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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

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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 2

AURKA regulates B7-H3 expression.

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AURKA regulates B7-H3 expression.
(A) Volcano plot of the proteomics dat...
(A) Volcano plot of the proteomics data showing reduced expression of B7-H3 and SDCBP (red dots) in U87-MG cells treated with shRNA targeting AURKA. (B and C) The protein expression levels of B7-H3, total AURKA, SDCBP, p-EGFR (Y1068), and total EGFR in LN18 cells (B) and U87-MG cells (C) expressing shNC or AURKA-shRNA#3 were detected via Western blotting, and the quantifications are shown on the right. β-Actin was used as the internal control. (D) B7-H3 expression on the cell surface in U87-MG cells expressing shNC or AURKA-shRNA#3 was detected by flow cytometry, and the quantification of the results is shown on the right. Cells that were only stained with isotype control antibodies were used as the negative control (NC). (E) The protein expression levels of B7-H3, total AURKA, SDCBP, p-EGFR (Y1068), and total EGFR in LN229 cells expressing vector or AURKA_cDNA_Flag were detected via Western blotting, and the quantifications are shown on the right. β-Actin was used as the internal control. (F) B7-H3 expression on the cell surface in LN229 cells expressing vector or AURKA_cDNA_Flag was detected by flow cytometry, and the quantification of the results is shown on the right. Cells that were only stained with isotype control antibodies were used as the negative control (NC). All samples were biologically independent, and 3 independent experiments were performed. Comparisons were performed via 1-tailed unpaired Student’s t test (A) or 2-tailed unpaired Student’s t test (B–F). The data are presented as the mean ± SD (B–F). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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