Abstract
SummaryGlioblastoma (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.
Highlights
Glioblastoma (GBM) is the most common and aggressive type of primary adult brain cancer
Glioma stem-like cells are effective targets of natural killer (NK) cells Effective therapy for GBM will require the elimination of the radioresistant GBM stem-like cells (GSCs) that are largely responsible for recurrence [23]
Tumour cells differentiated from GSCs are more sensitive to NK cell killing than the GSC themselves [26] but GSCs are killed by NK cells in the presence of activating cytokines (Figure 1A) [25]
Summary
Glioblastoma (GBM) is the most common and aggressive type of primary adult brain cancer. Current treatments include debulking neurosurgery and adjuvant chemo/radiotherapy. Despite these therapies, median overall survival is just 12-24 months [1]. Despite significant therapeutic impact on several solid tumour types, immune checkpoint blockade (ICB) is yet to demonstrate benefit in GBM treatment [3]. Tumours exploit the negative feedback mechanisms that the healthy immune system uses to dampen immune responses. These mechanisms include the recruitment of immune cells with suppressive activity, the expression of immunosuppressive cytokines, such as Transforming Growth Factor (TGF)-b, and immune checkpoints including Programmed cell Death (PD)-1 and Cytotoxic T Lymphocyte Antigen (CTLA)-4 [5]. Exhausted tumour infiltrating lymphocytes express immune checkpoints, and antibodies that target these molecules can reinvigorate anti-tumour immunity [7]
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