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

Gigante, M and Pontrelli, P and Herr, W and Gigante, M and D'Avenia, M and Zaza, G and Cavalcanti, E and Accetturo, M and Lucarelli, G and Carrieri, G and Battaglia, M and Storkus, WJ and Gesualdo, L and Ranieri, E (2016) 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. Journal of Translational Medicine, 14 (1).

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Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Gigante, M Pontrelli, P Herr, W Gigante, M D'Avenia, M Zaza, G Cavalcanti, E Accetturo, M Lucarelli, G Carrieri, G Battaglia, M Storkus, WJ storkusw@pitt.edu STORKUSW 0000-0001-8961-4444 Gesualdo, L Ranieri, E
Date:	11 April 2016
Date Type:	Publication
Access Restriction:	No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title:	Journal of Translational Medicine
Volume:	14
Number:	1
DOI or Unique Handle:	10.1186/s12967-016-0841-9
Institution:	University of Pittsburgh
Schools and Programs:	School of Medicine > Dermatology School of Medicine > Immunology
Refereed:	Yes
Date Deposited:	21 Jul 2016 20:27
Last Modified:	03 Mar 2023 16:55
URI:	http://d-scholarship.pitt.edu/id/eprint/28683

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