Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma.
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Date
2020-03-11ICR Author
Author
Close, HJ
Stead, LF
Nsengimana, J
Reilly, KA
Droop, A
Wurdak, H
Mathew, RK
Corns, R
Newton-Bishop, J
Melcher, AA
Short, SC
Cook, GP
Wilson, EB
Type
Journal Article
Metadata
Show full item recordAbstract
Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To understand this problem more clearly we used a combination of natural killer (NK) cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment. In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem-like cells, a source of post-treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM-infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of transforming growth factor (TGF)-β-mediated inhibition. This NK cell inhibition is accompanied by expression of multiple immune checkpoint molecules on T cells. Single-cell transcriptomics demonstrated that both tumour and haematopoietic-derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co-expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognized by the immune system but that anti-tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more probably benefit from combination immunotherapies directed against multiple immunosuppressive pathways.
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Subject
Killer Cells, Natural
Cells, Cultured
Cell Line, Tumor
Humans
Glioblastoma
Brain Neoplasms
Prognosis
Cohort Studies
Gene Expression Profiling
Signal Transduction
Cytotoxicity, Immunologic
Immune Tolerance
Gene Expression Regulation, Neoplastic
Phenotype
Gene Regulatory Networks
Neoplastic Stem Cells
Tumor Microenvironment
Research team
Translational Immunotherapy
Language
eng
Date accepted
2019-11-26
License start date
2020-04
Citation
Clinical and experimental immunology, 2020, 200 (1), pp. 33 - 44
Publisher
OXFORD UNIV PRESS