Sorafenib Inhibits Doxorubicin-Induced PD-L1 Upregulation to Improve Immunosuppressive Microenvironment in Osteosarcoma

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Abstract
Purpose: Although undergoing conventional chemotherapy significantly improves the prognosis of osteosarcoma, chemoresistance and failure of therapy is still a significant challenge. Furthermore, conventional chemotherapy, like doxorubicin, would upregulate the expression of Programmed death-ligand 1 (PD-L1) which caused an immunosuppressive microenvironment and unsatisfied treatment result in Osteosarcoma. Thus, it is urgent to explore a strategy to overcome this disadvantage.Methods: Human Osteosarcoma cell line MG63 and mouse Osteosarcoma cell line K7 were included in this study. Subcutaneous tumor model was used by injection K7 cells in BALB/C mice to test the effect of doxorubicin and sorafenib on tumor growth. PD-L1 expression was tested in vitro (flow cytometry, western blot and PCR) and in vivo (flow cytometry and immunohistochemistry). Proportion of immune cells (CD4, CD8, Tregs and cytotoxic T lymphocytes) in vivo was analyzed with flow cytometry.Results: Combination of sorafenib and doxorubicin inhibited tumor growth significantly in vivo. Doxorubicin increased PD-L1 expression in vitro and in vivo, while sorafenib inhibited doxorubicin-induced PD-L1 upregulation in vitro and in vivo. Proportion of interferon-γ-secreting CD8+ T lymphocytes in tumor tissue was increased significantly when combined sorafenib with doxorubicin, while proportion of CD4, CD8 and Tregs was not significantly changed. Extracellular Signal-Regulated Kinases (ERK) pathway could be one of the key mechanisms by which doxorubicin induced upregulation of PD-L1 in osteosarcoma cells.Conclusion: Combination of sorafenib and conventional chemotherapeutic reagents is a potent strategy to improve treatment effectiveness by modulating tumor micro environment in Osteosarcoma through increasing proportion of cytotoxic T lymphocytes.

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