The role of miR-3188-mediated transcriptional activation of IL-7Rα in tumor immunotherapy research

Abstract

Background

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 naïve and memory T lymphocytes in vitro. Upregulating the expression of interleukin-7 receptor alpha (IL-7Rα) helps T cells restore their responsiveness to IL-7 signaling, aids in their survival, and enables them to regain anti-tumor activity.

Methods

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.

Results

Bioinformatics analysis and clinical validation both confirmed decreased IL-7Rα expression in tumors. Moreover, in clinical samples, IL-7Rα and miR-3188 expression levels showed concordant changes and a positive correlation. miR-3188 can upregulate the expression level of IL-7Rα by specifically targeting the TATA-box region of CD127 promoter. Utilizing miR-3188 to upregulate IL-7Rα 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.

Conclusion

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