Autocrine secretion of Fas ligand shields tumor cells from Fas-mediated killing by cytotoxic lymphocytes.
Mechanisms responsible for resistance of tumors to death receptor-mediated damage by cytotoxic lymphocytes are not well understood. Uveal melanoma cells expressed Fas but were insensitive to Fas triggering induced by bystander cytotoxic T lymphocytes or a Fas-specific agonistic antibody; this could not be ascribed to tumor counterattack against T cells or general resistance of the tumors to apoptosis. Treatment with inhibitors of metalloproteases rendered uveal melanomas sensitive to Fas-mediated cytotoxicity. Metalloprotease inhibitors did not affect the expression of Fas but increased the surface expression of Fas ligand (FasL), which correlated with the disappearance of soluble FasL from culture supernatants of tumor cells. FasL eluted from the surface of uveal melanomas specifically inhibited cytotoxic T lymphocyte lysis of tumor cells pretreated with an inhibitor of metalloproteases. In addition to uveal melanomas, a number of other tumor cell lines of various cellular origins were sensitized to Fas-mediated cytotoxicity by metalloprotease inhibitors. Our results show that autocrine secretion of FasL shields tumor cells from Fas-mediated killing by cytotoxic lymphocytes. This defines a novel mechanism of tumor escape from immune surveillance.
Hallermalm
Kristian
K
Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
De Geer
Anna
A
Kiessling
Rolf
R
Levitsky
Victor
V
Levitskaya
Jelena
J
D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D053222:Fas Ligand Protein; D006801:Humans; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism*; D045726:Metalloproteases / Q000037:antagonists & inhibitors; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014604:Uveal Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000556:secondary
D051017:Apoptosis Regulatory Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D045726:Metalloproteases