CD8(+) T cells stimulated by exosomes derived from RenCa cells mediate specific immune responses through the FasL/Fas signaling pathway and, combined with GM-CSF and IL-12, enhance the anti-renal cortical adenocarcinoma effect

摘要

A satisfactory cure rate for renal cell carcinoma (RCC) is difficult to achieve through traditional immunotherapy. RCC has a relatively high spontaneous regression rate due to tumor immune escape. However, tumor-derived exosomes (TEXs), which effectively carry tumor-associated antigens (TAAs) and trigger stronger antigen-specific tumor immunity against autologous tumors than against other tumors, have been widely viewed as attractive potential vaccines for tumor treatment, although improvements are needed. Therefore, in our study, we determined whether RenCa cell-derived exosome (RDE)-stimulated CD8(+) T cells exert a stronger specific cytotoxic effect on autologous tumor cells than on other types of tumor cells through the Fas ligand (FasL)/Fas signaling pathway, and whether the combination of RDE-stimulated CD8(+) T cells with GM-CSF and IL-12 enhances the anticancer effect. The results showed that RDEs were isolated, as expected, and promoted an increased percentage of CD8(+)/CD4(+) T cells. RDE-stimulated CD8(+) T cells also more effectively facilitated cytotoxicity against RenCa cells when combined with GM-CSF and IL-12 in vitro. Furthermore, immunization with RDEs restrained the growth of RenCa tumors in mouse models, and facilitated the stimulation of a stronger specific cytotoxic CD8(+) T cell response via the FasL/Fas signaling pathway in vitro. However, these results were observed less frequently for other types of tumor cells after treatment with RDEs, suggesting that RDEs depend on their antigen specificity to trigger antitumor immune responses. These findings revealed that RDE-stimulated CD8(+) T cells combined with GM-CSF and IL-12 can more effectively exert a stronger cytotoxic effect than RDEs alone and that RDEs can induce immunization more effectively against renal cortical adenocarcinoma than against other types of cancer. Therefore, according to our study, exosomes are promising potential vaccines, and the combination of exosome-stimulated CD8(+) T cells with GM-CSF and IL-12 may be a novel strategy for the treatment of RCC.