Fas ligand mediates immune privilege and not inflammation in human colon cancer, irrespective of TGF-beta expression.
Many cancers express Fas ligand (FasL/CD95L) in vivo, and can kill lymphoid cells by Fas-mediated apoptosis in vitro. However, overexpression of recombinant FasL in murine tumour allografts revealed a potential antitumour effect of FasL, via recruitment of neutrophils. Transforming growth factor-beta1 (TGF-beta1) could inhibit these neutrophil-stimulatory effects of FasL. In the present study, we sought to determine directly whether FasL contributes to immune privilege or tumour rejection in human colon cancers in vivo, and whether TGF-beta1 regulates FasL function. Serial tumour sections were immunostained for FasL and TGF-beta1. Neutrophils and tumour infiltrating lymphocytes (TILs) were detected by immunohistochemistry for lactoferrin and CD45, respectively. Apoptotic TIL were identified by dual staining for TUNEL/CD45. FasL expression by nests of tumour cells was associated with a mean four-fold depletion of TILs (range 1.8-33-fold, n=16, P<0.001), together with a two-fold increase in TIL apoptosis (range 1.6-2.5-fold, n=14, P<0.001), relative to FasL-negative nests within the same tumours. The overall level of neutrophils present in all tumours examined was low (mean 0.3%, n=16), with FasL expression by tumour nests associated with a mean two-fold decrease in neutrophils, irrespective of TGF-beta1 expression. Together, our results suggest that tumour-expressed FasL is inhibitory rather than stimulatory towards antitumour immune responses.
Houston
A
A
Department of Medicine, Clinical Sciences Building, National University of Ireland, University Hospital, Cork, Ireland.
Bennett
M W
MW
O'Sullivan
G C
GC
Shanahan
F
F
O'Connell
J
J
D003110:Colonic Neoplasms / Q000276:immunology* / Q000473:pathology; D053222:Fas Ligand Protein; D006801:Humans; D007111:Immunity, Cellular; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D007781:Lactoferrin / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008024:Ligands; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008562:Membrane Glycoproteins / Q000502:physiology*; D009504:Neutrophils / Q000276:immunology; D016612:Paraffin Embedding; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017493:Leukocyte Common Antigens; D007781:Lactoferrin