TMIC-16. THE COLLAGEN RECEPTOR LAIR-1 ALTERS THE GLIOMA MICROENVIRONMENT AND REGULATES TUMOR AGGRESSIVE BEHAVIOR

Abstract

Abstract High-grade gliomas (HGG) are the most common malignant primary brain tumors in adults, with a median survival of 15-18 months. HGG are heterogeneous tumors with a complex extracellular matrix. Our previous work demonstrated the importance of the interaction between tumor cells and Collagen I. Employing genetically engineered mouse models (GEMM) of glioma, we identified Collagen 1α1 (Col1A1) as a regulator of tumor malignancy. Downregulation of Col1A1 in glioma cells extended median survival (MS), and reduced migration and proliferation. Nonetheless, the mechanisms underlining these effects remain unknown. LAIR-1 is a collagen receptor originally described as an inhibitory receptor in immune cells. We now describe the expression of LAIR-1 in glioma cells. Molecular ablation of LAIR-1 from glioma cells in GEMM (NPL: NRAS, shP53, shLAIR-1, and NPAL: NRAS, shP53, shATRX, shLAIR-1) significantly improved MS when compared to controls (NP: NRAS, shP53, and NPAL: NRAS, shP53, shATRX). The NPAL tumors had reduced cell proliferation (PCNA+), higher infiltration of astrocytes (GFAP+) and CD8+ T cells. Cells were obtained from these GEMM and cultured in vitro. LAIR-1 downregulation reduced cell proliferation, in both NPAL and NPL cells. To corroborate LAIR-1’s relationship with cell proliferation, control cells (NPA) were incubated with a LAIR-1 blocking antibody resulting in diminished glioma cell proliferation. When these cells were implanted in the brain LAIR-1 was downregulated resulted in increased MS. In vitro cytokines production assessment showed both NPAL and NPL cell had an enhanced production of RANTES(CCL5), G-CSF and IL-6 production, when compared to their controls. Our data suggest that LAIR-1 expression in glioma cells has a role in glioma malignant behavior both due to tumor cell proliferation and because of tumor composition. We hypothesize that blocking the interaction between LAIR-1 and collagen may improve median survival.