Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy

Abstract

Exciting progress in the field of cancer immunotherapy has renewed the urgency of the need for basic studies of immunoregulation in both adaptive cell lineages and innate cell lineages. Here we found a central role for major histocompatibility complex (MHC) class I in controlling the phagocytic function of macrophages. Our results demonstrated that expression of the common MHC class I component β2-microglobulin (β2M) by cancer cells directly protected them from phagocytosis. We further showed that this protection was mediated by the inhibitory receptor LILRB1, whose expression was upregulated on the surface of macrophages, including tumor-associated macrophages. Disruption of either MHC class I or LILRB1 potentiated phagocytosis of tumor cells both in vitro and in vivo, which defines the MHC class I–LILRB1 signaling axis as an important regulator of the effector function of innate immune cells, a potential biomarker for therapeutic response to agents directed against the signal-regulatory protein CD47 and a potential target of anti-cancer immunotherapy.

Immune Profiling of Atherosclerotic Plaques Identifies Innate and Adaptive Dysregulations Associated with Ischemic Cerebrovascular Events

“…In SYM plaques, T cells might also stimulate macrophage activation through unique TLR signaling cascades by which ligands ( VCAN, HSP90B1 ) bind to TLRs ( TLR1/2/7 ). Additionally, in SYM plaques we identified ligand-receptor interactions between T cells and macrophages involved in cell survival ( HLA-A/C-LILRB1 and B2M-LILRB1 ) 131 and pro-atherogenic functions linked to plaque vulnerability ( CCL5-CCR5 ) 91,92,132 . Interestingly, T cell expressed ligands that may promote the reparative macrophage polarization detected in these plaques by scRNA-seq analysis, through the expression of GDF11, a TGFβ superfamily member which bound to ACVR2A/1B on macrophages 133 .…”

Efficient Generation of Isogenic Primary Human Myeloid Cells using CRISPR-Cas9 Ribonucleoproteins

“…Comparatively, this route is difficult, expensive, and time-consuming (Sugimura et al, 2017). Another approach is to edit fully differentiated macrophages, which has shown some functional success in the literature (Barkal et al, 2017;Haney et al, 2018), though this also has limitations. The approach is specific to macrophages, rather than allowing for flexible differentiation, and is limited by the lifespan of mature macrophages in culture.…”

Effect of cytomegalovirus infection and leukocyte immunoglobulin like receptor B1 polymorphisms on receptor expression in peripheral blood mononuclear cells

“…LILRB1 is an inhibitory receptor that is expressed in diverse immune cells, including NK cells, T cells, B cells and monocytes. This receptor has been shown to play a role in a wide array of disorders, including infections, cardiovascular diseases and cancer . Therefore, understanding of factors associated with LILRB1 expression is important.…”

“…and monocytes. This receptor has been shown to play a role in a wide array of disorders, including infections, cardiovascular diseases and cancer (16)(17)(18)(19)(20). Therefore, understanding of factors associated with LILRB1 expression is important.…”