The Effect And Mechanism Of Decitabine In Combination With Adoptive ?? T Cell Therapy Against Osteosarcoma

Osteosarcoma is the most common primary malignant tumor in children and adolescents.Standard treatment involving neoadjuvant chemotherapy,surgery and post-operative chemotherapy has improved the five-year survival to the about 70%,however,the curative effect will be poor if patients unfortunately have relapsed or metastatic tumors.Immunotherapy has shown promising results in treating tumors in recent years.Adoptive cell therapy(ACT),as one of the major methods of immunotherapy,is widely studied in cancer treatment.?? T cell is the promising candidate for ACT because it can be easily acquired and expanded in vitro with unlimited quantity.However,adoptive ?? T cell therapy against OS has shown limited effect.Although several adjuvant methods have been used to enhance the cytotoxic effect of ?? T cell in the subsequent preclinical trials,the results seemed unsatisfactory.It is urgent to find a novel and safe way to overcome this challenge.Decitabine(DAC)not only induces tumor cell death but also has an immunomodulatory function.Importantly,it increases the expression of natural killer group 2D(NKG2D)ligands(NKG2DLs)on tumors,which enhances the NK cell-mediated cytotoxicity.In this study,we assessed the potential synergistic benefit of combining DAC and?? T cells for ACT against OS.DAC increased the expression of NKG2 DLs,like major histocompatibility complex class I-related chains B(MICB)and UL16-bindingprotein 1(ULBP1),on the OS cells,making them more sensitive to be recognized and killed by activated ?? T cells.Moreover,the cytotoxic effect of OS cells by ?? T cells was reversed by the inhibition of the NKG2 D receptor in part,indicating that the ?? T cell-mediated cytolysis of OS cells pretreated with DAC was mainly dependent on the NKG2D-NKG2 DL pathway.The in vivo study showed the similar results with that in vitro study.In summary,DAC could upregulate MICB and ULBP1 expression in OS cells and enhance the ?? T cell-mediated cytotoxic killing of OS cells.