Improving function of cytotoxic T-lymphocytes by transforming growth factor-β inhibitor in oral squamous cell carcinoma

Immunotherapy with immune-checkpoint therapy has recently been used to treat oral squamous cell carcinomas (OSCCs). However, improvements in current immunotherapy are expected because response rates are limited. Transforming growth factor-beta (TGF-beta) creates an immunosuppressive tumor microenvironment (TME) by inducing the production of regulatory T-cells (Tregs) and cancer-associated fibroblasts and inhibiting the function of cytotoxic T-lymphocytes (CTLs) and natural killer cells. TGF-beta may be an important target in the development of novel cancer immunotherapies. In this study, we investigated the suppressive effect of TGF-beta on CTL function in vitro using OSCC cell lines and their specific CTLs. Moreover, TGFB1 mRNA expression and T-cell infiltration in 25 OSCC tissues were examined by in situ hybridization and multifluorescence immunohistochemistry. We found that TGF-beta suppressed the function of antigen-specific CTLs in the priming and effector phases in vitro. Additionally, TGF-beta inhibitor effectively restored the CTL function, and TGFB1 mRNA was primarily expressed in the tumor invasive front. Interestingly, we found a significant negative correlation between TGFB1 mRNA expression and the CD8(+) T-cell/Treg ratio and between TGFB1 mRNA expression and the Ki-67 expression in CD8(+) T-cells, indicating that TGF-beta also suppressed the function of CTLs in situ. Our findings suggest that the regulation of TGF-beta function restores the immunosuppressive TME to active status and is important for developing new immunotherapeutic strategies, such as a combination of immune-checkpoint inhibitors and TGF-beta inhibitors, for OSCCs.