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AntagomiRs targeting miR-146a and miR-21 induce tumor cell death and reinvigorate CD8+ T-cell function in large-cell transformed mycosis fungoides

ABSTRACT: Large cell transformation in mycosis fungoides (LCT-MF) occurs in 20-50% of patients with advanced MF, the most common subtype of cutaneous T cell lymphoma (CTCL) and is associated with an aggressive clinical course and poor survival. We previously identified a distinct microRNA (miR) expression profile in LCT-MF with upregulation of miR-21 and miR-146a compared to non-LCT MF. Here, we investigated the efficacy of 2 novel synthesized and chemically modified antagomiRs amiR-146a, and amiR-21 linked to CpG–D19 for delivery on both tumor growth and T cell exhaustion. Targeting miR-146 and miR-21 alone or combined induced apoptosis through activated caspase 3/7 pathways and caused cell cycle arrest at the G2/M phase via the STAT3/CDK1/Cyclin B1 pathway in CTCL cell lines. In vivo, treatment reduced tumor growth and prolonged survival in mouse xenograft models. CD8+ T cells from LCT-MF patient biopsies exhibited upregulation of immune checkpoint proteins and activation of the STAT3/IRF4/BATF pathway, similar to exhausted CD8+ T cells from healthy donors stimulated to exhaustion in a CTCL culture model. Treatment of these exhausted CD8+ T cells with amiR-146a and amiR-21 alone or combined attenuated their exhaustion phenotype through decreased immune checkpoint expression, and enhanced cytokine production by inhibiting the STAT3/IRF4/BATF pathway. Collectively, our findings indicate that targeting miR-146a and miR-21 offers a promising new therapeutic approach for LCT-MF, by both suppressing tumor growth and restoring T cell function to enhance anti-tumor immunity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306408 | GEO | 2026/08/23

REPOSITORIES: GEO

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Project description:Increasing evidences support a potential role for the Signal Transducer and Activator of Transcription-3 (STAT3) as a tumor driver in cutaneous T-cell lymphoma (CTCL). However, the mechanisms leading to STAT3 pathway activation in CTCL and how STAT3 activation contributes to lymphomagenesis remains primarily not enough explored. Recently, we found that miR-124, a known STAT3 regulator in cancer, is robustly silenced in Mycosis Fungoides (MF) tumor-stage and CTCL cell lines and we have herein studied whether deregulation of miR-124 contributes to activate STAT3 pathway in CTCL. Material and Methods: DNA methylation status of miR-124 and its expression levels in response to the DNA-demethylating agent azacitidine were evaluated in CTCL cell lines by pyrosequencing analysis. CTCL cell lines were transient transfected with a lentiviral vector encoding miR-124 and transfected cells were analyzed for phosphorylated STAT3 (P-STAT3) levels. The impact on STAT3 signaling was evaluated using expression microarray on CTCL cell lines in both conditions, miR-124 absent (malignant condition) versus miR-124 expressed (lentiviral transduction). Results: A significant promoter methylation and silencing of miR-124 in MF tumor samples and CTCL cell lines was detected. DNA methylation levels of miR-124 in CTCL cell lines were restored (and subsequently miR-124 were overexpressed) after DNA demethylation. Ectopic lentiviral expression of miR-124 downregulated STAT3 in the different CTCL cell lines. Genes differentially expressed regarding miR-124 regulation in CTCL cell lines indicated impact on known cell survival and function pathways and, particularly, intervention on miR-124 expression modulated different STAT3 pathway components. Conclusions: Our study deciphers a novel epigenetic mechanisms regulating STAT3 pathway in CTCL. This might contribute to a better understanding the molecular basis in CTCL development. Deregulation of STAT3 seems to have a major impact on cell survival in CTCL cell lines indicating the potential interest of targeting STAT3 with specific therapies.

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AntagomiRs targeting miR-146a and miR-21 induce tumor cell death and reinvigorate CD8+ T-cell function in large-cell transformed mycosis fungoides

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