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Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

Lookup NU author(s): Dr Helen Close, Dr Jérémie Nsengimana

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2019 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for ImmunologyGlioblastoma (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.


Publication metadata

Author(s): 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

Publication type: Article

Publication status: Published

Journal: Clinical and Experimental Immunology

Year: 2020

Volume: 200

Issue: 1

Pages: 33-44

Print publication date: 11/03/2020

Online publication date: 30/11/2019

Acceptance date: 26/11/2019

Date deposited: 25/06/2020

ISSN (print): 0009-9104

ISSN (electronic): 1365-2249

Publisher: Blackwell Publishing Ltd

URL: https://doi.org/10.1111/cei.13403

DOI: 10.1111/cei.13403

PubMed id: 31784984


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