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Gap Junction Communication between Autologous Endothelial and Tumor Cells Induce Cross-Recognition and Elimination by Specific CTL¹

Houssem Benlalam^*, Abdelali Jalil^2,*, Meriem Hasmim^2,*, Baoxu Pang, Ryad Tamouza, Michèle Mitterrand^¶, Yann Godet^||, Nathalie Lamerant^¶, Caroline Robert, Marie-Françoise Avril^#, Jacques Neefjes, Thomas Tursz, Fathia Mami-Chouaib^*, Claudine Kieda^¶ and Salem Chouaib^3,*

^* Institut National de la Santé et de la Recherche Médicale Unite 753 (INSERM U753), Institut Fédératif de Recherche 54, and Département de Médecine, Institut Gustave Roussy, Villejuif, France; Division of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Département d’Immunologie et d’Histocompatibilité, INSERM U662, Hôpital Saint Louis, Paris, France; ^¶ Centre National de la Recherche Scientifique (CNRS), Centre de Biophysique Moléculaire, Unité Propre de Recherche 4301, Orléans, France; ^|| INSERM U601, Département de Recherche en Cancérologie, Nantes, France; and ^# Assistance Publique-Hôpital de Paris, Hôpital Cochin, Service de Dermatologie, Université Paris V, Paris, France

Cellular interactions in the tumor stroma play a major role in cancer progression but can also induce tumor rejection. To explore the role of endothelial cells in these interactions, we used an in vitro three-dimensional collagen matrix model containing a cytotoxic T lymphocyte CTL clone (M4.48), autologous tumor cells (M4T), and an endothelial cell (M4E) line that are all derived from the same tumor. We demonstrate in this study that specific killing of the endothelial cells by the CTL clone required the autologous tumor cells and involved Ag cross-presentation. The formation of gap junctions between endothelial and tumor cells is required for antigenic peptide transfer to endothelial cells that are then recognized and eliminated by CTL. Our results indicate that gap junctions facilitate an effective CTL-mediated destruction of endothelial cells from the tumor microenvironment that may contribute to the control of tumor progression.

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 This work was supported by grants from Institut National Du Cancer, Association pour la Recherche sur le Cancer (3922), La Ligue Contre le Cancer (Comité du Val-de-Marne), l’Agence Nationale de la Recherche, Cancéropole Ile-de-France, and Institut National de la Santé et de la Recherche Médicale.

² A.J. and M.H. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Salem Chouaib, Institut National de la Santé et de la Recherche Médicale Unité 753, Institut Gustave Roussy, 39 Rue Camille Desmoulins, F-94805 Villejuif, France. E-mail address: chouaib{at}igr.fr

⁴ Abbreviations used in this paper: EC, endothelial cell; AM, acetoxymethyl ester; β₂m, β₂-microglobulin; CMFDA, 5-chloromethylfluorescein diacetate; CMTMR, 5-(and –6)-(((4-chloromethyl)benzoyl)amino)tetramethylrhodamine; FL, fluorescently labeled; 18GA, 18-glycyrrhetinic; GJ, gap junction; GJIC, GJ intercellular communication; siRNA, small interfering RNA.

⁵ The online version of this article contains supplemental material.

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