The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/10/1033/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 7, October 4, 1999 1033-1038

Brief Definitive Report

Immune Escape of Tumors in Vivo by Expression of Cellular Flice-Inhibitory Protein

Jan Paul Medemaa, Joan de Jonga, Thorbald van Halla, Cornelis J.M. Meliefa, and Rienk Offringaa

a Department of Immunohematology and Bloodbank, Leiden University Medical Center, 2333AA Leiden, The Netherlands
Dept. of Immunohematology and Bloodbank, LUMC, Albinusdreef 2a, 2333AA Leiden, The Netherlands.31-71-52-1675131-71-52-63013

medema{at}mail.medfac.leidenuniv.nl

The antiapoptotic protein cellular FLICE (Fas-associated death domain–like IL-1β–converting enzyme) inhibitory protein (cFLIP) protects cells from CD95(APO-1/Fas)-induced apoptosis in vitro and was found to be overexpressed in human melanomas. However, cytotoxic T cell–induced apoptosis, which is critically involved in tumor control in vivo, is not inhibited by cFLIP in vitro, as only CD95- and not perforin-dependent lysis is affected. This calls into question whether cFLIP is sufficient to allow escape from T cell–dependent immunity. Using two murine tumors, we directly demonstrate that cFLIP does result in escape from T cell immunity in vivo. Moreover, tumor cells are selected in vivo for elevated cFLIP expression. Therefore, our data indicate that CD95-dependent apoptosis constitutes a more prominent mechanism for tumor clearance than has so far been anticipated and that blockade of this pathway can result in tumor escape even when the perforin pathway is operational.

Key Words: CD95 • apoptosis • CTL • perforin • cytotoxicity

© 1999 The Rockefeller University Press


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