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 Systems^TM bioactive recombinant human proteins and antibodies for all of the LILRB and LILRA subfamily members.

LILR Family - Products by Molecule

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