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The Leukocyte Immunoglobulin-like Receptors: Future Targets for Cancer Immunotherapy? 

The LILR Family Has Immune Cell Activating and Inhibitory Members

The leukocyte immunoglobulin-like receptors (LILRs), also known as Ig-like transcripts (ILTs), are a family of immunoregulatory receptors expressed by a range of hematopoietic cell types, including monocytes, macrophages, dendritic cells, granulocytes, natural killer (NK) cells, T cells, and B cells.1The LILR family consists of both stimulatory receptors that belong to the LILRA subfamily (LILRA1-6) and inhibitory receptors that belong to the LILRB subfamily (LILRB1-5). While the LILRA receptors promote immune cell activation by signaling through immunoreceptor tyrosine-based activation motifs (ITAMs), the LILRB receptors inhibit immune cell activation by signaling through immunoreceptor tyrosine-based inhibitory motifs (ITIMs).

The LILRB subfamily proteins are human and primate-specific, with paired immunoglobulin-like receptor B (PirB) and gp49B1 being the only mouse receptor orthologs identified to date.2 Several ligands have been reported for human LILRB1/ILT2 and LILRB2/ILT4 including classical (HLA-A, HLA-B, and HLA-C) and non-classical (HLA-E, HLA-F, and HLA-G) MHC class I molecules, S100A8 and S100A9, and the viral MHC homolog, UL18, for LILRB1/ILT2, and several angiopoietin-like proteins (ANGPTLs), CD1d, myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), oligomeric beta-amyloid (A beta), and reticulon 4 (RTN4/NOGO) for LILRB2/ILT4.2 Unlike LILRB2/ILT4, LILRB1/ILT2 requires beta2-microglobulin for binding to HLA ligands.3, 4 Additionally, LILRB1/ILT2 has been shown to bind more strongly to HLA-G than to classical HLA class I molecules, while LILRB2/ILT4 binds more strongly to ANGPTL proteins than to HLA-G.2-4 ANGPTL proteins have also been found to interact with both LILRB4 and LILRB5 and HLA-class I has also been reported to be a LILRB5 ligand, but the ligands for LILRB3 have yet to be identified.2, 5

Due to their immunosuppressive properties, members of the LILRB subfamily are considered to be immune checkpoint receptors. Ligands of LILRBs, such as HLA-G can be highly expressed on tumor cells and the interaction of HLA-G with LILRB1 has been shown to inhibit the functions of NK cells, dendritic cells, monocytes/macrophages, T cells, and B cells, allowing tumors to evade immune detection.1, 6, 7 LILRBs are also up-regulated or expressed on various cancer cell types, as well as on immune cells found in the tumor microenvironment including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), and are thought to contribute to tumor growth, angiogenesis, and metastasis.7 Blockade of LILRB2 in a Lewis lung carcinoma model was shown to enhance anti-tumor immune responses, reduce the numbers of granulocytic MDSCs and regulatory T cells, and inhibit tumor progression both on its own, and to a significantly greater extent when combined with anti-PD-L1 treatment.8 Taken together, these results suggest that LILRBs may represent future targets for cancer immunotherapy.

Bio-Techne offers a complete range of products for immuno-oncology researchers studying the effects of different LILRs, including R&D SystemsTM bioactive recombinant human proteins and antibodies for all of the LILRB and LILRA subfamily members.


The Leukocyte Immunoglobulin-like Receptor (LILR) Family Consists of Activating and Inhibitory Members that Can Stimulate or Inhibit Immune Cell Activity

The LILR family, also known as ILTs, consists of both immune cell stimulatory (LILRA) and inhibitory (LILRB) receptors.

Leukocyte immunoglobulin-like receptors mediate immune cell stimulatory and immune cell inhibitory effects. Members of the leukocyte immunoglobulin-like receptor family belong to the LILRA or LILRB subfamilies, which have immune cell stimulatory or inhibitory effects, respectively. LILRA and LILRB subfamilies bind to a range of different ligands including MHC class I molecules, angiopoietin (ANGPT) and angiopoietin-like (ANGPTL) proteins, and other proteins as shown in the graphic and described in the text. Interactions between the LILR family proteins and their ligands either promote (LILRA; shown on the left) or inhibit (LILRB; shown on the right) immune cell activation. LILRBs in particular are being investigated as potential therapeutic targets due to their immunosuppressive effects.

Analysis of the Binding of R&D Systems Recombinant Human LILRB2 and ANGPTL7 Proteins

Analysis of the binding response between R&D Systems Recombinant Human LILRB2 and Recombinant Human ANGPTL7 proteins.

Human Angiopoietin-like 7 (ANGPTL7) Binds to LILRB2/ILT4. Recombinant Human LILRB2/ILT4 (R&D Systems, Catalog # 8429-T4) was coated on a plate at 2 μg/mL and the indicated concentrations of Recombinant Human Angiopoietin-like 7 (R&D Systems, Catalog # 914-AN) were added. Recombinant Human ANGPTL7 bound with an ED50 of 25-150 ng/mL.

Analysis of the Binding of R&D Systems Recombinant Human LILRB2 and ANGPTL3 Proteins

Analysis of the binding response between R&D Systems Recombinant Human LILRB2 and Recombinant Human ANGPTL3 proteins.

Human Angiopoietin-like 3 (ANGPTL3) Binds to LILRB2/ILT4. This ELISA binding assay demonstrates Recombinant Human ANGPTL3 (Catalog # 3829-AN) binds to Recombinant Human LILRB2/CD85d/ILT4 (Catalog # 2078-T4) with a Kd = 24 nM.