Blockade of the Fas-triggered intracellular signaling pathway in human melanomas is circumvented by cytotoxic lymphocytes.
Fas and Fas ligand (FasL) have been found both in lymphoid and in non-lymphoid malignancies, and are thought to play a role in the interplay between tumors and the immune system. Here we investigated Fas/FasL expression, function and intracellular signalling pathways in human melanomas. Of 5 melanoma cell lines, 3 expressed Fas at their surface, and all of them expressed FasL. FasL was functional, since it triggered Fas-induced apoptosis of human T lymphocytes clones. Conversely, cross-linking of Fas molecule with a specific monoclonal antibody failed to induce apoptosis in any of the melanomas tested, or ceramide intracellular accumulation or caspase-3 activation, pointing to an early alteration in the Fas-triggered signaling cascade. All melanomas retained the ability to undergo apoptosis induced by cytotoxic lymphocytes, which was mediated by the granule exocytosis mechanism. This suggests that melanoma cells evade immune-mediated Fas-triggered apoptosis via a selective blockade of the Fas apoptotic pathway. Cytotoxic lymphocytes, however, may circumvent tumor resistance to Fas-induced death via granzyme-mediated apoptosis, further supporting the development of immunotherapeutic strategies in the treatment of cancer.
Ferrarini
M
M
Laboratorio di Immunologia dei Tumori, Divisione di Medicina II, H San Raffaele Scientific Institute, Milan, Italy. ferrarini.m@hsr.it
Imro
M A
MA
Sciorati
C
C
Heltai
S
S
Protti
M P
MP
Pellicciari
C
C
Rovere
P
P
Manfredi
A A
AA
Rugarli
C
C
D015703:Antigens, CD / Q000276:immunology; D017209:Apoptosis; D002478:Cells, Cultured; D002999:Clone Cells; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology / Q000502:physiology; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
D015703:Antigens, CD; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D019014:fas Receptor