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
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
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
1. van der Touw, W. et al (2017) LILRB receptor-mediated regulation of myeloid cell maturation and function. Cancer Immunol. Immunother. 66 1079 PMID: 28638976
2. Kang, X. et al (2016) Inhibitory leukocyte immunoglobulin-like receptors: Immune checkpoint proteins and tumor sustaining factors. Cell Cycle 15 25 PMID: 26636629
3. Allen, R.L. et al (2001) Leukocyte receptor complex-encoded immunomodulatory receptors show differing specificity for alternative HLA-B27 structures. J. Immunol. 167 5543 PMID: 11698424
4. Willcox, B.E. et al (2003) Crystal structure of HLA-A2 bound to LIR-1, a host and viral major histocompatibility complex receptor. Nat. Immunol. 4 913 PMID: 12897781
5. Zhang, Z. et al (2015) The leukocyte immunoglobulin-like receptor family member LILRB5 binds to HLA-class I heavy chains. PLoS One 10 129063 PMID: 26098415
6. Barkal, A.A. et al (2017) Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nat. Immunol. 19 76 PMID: 29180808
7. Zhao, J. et al (2019) The MHC class I-LILRB1 signalling axis as a promising target in cancer therapy. Scand. J. Immunol. 90 12804 PMID: 31267559