Loss of Cutaneous TSLP-Dependent Immune Responses Skews the Balance of Inflammation from Tumor Protective to Tumor Promoting

SummaryInflammation can promote or inhibit cancer progression. In this study we have addressed the role of the proinflammatory cytokine thymic stromal lymphopoietin (TSLP) during skin carcinogenesis. Using conditional loss- and gain-of-function mouse models for Notch and Wnt signaling, respectively, we demonstrate that TSLP-mediated inflammation protects against cutaneous carcinogenesis by acting directly on CD4 and CD8 T cells. Genetic ablation of TSLP receptor (TSLPR) perturbs T-cell-mediated protection and results in the accumulation of CD11b+Gr1+ myeloid cells. These promote tumor growth by secreting Wnt ligands and augmenting β-catenin signaling in the neighboring epithelium. Epithelial specific ablation of β-catenin prevents both carcinogenesis and the accumulation of CD11b+Gr1+ myeloid cells, suggesting tumor cells initiate a feed-forward loop that induces protumorigenic inflammation.

Graphical AbstractFigure optionsDownload high-quality image (321 K)Download as PowerPoint slideHighlights
► TSLP protects against skin cancer by acting directly on dermal T cells
► Protumorigenic CD11b+Gr1+ cells accumulate upon ablation of TSLPR signaling
► The development of skin tumors is β-catenin dependent
► Tumors establish a feed-forward loop by recruiting Wnt-secreting CD11b+Gr1+ cells