LILRB4, an immune checkpoint on myeloid cells

Abstract

Leukocyte immunoglobulin-like receptor B4 (LILRB4) is an inhibitory receptor in the LILR family mainly expressed on normal and malignant human cells of myeloid origin. By binding to ligands, LILRB4 is activated and subsequently recruits adaptors to cytoplasmic immunoreceptor tyrosine inhibitory motifs to initiate different signaling cascades, thus playing an important role in physiological and pathological conditions, including autoimmune diseases, microbial infections, and cancers. In normal myeloid cells, LILRB4 regulates intrinsic cell activation and differentiation. In disease-associated or malignant myeloid cells, LILRB4 is significantly correlated with disease severity or patient survival and suppresses T cells, thereby participating in the pathogenesis of various diseases. In summary, LILRB4 functions as an immune checkpoint on myeloid cells and may be a promising therapeutic target for various human immune diseases, especially for cancer immunotherapy.

Keywords: Autoimmune disease; Cancer; Immune checkpoint; Immunotherapy; Inhibitory receptor; LILR; LILRB4; MDSC; Myeloid cell; TAM.

Figure 1

The functions of LILRB4 in homeostasis, inflammation disorders, and tumors. The functions of LILRB4 include (1) eliciting immune functions in monocytes, macrophage activation by inactivation of FcγR signaling, suppressing the activation and maturation of CD4⁺ Th cells, or inducing the generation of CD8⁺ T suppression in tDCs; (2) exerting immunosuppressive functions in MDSCs and TAMs via regulation of the production of immune suppressive cytokines; (3) promoting leukemia cell infiltration and T cell suppression in AML through the NFκB signaling pathway. AML = acute myeloid leukemia, B-CLL = B-cell chronic lymphocytic leukemia, Mϕ = macrophage, MDSC = myeloid-derived suppressor cells, NFκB = nuclear factor kappa B, TAM = tumor-associated macrophages, TCL = T cell lymphoma, tDC = tolerogenic DC, Ts = suppressor T cell, uPAR = urokinase receptor, VEGF = vascular endothelial growth factor.