Abstract 4923: MyD88 and IL-17 have essential local and systemic functions in promoting tumors on mouse skin

Abstract

Abstract NF-kB has been causally implicated with cancer-associated inflammation. In the skin, ligands of the Toll-like receptor/IL-1 receptor superfamily induce the recruitment of MyD88 (Myeloid differentiation primary response gene 88), ultimately leading to NF-kB activation. We previously reported that MyD88 is required for two stage chemical carcinogenesis on mouse skin, and that MyD88 exerts a cell-intrinsic function in RAS-mediated transformation of keratinocytes (Ras-keratinocytes). Now, we explore the role of MyD88 during tumor promotion with 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Epidermal hyperplasia is reduced in MyD88 deficient mice relative to controls after multiple applications of TPA. Furthermore, the upregulation of the chemokines Cxcl1 and S100a8 in response to TPA was deficient in MyD88 null cultured keratinocytes revealing a necessary role for MyD88 in the intrinsic response of keratinocytes to phorbol ester. We also uncovered a systemic requirement for MyD88 in carcinogenesis since lineage specific ablation of MyD88 in T cells conferred significant resistance to skin tumorigenesis and reduced infiltration of IL-17 positive T cells in TPA treated MyD88 null mouse skin. IL-17 treatment of normal primary keratinocytes increased their proliferation while reducing their response to calcium-induced differentiation but had no effect on the proliferation of RAS-keratinocytes. The atypical nuclear IkBzeta protein can act as an activator of so-called secondary NF-kB response genes. IkBzeta deficiency blocked the keratinocyte proliferative response to IL-17 but had no effect on altered differentiation. Finally, both IL-17 and oncogenic RAS required IkBzeta to upregulate the expression of S100a8, lipocalin2 and Steap4 mRNAs. Collectively, these results demonstrate that MyD88 plays a pro-tumorigenic function during tumor promotion in both epithelial and T-cell compartments and that IL-17/IkBzeta could play a facilitating role on keratinocytes during tumor promotion beyond its pro-inflammatory activity. Citation Format: Mary Klosterman, Christophe Cataisson, Rosalba Salcedo, Kelly Shibuya, Jennifer Waters, Giorgio Trinchieri, Stuart H. Yuspa. MyD88 and IL-17 have essential local and systemic functions in promoting tumors on mouse skin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4923. doi:10.1158/1538-7445.AM2017-4923