Aurora A Inhibition Eliminates Myeloid Cell-Mediated Immunosuppression and Enhances the Efficacy of Anti-PD-L1 Therapy in Breast Cancer
Aurora A Inhibition Eliminates Myeloid Cell-Mediated Immunosuppression and Enhances the Efficacy of Anti-PD-L1 Therapy in Breast Cancer
复制标题
Aurora A 抑制可消除骨髓细胞介导的免疫抑制并增强乳腺癌抗 PD-L1 疗法的疗效
DOI：
10.1158/0008-5472.can-18-3397
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发表时间：
2019
期刊：
影响因子：
11.2
通讯作者：
Yang Zhenye
中科院分区：
文献类型：
--
作者：
Yin Tingting;Zhao Zhi Bin;Guo Jing;Wang Tianchen;Yang Jing Bo;Wang Chao;Long Jie;Ma Shisong;Huang Qiang;Zhang Kaiguang;Ma Xiaopeng;Liu Chenhai;Liu Suing;Lian Zhe Xiong;Yang Zhenye
Aurora A抑制剂alisertib在治疗晚期乳腺癌的临床试验中显示出令人鼓舞的活性。然而，炎症微环境是否以及如何参与其疗效尚不清楚。在这里，我们证明了抑制Aurora A通过去除促瘤髓细胞和富集抗癌T淋巴细胞直接重塑免疫微环境，从而建立肿瘤抑制微环境，并显著促进了小鼠乳腺肿瘤的消退。在机制上，alisertib治疗触发骨髓源性抑制细胞（MDSC）和巨噬细胞的凋亡，导致它们从肿瘤中消失。此外，alisertib治疗通过抑制stat3介导的ROS产生破坏了MDSC的免疫抑制功能。这些改变导致活性CD8+和CD4+T淋巴细胞显著增加，有效抑制肿瘤细胞的增殖。有趣的是，alisertib联合PD-L1阻断剂在治疗乳腺肿瘤中显示出协同效应。这些结果详细说明了Aurora A抑制对免疫微环境的影响，并为晚期乳腺癌提供了一种新的化学免疫治疗策略。这些发现表明，抑制Aurora A促进了抗癌免疫微环境的形成，从而抑制了肿瘤的进展，增强了乳腺癌的抗pd - l1治疗。参见Rivoltini等人的相关评论，第3169页
The Aurora A inhibitor alisertib shows encouraging activities in clinical trials against advanced breast cancer. However, it remains unclear whether and how the inflammatory microenvironment is involved in its efficacy. Here, we demonstrated that inhibition of Aurora A directly reshaped the immune microenvironment through removal of tumor-promoting myeloid cells and enrichment of anticancer 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.SignificanceThese findings show that inhibition of Aurora A facilitates an anticancer immune microenvironment, which can suppress tumor progression and enhance anti–PD-L1 therapy in breast cancer.See related commentary by Rivoltini et al., p. 3169