IFNγ-dependent tumor-cell MHC-II is restrained by MAPK signaling and associated with immunotherapy responsiveness in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive tumor microenvironment (TME) and poor prognosis. Although major histocompatibility complex class II (MHC-II) is typically expressed by professional antigen-presenting cells, its regulation and significance in malignant PDAC cells remain unclear. Here, we integrated single-cell RNA sequencing, spatial transcriptomics, bulk transcriptomics, multiplex immunohistochemistry, and functional studies in murine PDAC models to investigate tumor-cell MHC-II. Across human PDAC datasets, elevated tumor-cell MHC-II expression was associated with increased CD4⁺ and CD8⁺ T-cell infiltration and localization within immune-rich tumor niches. In paired biopsies from patients treated with cobimetinib, malignant cells showed increased expression of MHC-II pathway genes, suggesting therapy-induced activation of this program. In preclinical KPC models, MHC-IIhigh tumors exhibited greater T-cell infiltration, whereas MHC-IIlow tumors derived the greatest benefit from cobimetinib combined with immune checkpoint blockade. Mechanistically, direct tumor stimulation via in vitro administration of cobimetinib and recombinant interferon (IFN)-γ resulted in MHC-II induction in vitro by both MHCIIhigh and MHC-IIlow PDAC cell lines. In vivo, combined MEK inhibition and immune checkpoint blockade-controlled tumor growth, including in MHC-IIlow tumors. Deletion of the IFN-γ receptor abolished MHC-II induction and therapeutic benefit, demonstrating that this response is IFN-γ dependent. MEK inhibition enhanced downstream IFN-γ signaling and the combination was required for MHC II upregulation in vitro, indicating that MAPK activity restrains an IFN-γ-responsive MHC-II program. Collectively, these findings identify tumor-cell MHC-II as an IFN-γ-dependent, MAPK-restrained program that denotes immunotherapy sensitivity in PDAC.