Microenvironment and Immunology IL-17A Produced by gd T Cells Promotes Tumor Growth in Hepatocellular Carcinoma

Interleukin (IL)-17A is expressed in the tumor microenvironment where it appears to contribute to tumor development, but its precise role in tumor immunity remains controversial. Here, we report mouse genetic evidence that IL-17A is critical for tumor growth. IL-17A–deficientmice exhibited reduced tumor growth,whereas systemic administration of recombinant mouse IL-17A promoted the growth of hepatocellular carcinoma. The tumor-promoting effect of IL-17A wasmediated through suppression of antitumor responses, especially CD8þ Tcell responses. Furthermore, we found that IL-17Awas producedmainly byVg4 gd Tcells, insofar as depletingVg4 gd T cells reduced tumor growth, whereas adoptive transfer of Vg4 gd T cells promoted tumor growth. Mechanistic investigations showed that IL-17A induced CXCL5 production by tumor cells to enhance the infiltration of myeloid-derived suppressor cells (MDSC) to tumor sites in a CXCL5/CXCR2–dependent manner. IL-17A also promoted the suppressive activity of MDSC to reinforce suppression of tumoral immunity. Moreover, we found that MDSC could induce IL-17A–producing gd T cells via production of IL-1b and IL-23. Conversely, IL-17A could also enhance production of IL-1b and IL-23 in MDSC as a positive feedback. Together, our results revealed a novel mechanism involving cross-talk among gd T cells, MDSCs, and tumor cells through IL-17A production. These findings offer new insights into how IL-17A influences tumor immunity, with potential implications for the development of tumor immunotherapy. Cancer Res; 74(7); 1–14. 2014 AACR.