Keratin 17 promotes epithelial proliferation and tumor growth by polarizing the immune response in skin

Basaloid skin tumors, including basal cell carcinoma (BCC) and basaloid follicular hamartoma (BFH), are associated with aberrant Hedgehog (Hh) signaling1 and, in the case of BCC, an expanding set of genetic variants including keratin 5 (K5)2, an intermediate filament-forming protein. We show that genetic ablation of keratin 17 (K17) protein, which is induced in basaloid skin tumors3,4 and co-polymerizes with K5 in vivo5, delays BFH tumor initiation and growth in mice with constitutive Hh signaling in epidermis6,7. The delay is preceded by reduced inflammation and a polarization of inflammatory cytokines from a Th1/Th17- to a Th2-dominated profile. Absence of K17 also attenuates hyperplasia and inflammation in a model of acute dermatitis. Re-expression of K17 in Gli2(tg) K17(−/−) keratinocytes induces select Th1 chemokines with established roles in BCC. Our findings establish a novel immunomodulatory role for K17 in Hh-driven basaloid skin tumors that could impact additional tumor settings, psoriasis, and wound repair.