The MHC class I‐LILRB1 signalling axis as a promising target in cancer therapy

Abstract

Immune checkpoint inhibitors are among the newest, cutting-edge methods for the treatment of cancer. Currently, they primarily influence T cell adaptive immunotherapy targeting the PD-1/PD-L1 and CTLA-4/B7 signalling pathways. These inhibitors fight cancer by reactivating the patient's own adaptive immune system, with good results in many cancers. With the discovery of the "Don't Eat Me" molecule, CD47, antibody-based drugs that target the macrophage-related innate immunosuppressive signalling pathway, CD47-SIRPα, have been developed and have achieved stunning results in the laboratory and the clinic, but there remain unexplained instances of tumour immune escape. While investigating the immunological tolerance of cancer to anti-CD47 antibodies, a second "Don't Eat Me" molecule on tumour cells, beta 2 microglobulin (β2m), a component of MHC class I, was described. Some tumour cells reduce their surface expression of MHC class I to escape T cell recognition.However, other tumour cells highly express β2m complexed with the MHC class I heavy chain to send a "Don't Eat Me" signal by binding to leucocyte immunoglobulin-like receptor family B, member 1 (LILRB1) on macrophages, leading to a loss of immune surveillance. Investigating the mechanisms underlying this immunosuppressive MHC class I-LILRB1 signalling axis in tumour-associated macrophages will be useful in developing therapies to restore macrophage function and control MHC class I signalling in patient tumours. The goal is to promote adaptive immunity while suppressing the innate immune response to tumours. This work will identify new therapeutic targets for the development of pharmaceutical-based tumour immunotherapy.

Immune suppressive landscape in the human esophageal squamous cell carcinoma microenvironment

“…LILRB1 expression was upregulated on TAMs, disruption of either MHC class I or LILRB1 potentiated phagocytosis of tumor cells both in vitro and in vivo. Investigating the mechanisms underlying this immunosuppressive MHC class I-LILRB1 signaling axis in TAMs will be useful in developing therapies to restore macrophage function 46,61 , and blocking this pathway may promote antitumor immunity in ESCC.…”

Human inhibitory leukocyte Ig-like receptors: from immunotolerance to immunotherapy

“…A recent study investigating HLA class I–LILRB1 interactions detailed a complex interplay between LILRB1 and β 2 -microglobulin (β2m) that implicates LILRB1 as a “don’t eat me” molecule ( 37 , 38 ). As such, LILRB1 blockade (clone VMP55) augments tumor cell phagocytosis by macrophages, supporting the potential of modulating the HLA class I/LILRB1 signaling axis to promote antitumor immunity ( 37 , 38 ). LILRB1 may also be considered as a diagnostic and prognostic target in gastric cancers ( 39 ), in addition to certain subtypes of adenocarcinoma ( 40 ).…”

Immune-focused multi-omics analysis of prostate cancer: leukocyte Ig-Like receptors are associated with disease progression

“…These comprised predominantly HLA molecules, killer-cell immunoglobulin-like receptor (KIR), and leukocyte immunoglobulin-like receptor (LILR) genes (Supplementary Table S2). Since LILR are a family of immune regulators that are showing some potential as targets for cancer immunotherapy, we further analyzed the association between 30 LILR gene-associated features and BCR 17,18 (Supplementary Table S3). As shown in Figure 3, the 30 LILR gene-associated features alone could predict BCR in sPLS-DA analysis with a BER of 0.34 suggesting a role of this family of receptors in the progression of PCa.…”