Transforming growth factor-beta1 immobilises dendritic cells within skin tumours and facilitates tumour escape from the immune system.
Human skin tumours often regress spontaneously due to immune rejection. Murine skin tumours model this behaviour; some regress and others progress in syngeneic immunocompetent hosts. Previous studies have shown that progressor but not regressor skin tumours inhibit dendritic cell (DC) migration from the tumour to draining lymph nodes, and transforming growth factor-beta1 (TGF-beta1) has been identified as a responsible factor. To determine whether increased production of TGF-beta1 in the absence of other differences inhibits DC migration from the tumour and enables it to evade immune destruction, a murine regressor squamous cell carcinoma clone was transfected with the gene for TGF-beta1. This enhanced growth in vitro and in vivo, causing it to become a progressor. TGF-beta1 transfection reduced the number of infiltrating DCs by about 25%. Quantitation of CD11c+ E-cadherin+ (epidermally derived) DCs in lymph nodes determined that TGF-beta1 reduced the number of DCs that migrated from the tumour to undetectable levels. This was supported by showing that TGF-beta1 reduced DC migration from cultured tumour explants by greater than tenfold. TGF-beta1 transfection also reduced the number of infiltrating CD4 and CD8 T cells. Thus, TGF-beta1 production by skin tumours is sufficient to immobilise DCs within the tumour, preventing their migration to lymph nodes. This reduces the number of T cells that infiltrate the tumour, preventing regression. Thus, TGF-beta1 is a key regulator of whether skin tumours regress or progress.
Weber
Florian
F
Dermatology Research Unit, Melanoma and Skin Cancer Research Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, University of Sydney, Blackburn Building, D06, Sydney, NSW, 2006, Australia.
Byrne
Scott N
SN
Le
Shery
S
Brown
David A
DA
Breit
Samuel N
SN
Scolyer
Richard A
RA
Halliday
Gary M
GM
D000818:Animals; D039521:CD11c Antigen / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D012878:Skin Neoplasms / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*; D053773:Transforming Growth Factor beta1; D019139:Tumor Escape / Q000276:immunology*
D039521:CD11c Antigen; D015820:Cadherins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1