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Tumor-Derived TGF-1 Induces Dendritic Cell Apoptosis in the Sentinel Lymph Node

Manabu Ito^*, Yoshihiro Minamiya^1,*, Hideki Kawai^*, Satoshi Saito^*, Hajime Saito^*, Taku Nakagawa^*, Kazuhiro Imai^*, Makoto Hirokawa and Jun-ichi Ogawa^*

^* Division of Thoracic Surgery, Department of Surgery, and Division of Hematology and Oncology, Department of Medicine, Akita University School of Medicine, Hondo Akita City, Japan

Lymphatic flux from a primary tumor initially flows into a tumor-draining lymph node (LN), the so-called sentinel LN (SLN). Carried by the lymph fluid are a variety of mediators produced by the tumor that can influence immune responses within the SLN, making it a good model with which to investigate tumor-related immunology. For instance, dendritic cell (DC) numbers are reduced in SLNs from melanoma and breast cancer patients. In the present study, we investigated the mechanism by which DC numbers were reduced within SLNs from patients with non-small cell lung cancer. We found that the incidence of apoptosis among DCs was higher in SLNs than in non-SLNs, as were levels of TGF-1. In contrast, levels of TGF-1 mRNA did not differ between SLNs and non-SLNs, but were 30 times higher in tumors than in either LN type. In vitro, incubation for 2 days with TGF-1 induced apoptosis among both cultured DCs and DCs acutely isolated from normal thoracic LNs, effects that were blocked by the TGF-1 inhibitor DAN/Fc chimera. Taken together, these results suggest that tumor-derived TGF-1 induces immunosuppression within SLNs before the movement of tumor cells into the SLNs, thereby facilitating metastasis within those nodes.

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