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.