Abstract #LB-149: Tumor-infiltrating IL-17-producing \#947;\#948; T cells promote angiogenesis and subsequent tumor progression
Authors: Daiko Wakita, Kenji Chamoto, Takayuki Ohkuri, Kentaro Sumida, Harumichi Ishigame, Yoichiro Iwakura, Hiroyoshi Nishikawa, Yuji Togashi, Hidemitsu Kitamura, Takashi Nishimura
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

IL-17, a proinflammatory cytokine, is involved in various autoimmune disorders and infectious diseases. Although it has been indicated that IL-17 was expressed in both human and mice tumor tissues, the precise role of IL-17 in tumor immunology remains unclear. In this work, we established a tumor-bearing mouse model by transplantation with CMC-G4 fibrosarcoma and investigated the physiological function of IL-17 in the tumor growth. We found that angiogenesis around the tumor tissues and the growth of tumor were significantly suppressed in IL-17-deficient mice compared with wild-type mice. Interestingly, we revealed that tumor-infiltrating \#947;\#948; T cells predominantly produced IL-17 rather than CD4+ T cells and CD8+ T cells. Moreover, accumulation of IL-17-producing \#947;\#948; T cells was observed even in MCA-induced primary tumor tissues. The number of IL-17-producing \#947;\#948; T cells increased only in tumor tissues but not in the draining lymph nodes or spleen. The \#947;\#948; T cells in tumor tissue, which showed an effecter phenotype, produced IL-17 but not IFN-\#947; after stimulation with anti-CD3 and anti-CD28 mAb. We found that the IL-17 production of tumor-infiltrating \#947;\#948; T cells required the signaling via \#947;\#948; TCR and NKG2D molecules. Further analysis demonstrated that although the tumor-infiltrating \#947;\#948; T cells expressed NKG2D, these cells strikingly reduced expression of perforin, relative to spleen cells of equivalent phenotype. In the present model, mRNA expression of IL-23, IL-6, and TGF-\#946;, known as IL-17-inducible cytokines, were detected in the tumor tissues. In vivo administration of neutralizing antibodies against these cytokines significantly reduced IL-17 production by tumor-infiltrating \#947;\#948; T cells. Moreover, tumor-infiltrating \#947;\#948; T cells but not CD4+ T cells and CD8+ T cells produced IL-17 in response to IL-23 in vitro . We further revealed that IL-17-producing \#947;\#948; T cells, which induced in the presence of IL-6, TGF-\#946;, and IL-23 in vitro, had no cytotoxic activity. The co-injection of the IL-17-producing \#947;\#948; T cells together with tumor cells into IL-17-deficient mice significantly promoted the tumor growth compared with the injection of IL-17-deficient \#947;\#948; T cells in the same conditions. These findings suggest that IL-17-producing \#947;\#948; T cells, generated in response to tumor microenvironment factors including IL-23, IL-6, and TGF-\#946;, promote angiogenesis and the subsequent tumor progression. Thus, IL-17 and the related cytokines would be promising targets for establishment of a novel strategy in cancer therapy.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-149.