TGF-β1 in Tumor Microenvironments Induces Immunosuppression in the Tumors and Sentinel Lymph Nodes and Promotes Tumor Progression

In cancer patients, sentinel lymph nodes (SLNs) are crucial in the induction of antitumor T cells. However, in many cases, SLNs and tumors appear to be in immunosuppressive condition through mechanisms yet to be elucidated. In this study, the role of tumor-derived TGF-1 in the generation of immunosuppressive microenvironments of tumors and SLNs was investigated. Murine colorectal carcinoma CT26 transduced with TGF-1 cDNA (CT26-TGF-1) showed enhanced tumor growth compared with mock-transduced CT26 (CT26-Mock) when implanted in syngeneic Balb/c mice, even though CT26-TGF-1 shows slower growth in vitro. This enhanced growth was not observed when implanted in immunodeficient mice, suggesting that TGF-1 enhanced tumor growth by suppressing antitumor T-cell responses. Analysis of immune cells in CT26-TGF-1-implanted mice revealed impairment of dendritic cells (DCs), decrease of CD8(+) T cells, and increase of MDSCs and Tregs in the tumors. Similarly, the SLNs of these mice showed an increase of MDSCs, Tregs, and PD-L1(+) DCs, and decrease of T-cell stimulatory activity of DCs accompanied by decreased CD80 expression and TNF- production. In addition, induction of tumor antigen-specific T cells from SLNs of the CT26-TGF-1-implanted mice was significantly reduced. These results demonstrate that overproduction of TGF-1 is critical for the generation of immunosuppressive microenvironments in both tumors and SLNs, which may result in suppression of spontaneous antitumor CD8(+) T-cell responses. Therefore, TGF-1 is an attractive target for restoration of immunosuppressive condition in cancer patients.