T-Cell Deletion of MyD88 Connects IL17 and I kappa B zeta to RAS Oncogenesis

Cancer development requires a favorable tissue microenvironment. By deleting Myd88 in keratinocytes or specific bone marrow subpopulations in oncogenic RAS-mediated skin carcinogenesis, we show that IL17 from infiltrating T cells and I kappa B zeta signaling in keratinocytes are essential to produce a permissive microenvironment and tumor formation. Both normal and RAS-transformed keratinocytes respond to tumor promoters by activating canonical NF-kappa B and I kappa B zeta signaling, releasing specific cytokines and chemokines that attract Th17 cells through MyD88-dependent signaling in T cells. The release of IL17 into the microenvironment elevates I kappa B zeta in normal and RAS-transformed keratinocytes. Activation of I kappa B zeta signaling is required for the expression of specific promoting factors induced by IL17 in normal keratinocytes and constitutively expressed in RAS-initiated keratinocytes. Deletion of Nfkbiz in keratinocytes impairs RAS-mediated benign tumor formation. Transcriptional profiling and gene set enrichment analysis of I kappa B zeta-deficient RAS-initiated keratinocytes indicate that I kappa B zeta signaling is common for RAS transformation of multiple epithelial cancers. Probing The Cancer Genome Atlas datasets using this transcriptional profile indicates that reduction of I kappa B zeta signaling during cancer progression associates with poor prognosis in RAS-driven human cancers.

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