Identification of PD-L2, B7-H3 and CTLA-4 immune checkpoint proteins in genetic subtypes of meningioma

Abstract

Meningioma is the most common brain tumor in adults. Surgical resection remains the primary treatment. No chemotherapy exists. However, gene mutations now could explain~80% of meningioma and targeted therapies based on these are being investigated. Furthermore, with the recent discovery of PD-L1 in malignant meningioma, clinical trials using immunotherapy have commenced. Here, we report for the first time the expression profiles of immune checkpoint proteins PD-L2, B7-H3 and CTLA-4 in meningioma and their association to common gene mutations. PD-L2 and B7-H3 expression was significantly greater than all immune checkpoint proteins studied, and particularly elevated in patients with gene mutations affecting the PI3K/AKT/mTOR pathway. CTLA-4 expressing CD3+ lymphocytes were observed in atypical and malignant meningioma and tumors harboring a PIK3CA or SMO mutation. These results identify novel targets for immunotherapy irrespective of grade and distinguish potential patient populations based on genetic classification for stratification into checkpoint inhibitor clinical trials.

Basis for Immunotherapy for Treatment of Meningiomas

“…For example, meningiomas commonly have isolated monosomy 22/del(22q) mutations, which show increased tumor-infiltrating M1-subtype macrophages, NK cells, and T-cells ( 41 , 42 ). Another important aspect of genetic alterations in meningiomas is that molecular subtypes characterized by specific genetic mutations express different checkpoint molecules ( 34 , 43 ). It is conceivable that by molecularly classifying meningiomas to determine the presence of different mutations, chromosomal derangements, and their relationship to immune cell infiltration, we will be able to determine optimal immunotherapeutic strategies for patients.…”

“…Several recent studies have aimed to characterize the interactions between meningiomas and the immune system. Specifically, studies of the immune microenvironment in meningiomas have revealed that checkpoint molecules like NY-ESO-1, PD-L1, PD-L2, B7-H3, and CTLA-4 are expressed in meningiomas and may be at least partly responsible for the suppression of the anti-tumor immune response ( 43 , 78 – 81 ). Programmed Death Ligand-1 (PD-L1) is expressed in meningiomas, and expression levels are higher for higher-grade tumors ( 80 ).…”

“…Immune cells such as macrophages and lymphocytes bind to these ligands or checkpoint molecules and become quiescent and sometimes immunosuppressive, leaving tumor cells to proliferate unchecked. Checkpoint inhibitor therapy targeted at immune cells associated with checkpoint proteins, like PD-L1, PD-L2, B7-H3, and CTLA-4, could help disinhibit the host immune system to help combat tumor survival and growth ( 43 , 80 , 92 , 94 ).…”

A Rapid Robust Method for Subgrouping Non-NF2 Meningiomas According to Genotype and Detection of Lower Levels of M2 Macrophages in AKT1 E17K Mutated Tumours

“…Proctor et al [51] also recently linked mutations in the PI3K/AKT/mTOR pathway to elevated levels of the immune checkpoint proteins PD-L2 and B7-H3, strengthening the evidence that genetic changes can stimulate a different tumour microenvironment. The impact of somatic alternations on immune responses has previously been shown in BRAF mutations in melanoma [54] and IDH mutations in glioma [55].…”

“…The immune checkpoint marker PD-L1 has been shown to increase in anaplastic meningiomas [49], suggesting that higher-grade tumours harbour a more immunosuppressive tumour microenvironment [50], although immune therapy targeting PD-L1 in meningiomas may be limited due to expression levels [51,52]. Recently, lower proportions of PD-1 positive cytotoxic T cells (CD3 + CD8 + FOXP3 − ) have been associated with poorer survival, with longitudinal analyses of the tumour-infiltrating T-lymphocytes suggesting large changes in the microenvironment over the course of the disease [25].…”