The AURKA inhibitor alters the immune microenvironment and enhances targeting B7-H3 immunotherapy in glioblastoma
Jinqiu Liu, Yuxuan Deng, Zhuonan Pu, Yazhou Miao, Zhaonian Hao, Herui Wang, Shaodong Zhang, Hanjie Liu, Jiejun Wang, Yifan Lv, Boyi Hu, Hong Wan, Zhengping Zhuang, Tai Sun, Shuyu Hao, Nan Ji, Jie Feng
Jinqiu Liu, Yuxuan Deng, Zhuonan Pu, Yazhou Miao, Zhaonian Hao, Herui Wang, Shaodong Zhang, Hanjie Liu, Jiejun Wang, Yifan Lv, Boyi Hu, Hong Wan, Zhengping Zhuang, Tai Sun, Shuyu Hao, Nan Ji, Jie Feng
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Research Article Oncology Therapeutics

The AURKA inhibitor alters the immune microenvironment and enhances targeting B7-H3 immunotherapy in glioblastoma

Abstract

Glioblastoma (GBM) is one of the most lethal adult brain tumors with limited effective therapeutic options. Immunotherapy targeting B7-H3 (CD276) has shown promising efficacy in the treatment of gliomas. However, the response to this treatment varies among glioma patients due to individual differences. It’s necessary to find an effective strategy to improve the efficacy of targeting B7-H3 immunotherapy for nonresponders. In this study, we demonstrated a strong correlation between aurora kinase A (AURKA) and CD276 expression in glioma tissue samples. Additionally, both AURKA knockdown and overexpression resulted in parallel changes in B7-H3 expression levels in glioma cells. Mechanistically, AURKA elevated B7-H3 expression by promoting epidermal growth factor receptor (EGFR) phosphorylation, which was validated in glioma cell lines and primary GBM cells. What’s more, the combination of AURKA inhibitor (alisertib) and anti–B7-H3 antibody markedly reduced tumor size and promoted CD8+ T cell infiltration and activation in mouse orthotopic syngeneic glioma models. To our knowledge, this study is the first to demonstrate AURKA-mediated B7-H3 upregulation in glioma cells; moreover, it proposes a promising therapeutic strategy combining the AURKA inhibitor alisertib with B7-H3–specific blocking mAbs.

Authors

Jinqiu Liu, Yuxuan Deng, Zhuonan Pu, Yazhou Miao, Zhaonian Hao, Herui Wang, Shaodong Zhang, Hanjie Liu, Jiejun Wang, Yifan Lv, Boyi Hu, Hong Wan, Zhengping Zhuang, Tai Sun, Shuyu Hao, Nan Ji, Jie Feng

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Figure 6

AURKA inhibitors suppress tumor growth and upregulate B7-H3 expression.

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AURKA inhibitors suppress tumor growth and upregulate B7-H3 expression. ...
(A) Schematic diagram of the in vivo medication studies in G261-bearing mice. Alisertib or vehicle was administered daily on day 13 after tumor inoculation for 2 weeks. (B and C) Changes in the volume of orthotopic G261 tumors treated with or without alisertib at various time points were measured via the IVIS system (n = 5/group) and quantified. (D) The volume of orthotopic G261 tumors treated with or without alisertib on day 26 was measured via the IVIS system. (n = 5 for the alisertib group, n = 4 for the control group). (E) Kaplan-Meier survival plots of mice bearing orthotopic G261 tumors treated with or without alisertib (n = 5/group). (F) Schematic diagram of the in vivo medication studies in U87-MG–bearing mice. Alisertib or vehicle was administered daily on day 13 after tumor inoculation for 2 weeks. (G and H) Changes in the volume of orthotopic U87-MG tumors treated with or without alisertib at various time points were measured via the IVIS system (n = 6/group) and quantified. (I) The volume of orthotopic U87-MG tumors treated with or without alisertib on day 26 was measured via the IVIS system (n = 6 for the alisertib group, n = 5 for the control group). (J) IHC analysis of B7-H3 in orthotopic U87-MG tumors treated with or without alisertib; the quantifications are shown on the right (n = 6 for the alisertib group, n = 5 for the control group). Statistical significance was assessed by using a 2-tailed unpaired Student’s t test (D, I, and J) and the log-rank (Mantel-Cox) test (E). The data are presented as the mean ± SEM (C, D, H, I, and J). *P < 0.05, **P < 0.01. Scale bars: 50 µm.