Inhibition of Aurora-A Promotes CD8+ T-Cell Infiltration by Mediating IL10 Production in Cancer Cells.

Abstract

Intratumoral tumor-specific activated CD8+ T cells with functions in antitumor immune surveillance predict metastasis and clinical outcome in human colorectal cancer. Intratumoral CD8+ T cells also affect treatment with immune checkpoint inhibitors. Interestingly, inhibition of Aurora kinase A (Aurora-A) by its selective inhibitor alisertib obviously induced infiltration of CD8+ T cells. However, the mechanisms by which inhibition of Aurora-A promotes infiltration of intratumoral CD8+ T cells remain unclear. Our recent results demonstrated that conditional deletion of the AURKA gene or blockade of Aurora-A by alisertib slowed tumor growth in association with an increase in the infiltration of intratumoral CD8+ T cells as well as the mRNA levels of their IL10 receptor α (IL10Rα). The antitumor effects of targeting Aurora-A were attenuated in the absence of CD8+ T cells. In addition, antibody-mediated blockade of IL10Rα dramatically decreased the percentage of intratumoral CD8+ T cells. In further experiments, we found that the levels of IL10 were elevated in the serum of azoxymethane/dextran sodium sulfate-treated AURKAflox/+;VillinCre+ mice. Unexpectedly, we found that in addition to Aurora-A's mitotic role, inhibition of Aurora-A elevated IL10 transcription, which in turn increased the IL10Rα mRNA levels in CD8+ T cells. Thus, inhibition of Aurora-A could be a useful treatment strategy for recruiting tumor-specific intratumoral CD8+ T cells. IMPLICATIONS: Understanding the mechanisms by which inhibition of Aurora-A promotes CD8+ T-cell infiltration and activation, as mediated by the IL10 pathway could provide a potential strategy for tumor immunotherapy.

• Authors: Jing Han, Zhen Jiang, Chennan Wang, Xin Chen, Rongqing Li, Na Sun, Xiangye Liu, Hui Wang, Li Hong, Kuiyang Zheng, Jing Yang, Takayuki Ikezoe
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 18 Issue 10 Pg. 1589-1602 (10 2020) ISSN: 1557-3125 [Electronic] United States
• PMID: 32591441 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Interleukin-10
• Aurora Kinase A

Topics

• Animals
• Aurora Kinase A (metabolism)
• CD8-Positive T-Lymphocytes (metabolism)
• Humans
• Immunotherapy (methods)
• Interleukin-10 (metabolism)
• Mice
• Neoplasms (immunology, mortality)
• Survival Analysis