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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number84
JournalJournal of Translational Medicine
Volume14
Issue number1
DOIs
Publication statusPublished - Apr 11 2016

Keywords

  • Apoptosis
  • CD8 T cells
  • JAK3
  • MCL-1
  • MiRNA
  • Renal cell carcinoma

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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