing tumor development by detecting metabolites derived from tryptophan breakdown. In patients suffering from pancreatic ductal adenocarcinoma (PDAC), elevated levels of AhR are strongly correlated with poor clinical outcomes. Despite this, the cell-autonomous functions of AhR in pancreatic tumor cells, particularly its role in modulating anti-tumor immunity within the tumor microenvironment, remain poorly characterized and require further investigation.

[METHODS] CRISPR-Cas9 technology was used to generate Ahr/AHR Pan02, B16-F10 and Panc-1 cells. Subcutaneous tumor models in nude and C57BL/6J mice were used to evaluate the effect of tumor cell intrinsic Ahr on the anti-tumor immune response. Transcriptome sequencing, ATAC sequencing, CUT&Tag sequencing, ChIP and IP-MS were used to elucidate how AhR controls the expression and accessibility of major histocompatibility complex class I (MHC-I).

[RESULTS] Elevated AhR levels in PDAC patients correlate with worse outcomes. AhR protein is located in both cytoplasm and nucleus of tumor cells. Deletion of Ahr in Pan02 and B16-F10 leads to a significant upregulation of MHC-I and related gene expression. AhR drives tumor growth by suppressing T cell-mediated immunity. Mechanistically, AhR specifically suppressed MHC-I expression in pancreatic tumor cells by interacting with protein arginine methyltransferase 5 (PRMT5) to decrease chromatin accessibility, which led to impaired antigen presentation. We demonstrated that AhR inhibition improved the therapeutic efficacy of immune checkpoint blockade, chemotherapy, and PRMT5-targeted therapy in pancreatic cancer models.

[CONCLUSIONS] Tumor cell intrinsic AhR inhibits MHC-I expression in PDAC cells by epigenetic regulation mediated by PRMT5, resulting in reduced immunogenicity of pancreatic tumor cells. The discovery of the AhR-PRMT5-H4R3me2s-MHC-I axis provides critical mechanistic insights into how tumor-intrinsic epigenetic regulation of antigen presentation promotes the progression of PDAC.