Original ArticleExpression and Clinical Significance of Immune Checkpoint Regulator B7-H3 (CD276) in Human Meningioma
Introduction
Meningiomas represent the most common primary intracranial tumor found in adults.1,2 Treatment options for symptomatic meningiomas are limited to surgical resection where possible and adjuvant radiation therapy for tumors with concerning histopathologic features or recurrent disease.1,2 Cancer immunotherapy that targets immune checkpoints is a promising new treatment option in several tumor entities and is currently developing at a breathtaking speed. At the present time, immunotherapy is being investigated in patients with meningioma.3,4 Earlier studies discovered that programmed death ligand 1 (PD-L1) expression is increased in anaplastic meningioma and associated with a worse overall survival.3,5 A recent study identified programmed death ligand 2, B7-H3, and cytotoxic T lymphocyte antigen 4 immune checkpoint proteins in genetic subtypes of meningioma.6 Furthermore, clinical trials are currently investigating the efficacy of checkpoint inhibitors (nivolumab [ClinicalTrials.gov Identifier NCT02648997], pembrolizumab [ClinicalTrials.gov Identifier NCT03279692], and avelumab [ClinicalTrials.gov Identifier NCT03267836]) in recurrent or residual high-grade meningiomas.
Interactions of B7 family members with their receptor, CD28, play a significant role in the relationship between tumors and the host immune system.7 B7-H3 (CD276) is a negative costimulatory molecule expressed at high levels on a wide range of human solid cancers and often correlates with both negative prognosis and poor clinical outcome in patients.8 B7-H3 expression contributes to tumor immune evasion and metastatic potential and is correlated with poor prognosis.7, 8, 9 Importantly, with a preferential expression on tumor cells, B7-H3 has become a target for new immunotherapeutic treatments (ClinicalTrials.gov Identifiers NCT0262853, NCT0191893, and NCT00582608). Whereas B7-H3 is a putative target for chimeric antigen receptor T-cell therapy of solid tumors, little is currently known about the expression and prognostic impact of B7-H3 on large series of meningioma. In this retrospective study, we first examined the expression of a panel of immune checkpoint proteins (PD-L1, B7-H3, lymphocyte activation gene-3 [LAG3], programmed death 1 [PD-1], and V-domain Ig suppressor of T cell activation [VISTA]) in meningioma and observed strong expression of B7-H3 in most of the tested samples. To explore its clinical significance, the expression of B7-H3 was also quantified in an expanded cohort using immunohistochemical staining of tissue microarray (TMA) and digital scoring system.
Section snippets
Patients, Cohorts, and TMAs
We collected 301 meningioma samples from the Department of Neurosurgery, Huashan Hospital of Fudan University, Shanghai, China. We created a multispot TMA with up to 5 tumor spots (diameter = 5 mm) for each sample (8 patients in total) as a test cohort. Four normal brain tissue samples collected from patients with brain trauma were set as control. Additionally, we created a single spot TMA considering 294 additional patients as a validation cohort (spots diameter = 2 mm). All specimens had been
Expression of Immune Checkpoint Markers in Tested Cohort
In a pilot study, immunohistochemistry staining explored the relative expression of 5 different immune immunoregulatory proteins (PD-L1, B7-H3, LAG3, PD-1, and VISTA) in 8 meningioma cases (Table 1). B7-H3 expression (H-score ≥20) was detected in 75%–90% of the tumor tissues in 6 of 8 (75%) cases, whereas extremely low levels were detected in the normal brain tissues (H-score <20) (Figure 1A and C). VISTA was expressed in 10%–50% of the tumor parenchyma in 5 of 7 (71.43%) cases studied (
Discussion
B7 family members and their receptors play a central role in the regulation of T-cell responses through T-cell costimulation and coinhibition pathways that constitute attractive targets for the development of immunotherapy.7 In this retrospective study, we present the largest screen to date of meningioma tumor tissues for expression of B7-H3 and its potential clinical significance. We observed that B7-H3 was the most highly expressed immune checkpoint protein on solid portions of meningioma.
Conclusions
The present study, along with the encouraging results of preclinical and clinical studies targeting B7-H3, provides a rationale for therapeutic application of anti–B7-H3 agents in patients with meningioma.
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Conflict of interest statement: This study was supported by grants from the National Key R&D Program of China (2018YFC1312600, 2018YFC1312604 to Y. Gong), National Natural Science Foundation of China (81772674 to Y. Gong), and Science and Technology Commission of Shanghai Municipality (18140900200 to Y. Gong).
Jiaojiao Deng and Mengyin Ma are co–first authors.