TGFβ1-Induced Inflammation in Premalignant Epidermal Squamous Lesions Requires IL-17

Overexpression of transforming growth factor-beta 1 (TGF beta 1) in the normal epidermis can provoke an inflammatory response, but whether this occurs within a developing tumor is not clear. To test this, we used an inducible transgenic mouse to overexpress TGF beta 1 in premalignant squamous lesions. Within 48 hours of TGFb1 induction, there was an increase in IL-17 production by both CD4(+) and gamma delta(+) T cells, together with increased expression of T-helper-17 (Th17)-polarizing cytokines. Induction of TGF beta 1 in premalignant primary keratinocytes elevated the expression of proinflammatory and Th17-polarizing cytokines, and the keratinocyte-conditioned media caused IL-17 production by naive T cells that was dependent on T-cell TGF beta 1 signaling. Microarray analysis showed significant upregulation of proinflammatory genes 2 days after TGF beta 1 induction, and this was followed by increased MPO+, F4/80(+), and CD8(+) cells in tumors, increased CD8(+) effectors and IFN gamma(+) cells in skin-draining LNs, and tumor regression. In parallel, the percentage of tumor CD11b(+)Ly6G(+) neutrophils was reduced. Neutralization of IL-17 blocked TGF beta 1-induced CD11 beta(+) Ly6G(-) tumor infiltration but did not alter the reduction of neutrophils or tumor regression. Thus, TGF beta 1 overexpression causes IL-17-dependent and IL-17-independent changes in the premalignant tumor inflammatory microenvironment.