Abstract
The Ca(2+)-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-alpha and interleukin-2 (IL-2) production by CD8(+) T cells. Adoptive transfer of CD8(+) T cells of NFATc2((-/-)) mice induced transforming growth factor-beta(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-gamma levels in the airways, reversed the suppression by T(reg) cells, and costimulated effector CD4(+)CD25(+) (IL-2Ralpha) and memory CD4(+)CD127(+) (IL-7Ralpha) 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-2Ralpha(+) effector and IL-7Ralpha(+) memory-expressing T cells.
Highlights
There is substantial evidence that cancer patients harbor tumorreactive T cells, their number and/or activity is apparently insufficient to eradicate tumors [1]
Expression of this NFATc2 mRNA transcript was significantly decreased in tissues derived from bronchial adenocarcinoma compared with control tissues and tissues showing histopathologic signs of pneumonia [single patient values are given in Fig. 1B and Supplementary Fig. S1]
The current study reveals an unexpected role of the nuclear transcription factor NFATc2 in integrating the function of CD8+ and CD4+ T cells in a murine model of lung adenocarcinoma
Summary
There is substantial evidence that cancer patients harbor tumorreactive T cells, their number and/or activity is apparently insufficient to eradicate tumors [1]. How such tumor-reactive T cells can be expanded and activated to turn against established tumors is a promising scientific endeavor in effective immunotherapy for cancer [2]. IL-2 and IL-7 have been used to activate T-cell responses in patients with tumors. The immunosuppressive agents cyclosporin A and FK506 target calcineurin and prevent the nuclear translocation and activation of NFAT factors, which emerge as critical activators of the immune response [10]. Asked whether NFATc2 expression would be defective in the lungs of patients with lung adenocarcinomas
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