Impaired immunosurveillance by the simultaneous loss of both atypical PKCs drives serrated intestinal cancer

The serrated adenocarcinoma subtype accounts for 15-30% of all colorectal cancers (CRCs) and is aggressive and treatment-resistant. it is an alternative mechanism for CRC development characterized by dysregulation of the MAPK pathway. We show that human serrated tumors display reduced expression of PKCz and PKCl/i, and that the simultaneous inactivation of these genes in the mouse intestinal epithelium resulted in spontaneous tumorigenesis through the serrated pathway that progressed to advanced cancer. Whereas epithelial PKCl/i deficiency led to immunogenic cell death that repressed tumor initiation, interferon and CD8+ T cell responses were impaired concomitant with stromal activation and immunosuppression driven by PKCz loss. Thus, PKCz and PKCl/i cooperatively suppress serrated tumorigenesis. Targeting this stromal activation and immunosuppression showed synergistic curative activity. Overall design: RNA was extracted from small intestinal tissues from WT and intestinal epithelial cell-specific atypical PKC (both PKClambda/iota and PKCzeta) mice.