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

Calvin D De Louche,Ali Roghanian

doi:10.1172/jci.insight.151553

Abstract

In recent decades, immunotherapeutic strategies have been used to treat a wide range of pathologies, many of which were previously incurable, such as cancer and autoimmune disorders. Despite this unprecedented success, a considerable number of patients fail to respond to currently approved immunotherapies or develop resistance over time. Therefore, there is an urgent need to develop the next generation of immune-targeted therapies. Various members of the Ig superfamily play essential roles in regulating leukocyte functions. One such group, the leukocyte Ig-like receptors (LILRs), have been implicated in both innate and adaptive immune regulation. Human inhibitory LILRs (LILRBs) are primarily expressed on leukocytes and mediate their signaling through multiple cytoplasmic immunoreceptor tyrosine-based inhibitory motifs. Engagement of LILRBs by endogenous and pathogenic ligands can markedly suppress immune responses, leading to tolerance or immunoevasion, whereas blocking these inhibitory receptors can potentiate immune responses. In this Review, we discuss the immunoregulatory functions of human LILRBs and the potential of targeting them to manipulate immune responses in various pathologies.

Highlights

Immunotherapy regimens target and modulate the immune system to treat a pathology [1, 2]
Many patients still fail to respond to approved therapies, and development of new treatment regimens that benefit all disease categories, whether by amplifying or abrogating the immune response, is mandated
The LILRB field continues to expand, and the adaptable nature of targeting of LILRBs to combat a plethora of immune-related pathologies highlights these receptors as viable immunotherapeutic targets

Summary

Introduction

Immunotherapy regimens target and modulate the immune system to treat a pathology [1, 2]. Multiple groups, including ours, have demonstrated that LILRB1 ( known as LIR1, ILT2, CD85j) ligation renders DCs tolerogenic, hindering the onset of adaptive immunity and promoting immunoevasion [21,22,23,24] Both LILRB1 and LILRB2 ( known as LIR2, ILT4, CD85d) compete with CD8 for binding to the HLA class I molecule, inhibiting antigen-presenting cell activation and thereby altering downstream T cell responses [9]. These pathways minimize widespread tissue damage and maintain tolerance to self; tumors can modulate these inhibitory networks to promote immune cell exhaustion and resistance, which in turn fosters tumor proliferation and metastasis [30] This exploitation is achieved, in part, by the co-opting of immune checkpoints to suppress the recognition of tumor-associated antigens (TAAs) by T cell receptors (TCRs), thereby allowing tumors to avoid elimination [30].

Mast cell granules

Findings

Discussion