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 3

AURKA regulates B7-H3 expression through EGFR phosphorylation.

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AURKA regulates B7-H3 expression through EGFR phosphorylation. (A–F) The...
(A–F) The expression levels of various markers were analyzed in LN18 cells (A–C) and U87-MG cells (D–F) expressing shNC or AURKA-shRNA#3 treated with NSC228155 (10 μM, 8 hours) or DMSO. (A and D) Protein expression of B7-H3, total AURKA, p-EGFR (Y1068), and total EGFR was assessed by Western blotting. (B and E) The mRNA level of CD276 was measured by qPCR. (C and F) B7-H3 expression on the cell surface was analyzed using flow cytometry. (G and H) The expression levels of various markers were analyzed in U87-MG cells expressing shNC or AURKA-shRNA#3 with or without EGF (24 hours, 500 ng/mL). (G) Protein expression of B7-H3, total AURKA, p-EGFR (Y1068), and total EGFR was assessed by Western blotting. (H) The mRNA level of CD276 was measured by qPCR. (I–K) The expression levels of various markers were analyzed in LN229 cells expressing vector or AURKA_cDNA_Flag with erlotinib (24 hours, 60 μM) or DMSO. (I) Protein expression of B7-H3, total AURKA, p-EGFR (Y1068), and total EGFR was assessed by Western blotting. (J) The mRNA level of CD276 was measured by qPCR. (K) B7-H3 expression on the cell surface was analyzed using flow cytometry. The quantifications are shown on the right (A, C, D, F, G, I, and K). β-Actin was used as the internal control (A, D, G, and I). Cells that were only stained with isotype control antibodies were used as the negative control (NC) (C, F, and K). Statistical significance was assessed by 1-way ANOVA followed by Tukey’s multiple-comparison test (A–K). The data are presented as the mean ± SD (A–K). All samples were biologically independent, and 3 independent experiments were performed. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.