Abstract
Aim
Despite current treatments, high-grade meningiomas continue to have a poor prognosis. Immunotherapy targeting immune checkpoints, such as PD-L1, has demonstrated significant success in controlling numerous malignancies. In this study, we investigate the extent of systemic and local immunosuppression in meningiomas to assess the potential benefit of immune checkpoint inhibitors for the treatment of high-grade meningiomas.
Methods
Peripheral blood was collected from patients undergoing resection of meningiomas (WHO grade I, n = 18; grade II, n = 25; grade III, n = 10). Immunosuppressive myeloid cells (CD45+CD11b+PD-L1+), myeloid-derived suppressor cells (MDSCs) (CD11b+CD33+HLA-DRlow), and regulatory T cells (Tregs) (CD3+CD4+CD25+FoxP3+) were quantified through flow cytometry. Tissue sections from the same patients were assessed for PD-L1 expression and T cell infiltration via immunohistochemistry.
Results
Patients with grade III meningiomas demonstrated increased peripheral monocyte PD-L1 compared to patients with grade I/II meningiomas and healthy controls. Peripheral MDSC abundance was increased in grades II and III meningioma patients. PD-L1 staining of meningioma tissue demonstrated increased positivity in grade III meningiomas. Intratumoral PD-L1 was not associated with progression-free survival. High-grade meningiomas had increased T-cell infiltration. However, a significant proportion of these T cells were exhausted PD1+ T cells and immunosuppressive Tregs.
Conclusions
Patients with meningiomas exhibit signs of peripheral immunosuppression, including increased PD-L1 on myeloid cells and elevated MDSC abundance proportional to tumor grade. Additionally, the tumors express substantial PD-L1 proportional to tumor grade. These results suggest a role for immune checkpoint inhibitors targeting the PD-L1/PD-1 pathway in combination with standard therapies for the treatment of high-grade meningiomas.
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Abbreviations
- CTLA-4:
-
Cytotoxic T lymphocyte antigen 4
- FFPE:
-
Formalin-fixed, paraffin-embedded
- HPFs:
-
High powered fields
- IFN-γ:
-
Interferon-γ
- MDSC:
-
Myeloid-derived suppressor cells
- NCI:
-
National Cancer Institute
- NINDS:
-
National Institute of Neurological Disorders and Stroke
- PBMC:
-
Peripheral blood mononuclear cells
- PD-1:
-
Programmed death 1
- PD-L1:
-
Programmed death-ligand 1
- PFS:
-
Progression-free survival
- Treg:
-
Regulatory T cell
- WHO:
-
World Health Organization
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Acknowledgements
The authors would like to thank the Nervous System Tumor Bank at Northwestern University, without which the current study would not be possible. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by National Cancer Institute (NCI) CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center.
Funding
This work was supported by the Howard Hughes Medical Institute Medical Student Research Fellows program (Yuping Li) as well as by the NIH/NCI (National Cancer Institute) R01 (CA164714; Orin Bloch) and NIH/National Institute of Neurological Disorders and Stroke (NINDS) R00 (NS078055; Orin Bloch). The funding was received by National Cancer Institute (CA206413; Jonathan B. Lamano) and National Institute of Neurological Disorders and Stroke (NS101884; Gurvinder Kaur).
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YDL took part in conceptualization, experimental design, data curation, formal analysis, funding acquisition, methodology, validation, and writing the manuscript; DV took part in experimental design and data curation; JBL took part in data curation, formal analysis, methodology, and validation. JBL took part in data curation and formal analysis; GK, and DB took part in data curation; CMH took part in formal analysis and validation; TJK took part in conceptualization and methodology; OB took part in conceptualization, funding acquisition, investigation, methodology, and supervision. All authors read and approved the final manuscript.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Institutional Review Board of Northwestern University, Feinberg School of Medicine (STU00203854).
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Written informed consent was obtained from all individual participants included in the study for the use of their blood and tumor specimen for research. Consent was not required for collection of patient characteristics as information was de-identified.
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This work was previously published as an abstract at the 2018 American Association of Neurological Surgeons (AANS) Annual Scientific Meeting in New Orleans, LA, USA on April 29–May 2, 2018 [1].
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Li, Y.D., Veliceasa, D., Lamano, J.B. et al. Systemic and local immunosuppression in patients with high-grade meningiomas. Cancer Immunol Immunother 68, 999–1009 (2019). https://doi.org/10.1007/s00262-019-02342-8
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DOI: https://doi.org/10.1007/s00262-019-02342-8