Title |
miR-29b and miR-198 overexpression in CD8+ T cells of renal cell carcinoma patients down-modulates JAK3 and MCL-1 leading to immune dysfunction
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Published in |
Journal of Translational Medicine, April 2016
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DOI | 10.1186/s12967-016-0841-9 |
Pubmed ID | |
Authors |
Margherita Gigante, Paola Pontrelli, Wolfgang Herr, Maddalena Gigante, Morena D’Avenia, Gianluigi Zaza, Elisabetta Cavalcanti, Matteo Accetturo, Giuseppe Lucarelli, Giuseppe Carrieri, Michele Battaglia, Walter J. Storkus, Loreto Gesualdo, Elena Ranieri |
Abstract |
Mammalian microRNAs (miR) regulate the expression of genes relevant for the development of adaptive and innate immunity against cancer. Since T cell dysfunction has previously been reported in patients with renal cell carcinoma (RCC; clear cell type), we aimed to analyze these immune cells for genetic and protein differences when compared to normal donor T cells freshly after isolation and 35 days after in vitro stimulation (IVS) with HLA-matched RCC tumor cells. We investigated gene expression profiles of tumor-reactive CD8(+) T cells obtained from RCC patient and compared with their HLA-matched healthy sibling donors using a microarray approach. In addition, miRNAs analysis was performed in a validation cohort of peripheral blood CD8(+) T cells from 25 RCC patients compared to 15 healthy volunteers. We observed that CD8(+) T cells from RCC patients expressed reduced levels of anti-apoptotic and proliferation-associated gene products when compared with normal donor T cells both pre- and post-IVS. In particular, JAK3 and MCL-1 were down-regulated in patient CD8(+) T cells versus their normal counterparts, likely due to defective suppressor activity of miR-29b and miR-198 in RCC CD8(+) T cells. Indeed, specific inhibition of miR-29b or miR-198 in peripheral blood mononuclear cells (PBMCs) isolated from RCC patients, resulted in the up-regulation of JAK3 and MCL-1 proteins and significant improvement of cell survival in vitro. Our results suggest that miR-29b and miR-198 dysregulation in RCC patient CD8(+) T cells is associated with dysfunctional immunity and foreshadow the development of miR-targeted therapeutics to correct such T cell defects in vivo. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Unknown | 4 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 4 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 43 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 7 | 16% |
Student > Bachelor | 7 | 16% |
Researcher | 7 | 16% |
Student > Master | 5 | 12% |
Student > Doctoral Student | 2 | 5% |
Other | 4 | 9% |
Unknown | 11 | 26% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 13 | 30% |
Medicine and Dentistry | 5 | 12% |
Agricultural and Biological Sciences | 2 | 5% |
Psychology | 2 | 5% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 5% |
Other | 8 | 19% |
Unknown | 11 | 26% |