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Enhanced Antitumor Immunity in Mice Deficient in CD69

Enric Esplugues¹, David Sancho², Javier Vega-Ramos¹, Carlos Martínez-A³, Uta Syrbe⁴, Alf Hamann⁴, Pablo Engel⁵, Francisco Sánchez-Madrid² and Pilar Lauzurica¹

¹ Departamento de Fisiología, Universidad de Barcelona, Barcelona 08080, Spain
² Servicio de Immunología, Hospital de la Princesa, Madrid 28006, Spain
³ Department of Immunology and Oncology, Centro Nacional de Biotecnología, Spanish Council for Scientific Research-UAM, Madrid 28006, Spain
⁴ Experimentelle Rheumatologie, Medizinische Klinik, Charite, Humboldt-Universitat Berlin and Deutsches Rheumaforschungszentrum, Berlin 10117, Germany
⁵ Immunology Unit, Department of Cellular Biology and Pathology, University of Barcelona Medical School, Institut d'Investigacions Biomediques August Pi y Sunyer, Barcelona 08080, Spain

Address correspondence to Pilar Lauzurica, Departmento de Fisiología, Universidad de Barcelona, Avenida Diagonal, 645, Barcelona 08080 Spain. Phone: 34-93-403-5924; Fax: 34-93-411-0358; E-mail: lauzu{at}porthos.bio.ub.es

We investigated the in vivo role of CD69 by analyzing the susceptibility of CD69-/- mice to tumors. CD69-/- mice challenged with MHC class I^- tumors (RMA-S and RM-1) showed greatly reduced tumor growth and prolonged survival compared with wild-type (WT) mice. The enhanced anti–tumor response was NK cell and T lymphocyte–mediated, and was due, at least in part, to an increase in local lymphocytes. Resistance of CD69-/- mice to MHC class I^- tumor growth was also associated with increased production of the chemokine MCP-1, diminished TGF-ß production, and decreased lymphocyte apoptosis. Moreover, the in vivo blockade of TGF-ß in WT mice resulted in enhanced anti–tumor response. In addition, CD69 engagement induced NK and T cell production of TGF-ß, directly linking CD69 signaling to TGF-ß regulation. Furthermore, anti-CD69 antibody treatment in WT mice induced a specific down-regulation in CD69 expression that resulted in augmented anti–tumor response. These data unmask a novel role for CD69 as a negative regulator of anti–tumor responses and show the possibility of a novel approach for the therapy of tumors.

Key Words: cytokines • homeostasis • apoptosis

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