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

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

^* To whom correspondence should be addressed. E-mail: finotto{at}mail.uni-mainz.de.

	Abstract

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-₁ 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]

Key Words: lung, NFATc2, T cells