The Role Of Aurora-A Inhibitors In Remodelling Breast Cancer Tumor Microenvironment

The Aurora-A inhibitor alisertib shows encouraging activities in clinical trials against advanced breast cancer.Aurora-A,a conserved serine/threonine kinase,functions in centrosome maturation and spindle formation in cell division cycle.It is frequently overexpressed and/or amplified in various cancer types and upregulated Aurora-A has widely proved to be associated with drug resistance and worse prognosis.These factors make Aurora-A a promising chemotherapeutic target.Currently,Aurora-A kinase inhibitors are involved in a number of clinical trials for treatment of multiple cancer types.Alisertib,a selective Aurora-A kinase inhibitor,provides advantages over traditional anti-mitotic drugs.This drug has showed promising efficacy in a number of preclinical studies and several clinical trials including a recent five-arm phase II study against advanced breast cancer and small cell lung cancer.However,the in vivo mechanism of this agent remains vague.The tumor microenvironment has been demonstrated to play important roles not only in tumor progression,but also in cancer therapy.Tumor development is accompanied by the occurrence and persistence of an immunosuppressive microenvironment.The amplification of myeloid derived suppressor cells(MDSCs)and tumor associated macrophages(TAMs),which are major suppressive immune cells.Moreover,clinical investigations show that MDSCs or TAMs are correlated with reduced survival in breast cancer patients.Therefore,targeting MDSCs or TAMs has been a new strategy for breast cancer immunotherapy.Increasing studies demonstrated that besides killing tumor cells directly,chemotherapeutic drugs can also inhibit tumor growth via enhancing antitumor immunity through different mechanisms.However,the direct effect of Aurora-A inhibition on the immune microenvironment of breast cancer is barely known.Thereby,a comprehensive understanding of the mechanism underlying the efficacy of alisertib in breast cancer will promotes the design of more effective remedies with alisertib.Here we demonstrated that inhibition of Aurora-A directly reshaped the immune microenvironment through removal of tumor-promoting myeloid cells and enrichment of anti-cancer T lymphocytes,which established a tumor-suppressive microenvironment and significantly contributed to the regression of murine mammary tumors.Mechanistically,alisertib treatment triggered apoptosis in myeloid-derived suppressor cells(MDSC)and macrophages,resulting in their elimination from tumors.Furthermore,alisertib treatment disrupted the immunosuppressive functions of MDSC by inhibiting Stat3-mediated ROS production.These alterations led to significant increases of active CD8+ and CD4’ T lymphocytes,which efficiently inhibited the proliferation of tumor cells.Intriguingly,alisertib combined with PD-L1 blockade showed synergistic efficacy in the treatment of mammary tumors.These results detail the effects of Aurora-A inhibition on the immune microenvironment and provide a novel chemo-immunotherapy strategy for advanced breast cancers.