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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics*
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Adenocarcinoma / immunology*
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Adenocarcinoma / metabolism
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Animals
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Bronchial Neoplasms / genetics*
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Bronchial Neoplasms / immunology*
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Bronchial Neoplasms / metabolism
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CD4-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / immunology*
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Disease Models, Animal
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Forkhead Transcription Factors / biosynthesis
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Forkhead Transcription Factors / immunology
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Glucocorticoid-Induced TNFR-Related Protein
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Humans
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Interferon-gamma
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Interleukin-2 / biosynthesis
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Interleukin-2 / immunology
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Interleukin-2 Receptor alpha Subunit / biosynthesis
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Interleukin-2 Receptor alpha Subunit / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Transgenic
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NFATC Transcription Factors / biosynthesis*
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NFATC Transcription Factors / deficiency
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NFATC Transcription Factors / genetics
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Receptors, Interleukin-7 / biosynthesis
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Receptors, Interleukin-7 / immunology
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Receptors, Nerve Growth Factor / biosynthesis
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Receptors, Nerve Growth Factor / immunology
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Receptors, Tumor Necrosis Factor / biosynthesis
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Receptors, Tumor Necrosis Factor / immunology
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Transcription, Genetic
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Transforming Growth Factor beta1 / biosynthesis
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Transforming Growth Factor beta1 / immunology
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Transplantation, Heterologous
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / immunology
Substances
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Glucocorticoid-Induced TNFR-Related Protein
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Interleukin-2
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Interleukin-2 Receptor alpha Subunit
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NFATC Transcription Factors
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NFATC2 protein, human
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Receptors, Interleukin-7
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Receptors, Nerve Growth Factor
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Receptors, Tumor Necrosis Factor
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Tnfrsf18 protein, mouse
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Transforming Growth Factor beta1
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Tumor Necrosis Factor-alpha
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interleukin-7 receptor, alpha chain
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Interferon-gamma