Understanding NLRs and AIM2 cellular and molecular signalling in glioblastoma pathophysiology

Abstract Gliomas are the most prevalent primary brain tumors with immense clinical heterogeneity, poor prognosis and survival. Gliomas arise from glial cells and are heavily infiltrated with innate immune cells. In India high-grade gliomas or Glioblastomas (GBM) account for 59.5% of CNS tumours. A key challenge for clinical management of GBM is its highly heterogeneous nature-between patients and within a single tumour-making current therapies ineffective. The nucleotide-binding domain, and leucine-rich repeat containing receptors (NLRs) and absent-in-melanoma 2 (AIM2) are innate immune receptors crucial for initiation and progression of several cancers. There is a dearth of reports investigating NLRs and AIM2 in glioma pathology. We are interested in studying the cellular and molecular contribution of NLRs and AIM2 in malignant gliomas in the Indian subcontinent. We previously reported a data-driven approach to identify NLRs, AIM2 and NLR-associated gene expression in gliomas using The Cancer Genome Atlas (TCGA) patient datasets. However, TCGA data is obtained from diverse populations and cellular diversity within individual tumor tissues remains unexplored. In this study we carried out tumour primary cell culture, human brain immunohistochemistry and proteomic analysis and same patient serum controls (n=100). Our results characterize novel cell specific differential expression and signalling profile of several NLR genes (including NLRP3, NLRP12 and ASC) in microglia, astrocytes, endothelial cells and the tumour cell populations in GBM patient tissue. We provide critical insights into innate immune signalling within the GBM microenvironment and identify key markers for future therapeutic interventions.