Oral Cancer-Derived miR-762 Suppresses T-Cell Infiltration and Activation by Horizontal Inhibition of CXCR3 Expression

Oral squamous cell carcinoma (OSCC) is an immune-cold tumor characterized by an immunosuppressive microenvironment with low cytotoxic activity to eliminate tumor cells. Tumor escape is one of the initial steps in cancer development. Understanding the underlying mechanisms of cancer escape can help researchers develop new treatment strategies. In this study, we prove the oral oncogenic miR-762 can suppress T-cell recruitment and cytotoxic activation in the tumor microenvironment (TME) through horizontal transmission from OSCC cells to adaptive immune T cells. Public database analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were used to determine the prognosis and expression of miR-762 in OSCC. T-cell activation by flow cytometry, qRT-PCR, IL-12 secretion, and T-cell recruitment and cytotoxicity abilities were conducted in the miR-762 manipulation T-cell and OSCC-T-cell co-culture system. A luciferase reporter and CXCR3 protein expression were also carried out to validate the direct interaction between CXCR3 and microRNA (miR)-762. This horizontal transmission of miR-762 directly suppresses CXCR3 expression in T cells, inhibiting CXCR3-induced T-cell migration and downstream T-cell cytotoxic activity by disrupting AKT activation. Additionally, miR-762 transmission suppressed T-cell activation marker expression, T-cell proliferation, IL-12 secretion, and T-cell cytotoxicity. In conclusion, our findings reveal a novel miR-762/CXCR3 axis that regulates the immunosuppressive microenvironment in OSCC and may be a potential RNA-targeted therapeutic approach to restore the anti-tumor immune response in OSCC treatment.