LRIG2 promotes glioblastoma progression by modulating innate antitumor immunity through macrophage infiltration and polarization

Abstract

BackgroundGlioblastoma (GBM) is the most common malignant brain tumor with poor clinical outcomes. Immunotherapy has recently been an attractive and promising treatment of extracranial malignancies, however, most of clinical trials for GBM immunotherapy failed due to predominant accumulation of tumor-associated microglia/macrophages (TAMs).ResultsHigh level of LRIG2/soluble LRIG2 (sLRIG2) expression activates immune-related signaling pathways, which are associated with poor prognosis in GBM patients. LRIG2/sLRIGs promotes CD47 expression and facilitates TAM recruitment. Blockade of CD47–SIRPα interactions and inhibition of sLRIG2 secretion synergistically suppress GBM progression in an orthotropic murine GBM model.ConclusionsGBM cells with high level LRIG2 escape the phagocytosis by TAM via the CD47-SIRPα axis, highlighting a necessity for an early stage of clinical trial targeting LRIG2 and CD47-SIRPα as a novel treatment for patients with GBM.

Microglia and Brain Macrophages as Drivers of Glioma Progression

“…Notably, Li et al have shown that CD47 is expressed by human and mouse glioma cell lines and that positive cells have many characteristics of cancer stem cells [ 98 ]. The view is also supported by Hu et al [ 99 ] who report that overexpression of the LRIG2 (Leucine Rich Repeats And Immunoglobulin Like Domains 2) gene in GBM cells induces upregulation of CD47 and activation of the CD47-SIRPα anti-phagocytic axis [ 30 ]. Further experiments revealed that soluble LRIG (sLRIG) induces recruitment of BMDM that exhibit an immunosuppressive phenotype and also express high levels of CD47 receptor, SIRPα [ 99 ].…”

“…The view is also supported by Hu et al [ 99 ] who report that overexpression of the LRIG2 (Leucine Rich Repeats And Immunoglobulin Like Domains 2) gene in GBM cells induces upregulation of CD47 and activation of the CD47-SIRPα anti-phagocytic axis [ 30 ]. Further experiments revealed that soluble LRIG (sLRIG) induces recruitment of BMDM that exhibit an immunosuppressive phenotype and also express high levels of CD47 receptor, SIRPα [ 99 ]. As expected, knockdown of LRIG2 /sLRIG2 in GL261 (murine GBM) cells interferes with the activation of the CD47–SIRPα anti-phagocytic axis and enhances BMDM-mediated phagocytosis of GBM cells and suppresses GBM progression [ 99 ].…”

“…Further experiments revealed that soluble LRIG (sLRIG) induces recruitment of BMDM that exhibit an immunosuppressive phenotype and also express high levels of CD47 receptor, SIRPα [ 99 ]. As expected, knockdown of LRIG2 /sLRIG2 in GL261 (murine GBM) cells interferes with the activation of the CD47–SIRPα anti-phagocytic axis and enhances BMDM-mediated phagocytosis of GBM cells and suppresses GBM progression [ 99 ]. This is in keeping with the results of a xenograft study by Gholamin et al showing ubiquitous expression of CD47 in paediatric GBM and diffuse midline glioma [ 30 ].…”

Glioma-associated microglia/macrophages (GAMs) in glioblastoma: Immune function in the tumor microenvironment and implications for immunotherapy

“…Microglia/macrophages exhibit strong phagocytic activity. However, in glioma, the phagocytosis of GAMs is greatly reduced, due to the high expression of CD47 along with signal regulatory protein alpha (SIRPa) on the surface of GAMs ( 145 , 146 ). Therefore, a therapeutic approach involving a blockade of this signaling pathway using anti CD47 antibody to restore the phagocytic activity of GAMs has been proposed ( 145 , 146 ).…”

Glioma-derived LRIG3 interacts with NETO2 in tumor-associated macrophages to modulate microenvironment and suppress tumor growth

“…According to the activation state of cells, TAMs can be divided into tumor-suppressing M1-like subgroup and tumor-promoting M2-like subgroup. Among them, M1-like TAMs secrete pro-inflammatory cytokines, phagocytose cancer cells to present microbial antigen to activate the adaptive immune system [7,8]. Conversely, M2-like TAMs secrete anti-inflammatory cytokines and display immunesuppressive function to promote GBM malignant behavior and tumor growth [9,10].…”