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J. Biol. Chem., Vol. 283, Issue 46, 31665-31672, November 14, 2008

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Resistance of Tumor Cells to Cytolytic T Lymphocytes Involves Rho-GTPases and Focal Adhesion Kinase Activation^*

Soraya Abouzahr-Rifai¹, Meriem Hasmim¹, Habib Boukerche, Jocelyne Hamelin^¶, Bassam Janji^||, Abdelali Jalil, Claudine Kieda^**, Fathia Mami-Chouaib, Jacques Bertoglio^¶, and Salem Chouaib²

From the Institut Gustave Roussy, INSERM U753, 94800 Villejuif, France, Laboratoire Hémobiologie, EA 4174-INSERM/Université Lyon I, 69372 Lyon, France, ^¶INSERM U749, 92296 Châtenay-Malabry, France, ^||Laboratory of Experimental Hemato-Cancerology, Public Research Centre for Health, Luxembourg City, 1526 Luxembourg, and ^**Centre of Molecular Biophysics, 45071 Orleans, France

Tumor cells evade adaptive immunity by a variety of mechanisms, including selection of variants that are resistant to specific cytotoxic T lymphocyte (CTL) pressure. Recently, we have reported that the reorganization of the actin cytoskeleton can be used by tumor cells as a strategy to promote their resistance to CTL-mediated lysis. In this study, we further examined the functional features of a CTL-resistant tumor variant and investigated the relationship between cytoskeleton alteration, the acquisition of tumor resistance to CTL-induced cell death, Rho-GTPases, and focal adhesion kinase (FAK) pathways. Our data indicate that although the resistant cells do not display an increased migratory potential, an alteration of adhesion to the extracellular matrix was observed. When Rho-GTPases were activated in cells by the bacterial CNF1 (cytotoxic necrotizing factor 1), striking changes in the cell morphology, including actin cytoskeleton, focal adhesions, and membrane extensions, were observed. More importantly, such activation also resulted in a significant attenuation of resistance to CTL-induced cell death. Furthermore, we demonstrate that FAK signaling pathways were constitutively defective in the resistant cells. Silencing of FAK in the sensitive target cells resulted in the inhibition of immune synapse formation with specific CTLs and their subsequent lysis. Expression of the FAK mutant (Y397F) resulted in an inhibition of IGR-Heu cell adhesion and of their susceptibility to specific lysis. These results suggest that FAK activation plays a role in the control of tumor cell susceptibility to CTL-mediated lysis.

Received for publication, January 4, 2008 , and in revised form, August 22, 2008.

^* This work was supported by grants from INSERM, Association pour la Recherche Contre le Cancer Grants 4744, 3501, and 3922, by the Canceropole Ile-de-France, and by the Institut National du Cancer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Institut Gustave Roussy, INSERM U753, 39 Rue Camille Desmoulins, F-94805 Villejuif Cedex, France. Tel.: 33-1-42-11-45-47; Fax: 33-1-42-11-52-88; E-mail: chouaib{at}igr.fr.

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