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