miR-155-5p Silencing Does Not Alter BTLA Molecule Expression in CLL T Cells: Implications for Targeted Immunotherapy

TL;DR

The study finds that silencing miR-155-5p does not affect BTLA levels in T cells from CLL patients, suggesting it could be a safe immunotherapy target.

Contribution

This is the first study to show that anti-miR-155-5p therapy does not alter BTLA in T cells, supporting its potential in CLL immunotherapy.

Findings

miR-155-5p silencing significantly reduced miR-155-5p levels in PBMCs of CLL patients and healthy individuals.

BTLA protein expression in T cells remained unchanged after miR-155-5p silencing in both groups.

Anti-miR-155-5p therapy may be a favorable strategy in CLL without affecting T cell BTLA expression.

Abstract

Given that we have demonstrated that miR-155-5p is increased in CLL PBMCs and that its reduction with inhibitory siRNA partially restores the immune checkpoint BTLA protein level in CLL B cells, risk stratification for using anti-miR-155-based immunotherapy in CLL seems reasonable, particularly with its potential impact on T cells. Therefore, we aimed to assess the role of miR-155-5p in the epigenetic modification of BTLA levels in CLL T cells, especially since we observed that BTLA expression unfavorably promotes increased proliferative activity and IL-4 secretion in T cells, thus suggesting BTLA malfunction in the CLL T cell subset. Transfection of PBMCs with an inhibitor of miR-155-5p (INH) led to about a ten-fold down-regulation of miR-155-5p levels compared to control siRNA (NC) both in CLL patients and healthy individuals (HC), as assessed by RT-qPCR. Additionally, we did not find any significant differences in BTLA protein expression in T cells after silencing miR-155-5p in either examined group. We demonstrated for the first time that immunotherapy approaches based on systemic administration of anti-miR-155-5p therapeutics would be a favorable strategy in CLL, since they do not affect BTLA expression in T cell populations and could benefit CLL patients with impaired BTLA levels on CLL cells.

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