Tumor-intrinsic MHC-II activation in pancreatic ductal adenocarcinoma enhances immune response and treatment efficacy

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressivetumor microenvironment (TME) and poor prognosis. While major histocompatibility complexclass II (MHC-II) expression is traditionally associated with professional antigen-presentingcells, its role in PDAC malignant cells remains underexplored. Herein, we utilized single-cellRNA sequencing (scRNA-seq), spatial transcriptomics, bulk RNA sequencing, multipleximmunohistochemistry (mIHC) and ex vivo studies in culture with both human and murinemodels to investigate the prognostic relevance of MHC-II expression in malignant PDACcells. Elevated MHC-II expression in malignant cells was strongly associated with increasedinfiltration of CD4+ T and CD8+ T cells in human PDAC, and pronounced co-localization withplasma cells, indicative of an antigen-activated immune microenvironment. In the KPCmouse model of PDAC, pharmacologic induction of MHC-II expression by cobimetinibtreatment in malignant epithelial cells significantly enhanced the therapeutic response toimmune checkpoint blockade (ICB). These findings highlight the role of malignant cell-intrinsic MHC-II expression in promoting antigen presentation and fostering an anti-tumorimmune microenvironment. Our results position MHC-II as a promising prognostic biomarkerand therapeutic target in PDAC, paving the way for novel immunomodulatory strategies.