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

• Published in: Clinical and experimental immunology Vol. 200; no. 1; pp. 33 - 44
• Main Authors: Close, H. J., Stead, L. F., Nsengimana, J., Reilly, K. A., Droop, A., Wurdak, H., Mathew, R. K., Corns, R., Newton‐Bishop, J., Melcher, A. A., Short, S. C., Cook, G. P., Wilson, E. B.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.04.2020; John Wiley and Sons Inc
• Subjects: Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - immunology; Brain Neoplasms - pathology; Cell Line, Tumor; Cell surface; Cells, Cultured; Cohort Studies; Cytotoxicity, Immunologic - genetics; Cytotoxicity, Immunologic - immunology; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic - immunology; Gene Regulatory Networks - immunology; Glioblastoma; Glioblastoma - genetics; Glioblastoma - immunology; Glioblastoma - pathology; Glioma cells; Hematopoietic stem cells; Humans; Immune checkpoint; Immune system; Immune Tolerance - genetics; Immune Tolerance - immunology; immune‐inhibition; Immunogenicity; Immunology; Immunomodulation; Immunosuppression; Immunotherapy; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Lymphocytes T; Natural killer cells; Neoplastic Stem Cells - immunology; Neoplastic Stem Cells - metabolism; Neural stem cells; NK cells; Original; Phenotype; Phenotypes; Progenitor cells; Prognosis; Signal Transduction - genetics; Signal Transduction - immunology; Tumor microenvironment; Tumor Microenvironment - genetics; Tumor Microenvironment - immunology; Tumors; immune-inhibition; NK cells; glioblastoma
• ISSN: 0009-9104; 1365-2249; 1365-2249
• DOI: 10.1111/cei.13403

Summary 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. Our manuscript challenges the current paradigm that Glioblastoma (GBM) is a poor candidate for immunotherapy, therefore impacting on clinical approaches. We identify NK cells as a target for immunosuppression in GBM, with multiple suppressive pathways within GBM human tumours. We also identify a group of GBM patients with higher immunological activity, who will benefit from immunotherapies that target these immunosuppressive pathways.