Blockade of the Fas-triggered intracellular signaling pathway in human melanomas is circumvented by cytotoxic lymphocytes

Marina Ferrarini, Maria Adele Imro, Clara Sciorati, Silvia Heltai, Maria Pia Protti, Carlo Pellicciari, Patrizia Rovere, Angelo A. Manfredi, Claudio Rugarli

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)573-579
Number of pages7
JournalInternational Journal of Cancer
Volume81
Issue number4
DOIs
Publication statusPublished - 1999

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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