miR-3188 介导的 IL-7Rα 转录激活在肿瘤免疫治疗研究中的作用

Adoptive cell therapy (ACT) utilizing tumor-infiltrating lymphocytes (TIL) is a promising immunotherapeutic approach for disseminated malignancies. However, ex vivo-expanded tumor-infiltrating lymphocytes (TIL) often rapidly progress to a state of functional exhaustion or suppression within the tumor microenvironment. Interleukin-7(IL-7) not only supports the survival of T-lymphocyte in vivo but also induces vigorous expansion of na ve and memory T lymphocytes in vitro. Upregulating the expression of interleukin-7 receptor alpha (IL-7R ) helps T cells restore their responsiveness to IL-7 signaling, aids in their survival, and enables them to regain anti-tumor activity.

Firstly, we utilized databases to analyze the expression changes of CD127 in different tumor tissues, clarifying the correlation between its expression changes and patient prognosis. Subsequently, we collected clinical patient samples to validate the expression changes of CD127 in tumor-infiltrating T cells. We also simulated the tumor microenvironment through in vitro co-culture to explore the impact of tumor cells on the expression of CD127 on the surface of T cells. After then, we screened for miRNAs that are complementary to the sequence of the TATA box region in the CD127 promoter and employed a CD127 promoter driven dual-luciferase reporter system to identify the specific miRNA capable of upregulating CD127 expression. Finally, we analyzed the effects of miRNA-mediated upregulation of CD127 on T cell function.

Bioinformatics analysis and clinical validation both confirmed decreased IL-7R expression in tumors. Moreover, in clinical samples, IL-7R and miR-3188 expression levels showed concordant changes and a positive correlation. miR-3188 can upregulate the expression level of IL-7R by specifically targeting the TATA-box region of CD127 promoter. Utilizing miR-3188 to upregulate IL-7R expression can facilitate T cell survival, promote the development of memory T cells and enhance the secondary response and tumor-killing capacity of T cells.

Our findings reveal a novel mechanism of IL-7R regulation and propose a potential strategy to improve the persistence and functionality of T cells for ACT.