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A Key Regulatory Role of the Transcription Factor NFATc2 in Bronchial Adenocarcinoma via CD8⁺ T Lymphocytes

¹ Laboratory of Cellular and Molecular Immunology of the Lung, I. Medical Clinic, University of Mainz; ² Department of Internal Medicine III and ³ Institute of Molecular Medicine, Johannes Gutenberg University, Mainz, Germany and ⁴ Institute of Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland

Requests for reprints: Susetta Finotto, Laboratory of Cellular and Molecular Lung Immunology, I. Medical Clinic, University of Mainz, Obere Zahlbacher Strasse 63, Room 02-115, 55131 Mainz, Germany. Phone: 49-06131-3933376; Fax: 49-06131-3937140; E-mail: finotto{at}mail.uni-mainz.de.

Key Words: lung • NFATc2 • T cells

The Ca²⁺-regulated calcineurin/nuclear factor of activated T cells (NFAT) cascade controls alternative pathways of T-cell activation and peripheral tolerance. Here, we describe reduction of NFATc2 mRNA expression in the lungs of patients with bronchial adenocarcinoma. In a murine model of bronchoalveolar adenocarcinoma, mice lacking NFATc2 developed more and larger solid tumors than wild-type littermates. The extent of central tumor necrosis was decreased in the tumors in NFATc2^(–/–) mice, and this finding was associated with reduced tumor necrosis factor- and interleukin-2 (IL-2) production by CD8⁺ T cells. Adoptive transfer of CD8⁺ T cells of NFATc2^(–/–) mice induced transforming growth factor-β₁ in the airways of recipient mice, thus supporting CD4⁺CD25⁺Foxp-3⁺glucocorticoid-induced tumor necrosis factor receptor (GITR)⁺ regulatory T (T_reg) cell survival. Finally, engagement of GITR in NFATc2^(–/–) mice induced IFN- levels in the airways, reversed the suppression by T_reg cells, and costimulated effector CD4⁺CD25⁺ (IL-2R) and memory CD4⁺CD127⁺ (IL-7R) T cells, resulting in abrogation of carcinoma progression. Agonistic signaling through GITR, in the absence of NFATc2, thus emerges as a novel possible strategy for the treatment of human bronchial adenocarcinoma in the absence of NFATc2 by enhancing IL-2R⁺ effector and IL-7R⁺ memory-expressing T cells. [Cancer Res 2009;69(7):3069–76]