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极光激酶A（AURKA）抑制剂可改变免疫微环境并增强胶质母细胞瘤中靶向B7-H3的免疫治疗效果。

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

作者信息

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

机构信息

Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

出版信息

JCI Insight. 2025 Feb 10;10(5):e173700. doi: 10.1172/jci.insight.173700.

DOI:10.1172/jci.insight.173700
PMID:39928563
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11949004/
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.

摘要

胶质母细胞瘤（GBM）是最致命的成人脑肿瘤之一，有效的治疗选择有限。靶向B7-H3（CD276）的免疫疗法在神经胶质瘤治疗中显示出有前景的疗效。然而，由于个体差异，神经胶质瘤患者对这种治疗的反应各不相同。有必要找到一种有效的策略来提高对无反应者靶向B7-H3免疫疗法的疗效。在本研究中，我们证明了胶质瘤组织样本中极光激酶A（AURKA）与CD276表达之间存在强相关性。此外，AURKA的敲低和过表达均导致胶质瘤细胞中B7-H3表达水平的平行变化。机制上，AURKA通过促进表皮生长因子受体（EGFR）磷酸化来提高B7-H3表达，这在胶质瘤细胞系和原发性GBM细胞中得到了验证。此外，在小鼠原位同基因胶质瘤模型中，AURKA抑制剂（alisertib）和抗B7-H3抗体的联合使用显著减小了肿瘤大小，并促进了CD8+T细胞的浸润和活化。据我们所知，本研究首次证明了AURKA介导的胶质瘤细胞中B7-H3上调；此外，它提出了一种将AURKA抑制剂alisertib与B7-H3特异性阻断单克隆抗体相结合的有前景的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/d0d059a1bd09/jciinsight-10-173700-g121.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/4a95a0c3aadf/jciinsight-10-173700-g113.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/3faa8da6a209/jciinsight-10-173700-g114.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/d719989ac51f/jciinsight-10-173700-g115.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/cadae2297dfa/jciinsight-10-173700-g116.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/7ff6148f6398/jciinsight-10-173700-g117.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/b3ba60c776b2/jciinsight-10-173700-g118.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/90e177946b2a/jciinsight-10-173700-g119.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/d6d19abfc496/jciinsight-10-173700-g120.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/d0d059a1bd09/jciinsight-10-173700-g121.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/4a95a0c3aadf/jciinsight-10-173700-g113.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/3faa8da6a209/jciinsight-10-173700-g114.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/d719989ac51f/jciinsight-10-173700-g115.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/cadae2297dfa/jciinsight-10-173700-g116.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/7ff6148f6398/jciinsight-10-173700-g117.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/b3ba60c776b2/jciinsight-10-173700-g118.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/90e177946b2a/jciinsight-10-173700-g119.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/d6d19abfc496/jciinsight-10-173700-g120.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b48/11949004/d0d059a1bd09/jciinsight-10-173700-g121.jpg

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