Loss of cutaneous TSLP-dependent immune responses skews the balance of inflammation from tumor protective to tumor promoting.
Inflammation 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.
Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Institute for Experimental Cancer Research, Lausanne, Vaud 1015, Switzerland.
Matteo
M
Di Piazza
Craig S
CS
Nowell
Ute
U
Koch
André-Dante
AD
Durham
Freddy
F
Radtke
D000818:Animals; D039481:CD11b Antigen / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D016207:Cytokines / Q000502:physiology*; D006413:Hematopoietic System / Q000166:cytology; D007136:Immunoglobulins / Q000502:physiology; D007249:Inflammation / Q000150:complications / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000502:physiology; D018121:Receptors, Cytokine / Q000502:physiology; D051880:Receptors, Notch / Q000502:physiology; D012867:Skin / Q000276:immunology*; D012878:Skin Neoplasms / Q000209:etiology* / Q000517:prevention & control; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000502:physiology; D000094632:Thymic Stromal Lymphopoietin
D039481:CD11b Antigen; D016207:Cytokines; D007136:Immunoglobulins; D018121:Receptors, Cytokine; D051880:Receptors, Notch; C410591:Tslpr protein, mouse; D051176:beta Catenin; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse