Role of the collagen receptor LAIR-1 in glioma progression and the tumor immune microenvironment

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ABSTRACT High-grade gliomas (HGG) are the deadliest of all primary brain tumors. They are incurable and median survival is between 18-24 months. Gliomas infiltrate the healthy brain tissue surrounding the tumor. Thus, even if these tumors do not metastasize, patients die due to local tumor recurrence. Collagens are a central component of the extracellular matrix of high-grade gliomas, and promote invasion and tumor growth. How they do so is complex, and not fully understood. Collagen provides structural stiffness to the extracellular matrix, through physical mechanisms. In addition to physical mechanisms, biochemically collagen affects intracellular mechanisms. Collagen affects intracellular signaling by interacting with a large number of collagen receptors. These receptors are: integrins, discoidin domain receptors DDR1 and DDR2, GPVI, MRC2 and LAIR-1. Leukocyte-associated immunoglobulin-like receptor-1 (LAIR- 1) is a transmembrane glycoprotein, its extracellular segment contains a single immunoglobulin-like (Ig- like) domain, and its intracellular segment has two immuno- receptor tyrosine- based inhibitory motifs (ITIMs). LAIR-1 is strongly expressed on T cells, B cells, natural killer (NK) cells, macrophages and other immune cells. LAIR-1 strongly suppresses immune cell activation, thus reducing immune responses. Collagen-rich tumors, especially collagens I and III activate LAIR-1 in CD8+ T cells, and reduce T cell-mediated cytotoxicity. Thus, activation of LAIR-1 on immune cells has been proposed as a mechanism by which tumors inhibit antitumor immune responses. Surprisingly, we found that LAIR-1 is also expressed in glioma cells. Expression of LAIR-1 in other solid tumors, such as cervical, breast and kidney cancer increases tumor aggressiveness. Thus, we postulate that LAIR-1 could affect glioma progression by directly increasing the pathogenesis of cancer cells, and indirectly, by inhibiting the anti-tumor cytotoxic immune responses. Knockdown of collagen from genetically engineered mouse models of glioma increased median survival, and reduced LAIR-1 expression within brain tumors. Thus, collagen could directly inhibit anti-glioma immune responses, or affect the malignant behavior of glioma cells. There is thus a critical need for a mechanistic understanding of how LAIR-1 expressed by either infiltrating immune cells or glioma tumor cells contributes to glioma progression and invasion and how it remodels the tumor immune microenvironment. Our long-term goal is to understand how the extracellular tumor matrix, through its expression of collagen affects tumor progression and anti-tumor immunity. Our overall objectives in this application are to test the hypothesis that LAIR-1 expression in glioma cells increases tumor progression (AIM 1), the role of LAIR-1 expression in regulating the function of infiltrating immune cells (AIM 2), and determine the therapeutic potential of the inhibition of LAIR-1 in glioma models (AIM 3). Our central hypothesis is that LAIR-1 plays essential pathological roles that contribute to glioma progression through its expression in glioma cells and in immune cells and that inhibiting LAIR-1 signaling could uncover novel therapeutic targets for HGG.