A key regulatory role of the transcription factor NFATc2 in bronchial adenocarcinoma via CD8+ T lymphocytes.

Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE

Publication: Baltimore, Md. : American Association for Cancer Research
Original Publication: Chicago [etc.]

Adenocarcinoma/*genetics ; Adenocarcinoma/*immunology ; Bronchial Neoplasms/*genetics ; Bronchial Neoplasms/*immunology ; CD8-Positive T-Lymphocytes/*immunology ; NFATC Transcription Factors/*biosynthesis; Adenocarcinoma/metabolism ; Animals ; Bronchial Neoplasms/metabolism ; CD4-Positive T-Lymphocytes/immunology ; Disease Models, Animal ; Forkhead Transcription Factors/biosynthesis ; Forkhead Transcription Factors/immunology ; Glucocorticoid-Induced TNFR-Related Protein ; Humans ; Interferon-gamma ; Interleukin-2/biosynthesis ; Interleukin-2/immunology ; Interleukin-2 Receptor alpha Subunit/biosynthesis ; Interleukin-2 Receptor alpha Subunit/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; NFATC Transcription Factors/deficiency ; NFATC Transcription Factors/genetics ; Receptors, Interleukin-7/biosynthesis ; Receptors, Interleukin-7/immunology ; Receptors, Nerve Growth Factor/biosynthesis ; Receptors, Nerve Growth Factor/immunology ; Receptors, Tumor Necrosis Factor/biosynthesis ; Receptors, Tumor Necrosis Factor/immunology ; Transcription, Genetic ; Transforming Growth Factor beta1/biosynthesis ; Transforming Growth Factor beta1/immunology ; Transplantation, Heterologous ; Tumor Necrosis Factor-alpha/biosynthesis ; Tumor Necrosis Factor-alpha/immunology

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.

0 (Forkhead Transcription Factors)
0 (Foxp3 protein, mouse)
0 (Glucocorticoid-Induced TNFR-Related Protein)
0 (Interleukin-2)
0 (Interleukin-2 Receptor alpha Subunit)
0 (NFATC Transcription Factors)
0 (NFATC2 protein, human)
0 (Receptors, Interleukin-7)
0 (Receptors, Nerve Growth Factor)
0 (Receptors, Tumor Necrosis Factor)
0 (Tnfrsf18 protein, mouse)
0 (Transforming Growth Factor beta1)
0 (Tumor Necrosis Factor-alpha)
0 (interleukin-7 receptor, alpha chain)
82115-62-6 (Interferon-gamma)

Date Created: 20090326 Date Completed: 20090602 Latest Revision: 20111117

20231215

10.1158/0008-5472.CAN-08-1678

19318584