CCR4 mediated chemotaxis of regulatory T cells suppress the activation of T cells and NK cells via TGF-β pathway in human non-small cell lung cancer.

C-C chemokine receptor type 4 has been reported to correlate with lung cancer. However, the role of CCR4 in human non-small cell lung cancer patients is not well defined. Here, we demonstrated that increased expression of CCR4 was associated with clinical stage and CCR4 was an independent risk factor for overall survival in NSCLC patients. Moreover, tumor-infiltrating Treg cells were higher expression than matched adjacent tissues in CCR4+ NSCLC. Higher expression of chemokine CCL17 and CCL22 could recruit Treg cells to tumor sites in NSCLC. Treg in TIL exhibit a higher level of suppressive activity on effector T cells than matched adjacent tissues in NSCLC patients. Significant NK cell reduction was observed in tumor regions compared to non-tumor regions. NK cells demonstrated that reduced the killing capacity against target cells and the expression of CD69  in vitro. The addition of Treg cells from NSCLC patients efficiently inhibited the anti-tumor ability of autologous NK cells. Treatment with anti-TGF-β antibody restored the impaired cytotoxic activity of T cells and NK cells from tumor tissues. Our results indicate that TGF-β plays an important role in impaired Teff cells and NK cells. It will therefore be valuable to develop therapeutic strategies against CCR4 and TGF-β pathway for therapy of NSCLC.