Tumor-derived TGFbeta-1 induces dendritic cell apoptosis in the sentinel lymph node.
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 TGFbeta-1. In contrast, levels of TGFbeta-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 TGFbeta-1 induced apoptosis among both cultured DCs and DCs acutely isolated from normal thoracic LNs, effects that were blocked by the TGFbeta-1 inhibitor DAN/Fc chimera. Taken together, these results suggest that tumor-derived TGFbeta-1 induces immunosuppression within SLNs before the movement of tumor cells into the SLNs, thereby facilitating metastasis within those nodes.
Ito
Manabu
M
Division of Thoracic Surgery, Department of Surgery, Akita university School of medicine, 1-1-1 Hondo, Akita City 01-8543, Japan.
Minamiya
Yoshihiro
Y
Kawai
Hideki
H
Saito
Satoshi
S
Saito
Hajime
H
Nakagawa
Taku
T
Imai
Kazuhiro
K
Hirokawa
Makoto
M
Ogawa
Jun-ichi
J
D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000473:pathology*; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D018655:Lymphocyte Count; D009367:Neoplasm Staging; D021701:Sentinel Lymph Node Biopsy; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1