Document Detail


Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors.
MedLine Citation:
PMID:  19028999     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 because large parts of many brain tumors are resected using ultrasonic aspiration. We analyzed ultrasonic tumor aspirates as a biosource 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+CD25(high) CD127(low) 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 seen only 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 were 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 biosource we identified Tregs and the PD-L1/PD-1 pathway as immune suppressive mechanisms in malignant but not benign human brain tumors.
Authors:
Joannes F M Jacobs; Albert J Idema; Kalijn F Bol; Stefan Nierkens; Oliver M Grauer; Pieter Wesseling; J André Grotenhuis; Peter M Hoogerbrugge; I Jolanda M de Vries; Gosse J Adema
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-11-21
Journal Detail:
Title:  Neuro-oncology     Volume:  11     ISSN:  1522-8517     ISO Abbreviation:  Neuro-oncology     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-08-07     Completed Date:  2009-09-10     Revised Date:  2010-09-23    
Medline Journal Info:
Nlm Unique ID:  100887420     Medline TA:  Neuro Oncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  394-402     Citation Subset:  IM    
Affiliation:
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences /278 TIL, Post Box 9101, 6500 HB Nijmegen, The Netherlands.
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MeSH Terms
Descriptor/Qualifier:
Antigens, CD / metabolism*
Apoptosis Regulatory Proteins / metabolism*
Brain Neoplasms / immunology*,  pathology
Flow Cytometry
Forkhead Transcription Factors / metabolism
Humans
Immunoenzyme Techniques
Immunosuppression*
Lymphocyte Activation
Signal Transduction
T-Lymphocyte Subsets
T-Lymphocytes, Regulatory / physiology*
Chemical
Reg. No./Substance:
0/Antigens, CD; 0/Apoptosis Regulatory Proteins; 0/CD274 protein, human; 0/FOXP3 protein, human; 0/Forkhead Transcription Factors; 0/cytotoxic T-lymphocyte antigen 4; 146588-21-8/PDCD1 protein, human
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