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

Meng Zhang,Qing Li,Yanmei Shi,Yujuan Zhang,Zhu-Xu Zhang,Rakesh Joshi,Hongmei Wang,Daheng Liu,Weiping Min,James Koropatnick,Dian Gao,Qiongfang Yu,Yifan Wang,Faizah Alotaibi

doi:10.1098/rsob.190061

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.

Highlights

T-cell exhaustion was first defined as a state of immune dysfunction in chronic lymphocytic choriomeningitis virus infection [1]
Exhaustion is characterized by elevated levels of inhibitory receptors (IRs) such as programmed death-1 (PD1), cytotoxic T-lymphocyte antigen 4 (CTLA4), T-cell immunoglobulin domain and mucin domain 3 (TIM3), B- and T-lymphocyte attenuator (BTLA), and lymphocyte activation gene 3 (LAG3), CD244 (2B4) [4,5,6,7,8,9]; diminished levels of effector cytokines, such as interlekin-2 (IL-2), tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ); and impaired CD8+ T-cell cytotoxicity [10]
To evaluate CD8+ T-cell exhaustion in 4T1 breast tumourbearing mice, we examined the level of IR mRNAs, including

Summary

Introduction

T-cell exhaustion was first defined as a state of immune dysfunction in chronic lymphocytic choriomeningitis virus infection [1]. During the process of exhaustion, T cells chronically exposed to tumour antigens or viral antigens gradually lose their ability to kill cancer cells or virus-infected cells expressing those antigens. A member of subfamily P of the forkhead box (FOX) transcription factor family, plays a pivotal role in modulating early B-cell development, T-cell quiescence and monocyte differentiation, and in mediating effective antitumour immune response [11,12,13,14]. Foxp is highly expressed in oestrogen receptor-positive human breast cancer cells and can inhibit the migration of tumour-infiltrating T cells [15]. Targeting Foxp may improve PD-1/PD-L1 pathway-associated antitumour immunity

Methods

Results

Conclusion