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Intratumoral Induction of CD103 Triggers Tumor-Specific CTL Function and CCR5-Dependent T-Cell Retention

¹ Institut National de la Santé et de la Recherche Médicale U753, Laboratoire "Immunologie des tumeurs humaines: Interaction Effecteurs cytotoxiques-système tumoral," Institut Fédératif de Recherche-54, Institut de cancérologie Gustave Roussy; ² CNRS UMR 8121 Vectorologie et Transfert de Gènes and ³ Unité de génomique fonctionnelle, Institut de cancérologie Gustave Roussy, Villejuif, France; ⁴ Department of Cancer Immunology, Poznan University of Medical Sciences and Great Poland Cancer Center, Poznan, Poland; and ⁵ Service d'Anatomie-Pathologie, Institut Mutualiste Montsouris; ⁶ Institut National de la Santé et de la Recherche Médicale U543, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine, Université Pierre et Marie Curie-Paris 6, Paris, France

Requests for reprints: Fathia Mami-Chouaib, Institut National de la Santé et de la Recherche Médicale U753, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France. Phone: 33-1-42-11-49-65; Fax: 33-1-42-11-52-88; E-mail: cfathia{at}igr.fr.

Key Words: CTL • CD103 • CCR5 • T-cell migration • TIL

We have reported previously that the interaction of _E(CD103)β₇ integrin, expressed on a CD8⁺ tumor-infiltrating lymphocyte (TIL) clone but not on a peripheral blood lymphocyte (PBL) counterpart, with the epithelial marker E-cadherin on human lung tumor cells plays a crucial role in T-cell receptor–mediated cytotoxicity. We show here that both TIL and PBL clones are able to migrate toward autologous tumor cells and that chemokine receptor CCR5 is involved in this process. Adoptive transfer of the PBL clone in the cognate tumor engrafted in nonobese diabetic/severe combined immunodeficient mice and subsequent coengagement of T-cell receptor and transforming growth factor-β1 receptor triggers CD103 expression on T-cell surface resulting in strong potentiation of antitumor lytic function. Moreover, interaction of _Eβ₇ integrin with E-cadherin, but not lymphocyte function-associated antigen-1 with intercellular adhesion molecule-1, promotes CCR5 recruitment at the immunologic synapse formed between TIL and tumor cells, leading to inhibition of T-cell sensitivity to CCL5 chemotactic gradient. These results provide evidence for a role of tumor microenvironment, namely MHC class I–restricted antigen presentation and transforming growth factor-β1 secretion, in regulating the effector phase of tumor-specific CTL response. They also suggest a unique role of CD103 in T-cell retention at the tumor site by a CCR5-dependent mechanism. [Cancer Res 2009;69(15):6249–55]