miR-149-3p reverses CD8 ⁺ T-cell exhaustion by reducing inhibitory receptors and promoting cytokine secretion in breast cancer cells

Abstract

Blockade of inhibitory receptors (IRs) is one of the most effective immunotherapeutic approaches to treat cancer. Dysfunction of miRNAs is a major cause of aberrant expression of IRs and contributes to the immune escape of cancer cells. How miRNAs regulate immune checkpoint proteins in breast cancer remains largely unknown. In this study, downregulation of miRNAs was observed in PD-1-overexpressing CD8+ T cells using miRNA array analysis of mouse breast cancer homografts. The data reveal that miR-149-3p was predicted to bind the 3'UTRs of mRNAs encoding T-cell inhibitor receptors PD-1, TIM-3, BTLA and Foxp1. Treatment of CD8+ T cells with an miR-149-3p mimic reduced apoptosis, attenuated changes in mRNA markers of T-cell exhaustion and downregulated mRNAs encoding PD-1, TIM-3, BTLA and Foxp1. On the other hand, T-cell proliferation and secretion of effector cytokines indicative of increased T-cell activation (IL-2, TNF-α, IFN-γ) were upregulated after miR-149-3p mimic treatment. Moreover, the treatment with a miR-149-3p mimic promoted the capacity of CD8+ T cells to kill targeted 4T1 mouse breast tumour cells. Collectively, these data show that miR-149-3p can reverse CD8+ T-cell exhaustion and reveal it to be a potential antitumour immunotherapeutic agent in breast cancer.

Inhibition of long non-coding RNA XIST upregulates microRNA-149-3p to repress ovarian cancer cell progression

“…Consistently, Zhu et al 24 have discovered that XIST is OE in cervical cancer tissues and cell lines, and this overexpression is also demonstrated by another study focusing on cervical cancer 10 . Moreover, miR-149-3p expression has been demonstrated to be repressed in tumor-bearing mouse spleens in BC 25 and Sun et al 14 have supported that miR-149 is decreased in OC tissues and cells. A higher expression of FOXP3 in epithelial OC tissues at advanced stages has been found in a recent study 26 .…”

Circular PVT1 regulates cell proliferation and invasion via miR-149-5p/FOXM1 axis in ovarian cancer

“…To deeply investigate the phenomenon of ovarian cancer cell viability and apoptosis induced by circular PVT1, we conducted bioinformatics analysis and found circular PVT1 regulated miR-149-5p in the form of ceRNA, and miR-149-5p directly bond to 3'UTR of FOXM1 mRNA to repress FOXM1 expression. MiR-149 is considered to be a versatile tumor suppressor, which is down-regulated in several cancer types [47][48][49][50][51]. MiR-149-5p was identified to be a suppressor of ovarian cancer.…”

miRNA-Based Therapeutics in the Era of Immune-Checkpoint Inhibitors

“…They analyzed CD8+ spleen T cells from TNBC bearing mice and noted relevant expression of exhaustion markers (i.e., LAG-3, TIM-3, PD-1). When they transfected the CD8+ T cells with a miR-149-3 mimic, they noted a reversal of T cell exhaustion with increased secretion of effector cytokines (i.e., TNF-α, IFN-γ, interleukin (IL)-2) leading to tumor cell killing in vitro, rendering this miRNA a potential candidate for therapeutic interventions [ 100 ].…”