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.

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.

• 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
• Journal: Journal of translational medicine (J Transl Med) Vol. 14 Pg. 84 (Apr 11 2016) ISSN: 1479-5876 [Electronic] England
• PMID: 27063186 (Publication Type: Journal Article)

Chemical References

• MCL1 protein, human
• MIRN198 microRNA, human
• MIRN29a microRNA, human
• MicroRNAs
• Myeloid Cell Leukemia Sequence 1 Protein
• JAK3 protein, human
• Janus Kinase 3

Topics

• Adult
• Aged
• Apoptosis (genetics)
• CD8-Positive T-Lymphocytes (metabolism)
• Carcinoma, Renal Cell (genetics, immunology)
• Cell Separation
• Down-Regulation (genetics)
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Janus Kinase 3 (genetics, metabolism)
• Kidney Neoplasms (genetics, immunology)
• Leukocytes, Mononuclear (metabolism)
• Male
• MicroRNAs (genetics, metabolism)
• Middle Aged
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Phenotype
• Tissue Donors
• Transfection
• Transplantation, Homologous
• Tumor Cells, Cultured
• Up-Regulation (genetics)