© Copyright 2008 by the Society for Neuro-Oncology
Received May 22, 2008
Accepted August 8, 2008
Basic and Translational Investigations
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Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors
Joannes F. M. Jacobs 1,
Albert J. Idema 1,
Kalijn F. Bol 2,
Stefan Nierkens 2,
Oliver M. Grauer 3,
Pieter Wesseling 4,
J. André Grotenhuis 1,
Peter M. Hoogerbrugge 1,
I. Jolanda M. de Vries 5,
Gosse J. Adema 2*
1 Departments of Pediatric Oncology, Neurosurgery, and Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
2 Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
3 Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands; Department of Neurology, University of Regensburg, Regensburg, Germany
4 Departments of Pediatric Oncology, Neurosurgery, and Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Pathology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands
5 Departments of Pediatric Oncology, Neurosurgery, and Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
* To whom correspondence should be addressed. E-mail: G.Adema{at}ncmls.ru.nl.
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Abstract |
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The brain is a specialized immune site representing a unique tumor microenvironment. The availability of fresh brain tumor material for ex-vivo analysis is often limited as large parts of many brain tumors are resected using ultrasonic aspiration. We now analyzed ultrasonic tumor aspirates as a bio-source to study immune suppressive mechanisms in 83 human brain tumors. Lymphocyte-infiltrates in brain tumor tissues and ultrasonic aspirates were comparable with respect to lymphocyte content and viability. Applying ultrasonic aspirates, we detected massive infiltration of CD4+FOXP3+CD25highCD127low regulatory T cells (Tregs) in glioblastomas (n=29) and metastatic brain tumors (n=20). No Treg accumulation was observed in benign tumors such as meningiomas (n=10) and pituitary adenomas (n=5). A significant Treg increase in blood was only seen in patients with metastatic brain tumors. Tregs in high-grade tumors exhibited an activated phenotype as indicated by decreased proliferation and elevated CTLA-4 and FoxP3 expression relative to blood Tregs. Functional analysis showed that the tumor derived Tregs efficiently suppressed cytokine secretion and proliferation of autologous intratumoral lymphocytes. Most tumor infiltrating Tregs localized in close proximity to effector T cells, as visualized by immunohistochemistry. Furthermore, 61% of the malignant brain tumors expressed programmed death ligand-1 (PD-L1), while the inhibitory PD-1 receptor was expressed on CD4+ effector cells present in 26% of tumors. In conclusion, using ultrasonic tumor aspirates as a bio-source we identify Tregs and the PD-L1/PD-1 pathway as immune suppressive mechanisms in malignant but not benign human brain tumors.
Key Words:
Tumor infiltrating lymphocyte, Regulatory T cell, PD-L1, brain tumor, immunotherapy
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