Next Generation Sequencing was performed on MDSCs from tumors of control or alisertib treated tumor-bearing mice

The Aurora-A inhibitor alisertib shows encouraging activities in clinical trials against multiple malignances including advanced breast cancer. However, its mechanism of action remains unclear, especially regarding how the inflammatory microenvironment is involved in the efficacy of alisertib. Here, we demonstrated that Aurora-A inhibition directly reshapes the immune microenvironment through removal of tumor-promoting myeloid cells and enrichment of anti-cancer T lymphocytes, which restores a tumor-suppressive microenvironment and significantly contributes to the regression of murine mammary tumors. Mechanistically, the Aurora-A inhibitor effectively eliminated myeloid cells including myeloid-derived suppressor cells (MDSCs) and macrophages in tumors by triggering apoptosis of these cells. Further, Aurora-A inhibition could disrupt the immunosuppressive functions of MDSCs through inhibiting Stat3 mediated ROS production. These alterations led to significant increases in the proportion and the number of CD8+ and CD4+ T lymphocytes, which efficiently inhibited the proliferation of tumor cells. In summary, these data revealed that in addition to suppressing the proliferation of tumor cells, Aurora-A inhibitor directly modulates and restores an anti-tumor immune-microenvironment in breast cancer. Intriguingly, Aurora-A inactivation combined with PD-L1 blockade showed synergistic efficacy in the treatment of mammary tumors, providing an effective strategy for clinical trials of chemo-immunotherapy in breast cancer. Overall design: TA-MDSCs were sorted from 20 tumors of alisertib treated tumor bearing mice and pooled together. TC-MDSCs were sorted from 20 tumors of control tumor bearing mice and pooled together. BM-neu were sorted from the bone marrows of 5 WT BALB/c mice.