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1.
Science ; 339(6124): 1219-24, 2013 Mar 08.
Article in English | MEDLINE | ID: mdl-23471412

ABSTRACT

Despite considerable interest in the modulation of tumor-associated Foxp3(+) regulatory T cells (T(regs)) for therapeutic benefit, little is known about the developmental origins of these cells and the nature of the antigens that they recognize. We identified an endogenous population of antigen-specific T(regs) (termed MJ23 T(regs)) found recurrently enriched in the tumors of mice with oncogene-driven prostate cancer. MJ23 T(regs) were not reactive to a tumor-specific antigen but instead recognized a prostate-associated antigen that was present in tumor-free mice. MJ23 T(regs) underwent autoimmune regulator (Aire)-dependent thymic development in both male and female mice. Thus, Aire-mediated expression of peripheral tissue antigens drives the thymic development of a subset of organ-specific T(regs), which are likely coopted by tumors developing within the associated organ.


Subject(s)
Immune Tolerance , Prostate/immunology , Prostatic Neoplasms/immunology , T-Lymphocytes, Regulatory/immunology , Thymus Gland/growth & development , Thymus Gland/immunology , Transcription Factors/immunology , Animals , Antigens, Polyomavirus Transforming/genetics , Autoantigens/immunology , CD4 Antigens/analysis , Female , Forkhead Transcription Factors/analysis , Homeodomain Proteins/genetics , Male , Mice , Mice, Transgenic , Prostate-Specific Antigen/immunology , Transcription Factors/genetics , AIRE Protein
2.
Nature ; 462(7269): 104-7, 2009 Nov 05.
Article in English | MEDLINE | ID: mdl-19847165

ABSTRACT

NF-kappaB transcription factors function as crucial regulators of inflammatory and immune responses as well as of cell survival. They have also been implicated in cellular transformation and tumorigenesis. However, despite extensive biochemical characterization of NF-kappaB signalling during the past twenty years, the requirement for NF-kappaB in tumour development in vivo, particularly in solid tumours, is not completely understood. Here we show that the NF-kappaB pathway is required for the development of tumours in a mouse model of lung adenocarcinoma. Concomitant loss of p53 (also known as Trp53) and expression of oncogenic Kras(G12D) resulted in NF-kappaB activation in primary mouse embryonic fibroblasts. Conversely, in lung tumour cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-kappaB inhibition. Furthermore, the inhibition of NF-kappaB signalling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumours in vivo, from the time of tumour initiation or after tumour progression, resulted in significantly reduced tumour development. Together, these results indicate a critical function for NF-kappaB signalling in lung tumour development and, further, that this requirement depends on p53 status. These findings also provide support for the development of NF-kappaB inhibitory drugs as targeted therapies for the treatment of patients with defined mutations in Kras and p53.


Subject(s)
Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Disease Models, Animal , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , NF-kappa B/metabolism , Signal Transduction , Animals , Apoptosis , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line , Cell Line, Tumor , Cell Survival , Cells, Cultured , DNA/metabolism , Fibroblasts , Genes, p53/genetics , Humans , Mice , NF-kappa B/antagonists & inhibitors , Oncogene Protein p21(ras)/genetics , Oncogene Protein p21(ras)/metabolism , Transcription Factor RelA/metabolism , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
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