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J Neurooncol. 2019 Jun 8. doi: 10.1007/s11060-019-03198-9. [Epub ahead of print]

Non-NF2 mutations have a key effect on inhibitory immune checkpoints and tumor pathogenesis in skull base meningiomas.

Hao S1, Huang G2,3, Feng J4, Li D2, Wang K2, Wang L2, Wu Z2,5, Wan H4, Zhang L2,5,6,7, Zhang J8,9,10,11.

Author information

1
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 119 Nan Si Huan Xi Road, Feng Tai District, Beijing, 100070, China. shuyuhao@hotmail.com.
2
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 119 Nan Si Huan Xi Road, Feng Tai District, Beijing, 100070, China.
3
The Second People's Hospital of Guiyang, Guiyang, China.
4
Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
5
China National Clinical Research Center for Neurological Diseases, Beijing, China.
6
Center for Brain Tumors, Beijing Institute for Brain Disorders, Beijing, China.
7
Beijing Key Laboratory of Brain Tumors, Beijing, China.
8
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 119 Nan Si Huan Xi Road, Feng Tai District, Beijing, 100070, China. zhangjunting2003@aliyun.com.
9
China National Clinical Research Center for Neurological Diseases, Beijing, China. zhangjunting2003@aliyun.com.
10
Center for Brain Tumors, Beijing Institute for Brain Disorders, Beijing, China. zhangjunting2003@aliyun.com.
11
Beijing Key Laboratory of Brain Tumors, Beijing, China. zhangjunting2003@aliyun.com.

Abstract

AIMS:

Skull base meningiomas represent approximately 25% of all meningiomas, nearly 20% of which are atypical or anaplastic. To date, effective medical treatments for meningiomas are still lacking. Genetic aberrations (TRAF7, KLF4, AKT1, and SMO) and the effects of genetic aberrations on the expression of inhibitory immune checkpoint molecules (PD-L1, IDO, and TDO2) in skull base meningiomas are still unclear.

METHODS:

Genetic alterations in the four genes were identified in 92 skull base meningiomas by Sanger sequencing. The expression differences in immune checkpoints between mutant and wild-type (WT) tumors were determined by immunohistochemistry (IHC) and Western blot (WB).

RESULTS:

The four mutations were not concurrently detected in the patients with skull base meningiomas. Among the tumors from the KLF4-mutated group, almost half were petroclival meningiomas. KLF4- and TRAF7-mutated tumors were predominantly secretory meningiomas. SMO-mutated tumors exhibited higher calcification, and half of these tumors were observed in the brain midline. Receiver operating characteristic curve analysis indicated that tumor volume can predict KLF4 and TRAF7 mutation status with high sensitivity and specificity, respectively. The IHC and WB analyses indicated that PD-L1, IDO, and TDO2 levels in tumors with TRAF7 mutations were significantly higher than those in WT tumors. Meanwhile, there was a significant difference in TDO2 between tumors with AKT1 mutations and WT tumors. Specifically, TRAF7 mutations could play a key role in skull base meningiomas by regulating the expression of inhibitory immune checkpoints and thus suppressing immune responses.

CONCLUSIONS:

Checkpoint inhibitors may be potential strategies for targeted immunotherapies of these mutant meningiomas.

KEYWORDS:

Gene mutation; Immune checkpoint inhibitors; Meningioma; Skull base

PMID:
31177425
DOI:
10.1007/s11060-019-03198-9

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