Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles

Giovanna Andreola, Licia Rivoltini, Chiara Castelli, Veronica Huber, Paola Perego, Paola Deho, Paola Squarcina, Paola Accornero, Francesco Lozupone, Luana Lugini, Annarita Stringaro, Agnese Molinari, Giuseppe Arancia, Massimo Gentile, Giorgio Parmiani, Stefano Fais

Research output: Contribution to journalArticlepeer-review

Abstract

The hypothesis that FasL expression by tumor cells may impair the in vivo efficacy of antitumor immune responses, through a mechanism known as 'Fas tumor counterattack,' has been recently questioned, becoming the object of an intense debate based on conflicting results. Here we definitely show that FasL is indeed detectable in the cytoplasm of melanoma cells and its expression is confined to multivesicular bodies that contain melanosomes. In these structures FasL colocalizes with both melanosomal (i.e., gp100) and lysosomal (i.e., CD63) antigens. Isolated melanosomes express FasL, as detected by Western blot and cytofluorimetry, and they can exert Fas-mediated apoptosis in Jurkat cells. We additionally show that melanosome-containing multivesicular bodies degranulate extracellularly and release FasL-bearing microvesicles, that coexpress both gp100 and CD63 and retain their functional activity in triggering Fas-dependent apoptosis of lymphoid cells. Hence our data provide evidence for a novel mechanism potentially operating in Fas tumor counterattack through the secretion of subcellular particles expressing functional FasL. Such vesicles may form a sort of front line hindering lymphocytes and other immunocompetent cells from entering neoplastic lesions and exert their antitumor activity.

Original languageEnglish
Pages (from-to)1303-1316
Number of pages14
JournalJournal of Experimental Medicine
Volume195
Issue number10
DOIs
Publication statusPublished - May 20 2002

Keywords

  • Apoptosis
  • Melanoma
  • Melanosome
  • Microvesicles
  • T cells

ASJC Scopus subject areas

  • Immunology

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