title: A key regulatory role of the transcription factor NFATc2 in bronchial adenocarcinoma via CD8+ T lymphocytes.
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.
authors.affiliation: Laboratory of Cellular and Molecular Immunology of the Lung, I. Medical Clinic, University of Mainz, Mainz, Germany.
authors.forename: Joachim H
authors.initials: JH
authors.lastname: Maxeiner
authors.forename: Roman
authors.initials: R
authors.lastname: Karwot
authors.forename: Kerstin
authors.initials: K
authors.lastname: Sauer
authors.forename: Petra
authors.initials: P
authors.lastname: Scholtes
authors.forename: Ildiko
authors.initials: I
authors.lastname: Boross
authors.forename: Michael
authors.initials: M
authors.lastname: Koslowski
authors.forename: Ozlem
authors.initials: O
authors.lastname: Türeci
authors.forename: Rainer
authors.initials: R
authors.lastname: Wiewrodt
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.forename: Hans A
authors.initials: HA
authors.lastname: Lehr
authors.forename: Susetta
authors.initials: S
authors.lastname: Finotto