Abstract
Inhibitory leukocyte immunoglobulin-like receptors (LILRB1-5) signal through immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their intracellular domains and recruit phosphatases protein tyrosine phosphatase, non-receptor type 6 (PTPN6, SHP-1), protein tyrosine phosphatase, non-receptor type 6 (PTPN6, SHP-2), or Src homology 2 domain containing inositol phosphatase (SHIP) to negatively regulate immune cell activation. These receptors are known to play important regulatory roles in immune and neuronal functions. Recent studies demonstrated that several of these receptors are expressed by cancer cells. Importantly, they may directly regulate development, drug resistance, and relapse of cancer, and the activity of cancer stem cells. Although counterintuitive, these findings are consistent with the generally immune-suppressive and thus tumor-promoting roles of the inhibitory receptors in the immune system. This review focuses on the ligands, expression pattern, signaling, and function of LILRB family in the context of cancer development. Because inhibition of the signaling of certain LILRBs directly blocks cancer growth and stimulates immunity that may suppress tumorigenesis, but does not disturb normal development, LILRB signaling pathways may represent ideal targets for treating hematological malignancies and perhaps other tumors.
Highlights
Introduction toITIM-containing receptors and leukocyte Ig-like receptor subfamily B (LILRB)First described in 1995, the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) are conserved 6 amino acid stretches (S/I/V/LxYxxI/V/L) found in the cytoplasmic tails of certain surface transmembrane receptors [1]
We recently demonstrated that multimeric angiopoietin-like proteins (Angptls) bind and activate LILRB2 more effectively than does human leukocyte antigen (HLA)-G [42]
We showed that LILRB2 is required for ex vivo expansion of hematopoietic stem cells (HSCs) [21]
Summary
(Fc RIIB), which is the ITIM-containing receptor that only recruits the inositol-phosphatase SHIP, these receptors all bind tyrosine phosphatases SHP-1 or SHP-2 [2,3,4]. An isoleucine at the first position of the ITIM (IxYxxL/V) favors binding to SHP-1, whereas a leucine in the same position (LxYxxL/V) favors SHIP binding [5] These phosphatases are known to negatively regulate immune cell activation. Like to ITIM-containing receptors, ligand engagement at a relevant receptor results in the activation of Src kinases, leading to the phosphorylation of tyrosines within the ITAM. We will focus on the ligands, expression pattern, signaling, and the immune-modulatory and direct tumor-supportive roles of LILRBs in cancer development
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