TGF-β Receptor II Loss Promotes Mammary Carcinoma Progression by Th17-Dependent Mechanisms

We report that interleukin (IL)-17 significantly increases the secretion of CXC chemokine ligand 1 and 5 (CXCL1/5) from mammary carcinoma cells, and that stimulated secretion of CXCL1/5 by IL-17 is down-regulated by TGF-beta through the type II TGF-beta receptor (T beta RII). Carcinoma cells with conditional knockout of T beta RII (Tgfbr2(KO)) have enhanced sensitivity to IL-17a in the stimulation of chemokine secretion. During polyoma middle T (PyMT)-induced tumor progression, levels of Th17-inducing cytokines TGF-beta, IL-6, and IL-23 were increased in PyMT/Tgfbr2(KO) tumors, which was associated with an increased number of Th17 cells. IL-17 increased the suppressive function of myeloid-derived suppressor cells (MDSC) on T cells through the up-regulation of Arg, IDO, and cyclooxygenase-2. Treatment of PyMT/Tgfbr2KO mice with anti-IL-17 Ab decreased carcinoma growth and metastatic burden. Analysis of human breast cancer transcriptome databases demonstrated a strong association between IL-17 gene expression and poor outcome in lymph node-positive, estrogen receptor-negative, or luminal B subtypes, suggesting potential therapeutic approaches. SIGNIFICANCE: TGF-beta signaling is a major tumor suppressor pathway and is therefore difficult to target therapeutically. Understanding the downstream effects of abrogation of TGF-beta signaling in tumor cells may identify processes that can be targeted therapeutically. We present data indicating that targeting IL-17 signaling, a pathway that is greatly enhanced by loss of TGF-beta signaling, could provide a therapeutic benefit. Analysis of human databases indicated a specific group of patients in whom treatment could be more efficient. Cancer Discovery;1(5):430-41. (C) 2011 AACR.