Human inhibitory leukocyte Ig-like receptors: from immunotolerance to immunotherapy
Calvin D. De Louche, Ali Roghanian
Calvin D. De Louche, Ali Roghanian
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Review

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

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.

Authors

Calvin D. De Louche, Ali Roghanian

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Figure 2

LILRB3- and LILRB4-mediated regulation of myeloid cells and their therapeutic potential.

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LILRB3- and LILRB4-mediated regulation of myeloid cells and their therap...
(A) Cross-linking of LILRB3 with agonistic mAb is capable of inducing both suppressive “M2-skewed” myeloid cells and immune tolerance. Therefore, ligating LILRB3 may have applications in both autoimmunity and transplant settings and could be especially useful in the transient induction of immune tolerance (top). Natural LILRB3 ligands expressed by necrotic cancer epithelial cells are able to induce inhibitory signaling through LILRB3, which is expected to lead to tumor immunoevasion. Thus, by modulating and disrupting the interaction between LILRB3 and its potential ligands, such extrinsic and intrinsic immunoevasion strategies may be prevented. This modulation would also allow both T cell proliferation and the induction of classically activated “M1-skewed” macrophages that are traditionally associated with an inflammatory milieu (bottom). (B) AML cell subsets overexpress LILRBs, including LILRB4. LILRB4 mAbs are capable of exerting potent anti-AML activity via activation of FcγRs on immune effector cells, such as macrophages and NK cells (top). Likewise, CAR T cells that target and bind LILRB4 epitopes with high affinity provide potent anti-AML capacity via T cell–mediated cytotoxicity (middle). Additionally, AML cells may be targeted for destruction by LILRB4-specific mAbs conjugated to toxins. Upon binding to LILRB4 and endocytosis by the target AML cells, the therapeutic toxic agent is internalized where it is subsequently capable of exerting a cytotoxic effect (bottom). ADC, antibody-drug conjugate; ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; AML, acute myeloid leukemia; CAR, chimeric antigen receptor; FcγR, Fcγ receptor; MΦ, macrophage.