Increased Fas ligand expression by T cells and tumour cells in the progression of actinic keratosis to squamous cell carcinoma.
BACKGROUND
In the counterattack model of tumorigenesis, it has been proposed that tumours develop resistance to attack from Fas ligand (FasL)-expressing cytotoxic T cells by downregulating Fas (immune escape), while at the same time upregulating FasL expression to induce apoptosis in Fas-expressing T cells (counterattack).


OBJECTIVE
The aim of this study was to examine Fas and FasL expression on tumour cells and infiltrating T cells during the progression of actinic keratoses (AK), the benign precursor lesion, to squamous cell carcinoma (SCC).


METHODS
Samples of AK (n = 20) and SCC (n = 20) were collected from immunocompetent patients attending dermatology clinics. Double-label immunohistochemistry was performed on frozen sections using mouse monoclonal antibodies to Fas or FasL, simultaneously with a rabbit polyclonal antibody to either CD3 or cytokeratin, markers of T cells and keratinocytes, respectively. Cell densities and the optical density of tumour Fas expression were measured using image analysis.


RESULTS
FasL-expressing T cells were observed in nine of 19 SCCs, compared with three of 20 AKs (P < 0.05). FasL-expressing tumour cells were found in nine of 18 SCCs, compared with only one of 20 AK specimens (P < 0.005). There was no difference in the number of Fas-expressing T cells infiltrating AK and SCC. Fas expression by keratinocytes, measured by optical density, was lower in SCC (range 0.1-40, median 17) compared with AK (range 4-62, median 25) (P < 0.05).


CONCLUSIONS
These results suggest that the greater numbers of FasL-expressing T cells infiltrating into SCC compared with AK are targeting Fas-expressing tumour cells. As AK cells progress to SCC, they subvert this T-cell-mediated killing of tumour cells by downregulating their Fas expression (immune escape). Furthermore, tumour cells upregulate their expression of FasL, possibly as a counterattack measure to induce apoptosis in the increased number of tumour-infiltrating T cells. Thus changes in Fas/FasL-mediated interactions between T cells and tumour cells occur during the progression of AK into SCC.
Department of Medicine (Dermatology), Melanoma and Skin Cancer Research Institute, Sydney Cancer Centre, Blackburn Building DO6, Royal Prince Alfred Hospital at The University of Sydney, NSW 2006, Australia.
A C
AC
Satchell
R StC
RS
Barnetson
G M
GM
Halliday
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000473:pathology; D018450:Disease Progression; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D007150:Immunohistochemistry / Q000379:methods; D007642:Keratosis / Q000276:immunology* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis*; D008875:Middle Aged; D010787:Photosensitivity Disorders / Q000276:immunology* / Q000473:pathology; D012878:Skin Neoplasms / Q000276:immunology*; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000032:analysis
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor