Overexpression of transforming growth factor-Β1 (TGFΒ1) 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 TGFΒ1 in premalignant squamous lesions. Within 48 hours of TGFΒ1 induction, there was an increase in IL-17 production by both CD4+ and γδ+ T cells, together with increased expression of T-helper-17 (Th17)-polarizing cytokines. Induction of TGFΒ1 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 TGFΒ1 signaling. Microarray analysis showed significant upregulation of proinflammatory genes 2 days after TGFΒ1 induction, and this was followed by increased MPO+, F4/80 +, and CD8+ cells in tumors, increased CD8+ effectors and IFNγ+ cells in skin-draining LNs, and tumor regression. In parallel, the percentage of tumor CD11b+ Ly6G + neutrophils was reduced. Neutralization of IL-17 blocked TGFΒ1-induced CD11b+ Ly6G- tumor infiltration but did not alter the reduction of neutrophils or tumor regression. Thus, TGFΒ1 overexpression causes IL-17-dependent and IL-17-independent changes in the premalignant tumor inflammatory microenvironment.
Bibliographical noteFunding Information:
We thank Dr Stuart Yuspa for support in the initial stages of this project, the NCI Center for Information Technology for advice on analysis of microarray data, the Huck Institute Flow Cytometry Core Facility for help with flow cytometry, and Dr Surojit Sarkar for advice on flow analysis of tumor-infiltrating leukocytes. This study was funded by grants CA117957 and 122109 to AG from the NCI.