ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function

Abstract

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1.

A Comparative Review of Pregnancy and Cancer and Their Association with Endoplasmic Reticulum Aminopeptidase 1 and 2

“…The presentation of cancer-specific antigens and T-cell infiltration is necessary for an effective antitumor immune response. ERAP1 inhibition results in the greater activation of T and NK cells and a substantial change in the peptides present on the cancer cell surface to immune effector cells [ 92 , 93 ]. Thus, the role of these ERAP enzymes in cancer immune responses indicates the emerging interest in cancer immunotherapy [ 86 ].…”

The ER Aminopeptidases, ERAP1 and ERAP2, synergize to self-modulate their respective activities

“…By synergizing and cross modulating each other’s activities, proper feedback between ERAP1 and ERAP2 activities will have important effects in optimizing the peptidome presented by HLA molecules. Clearly, perturbations of this finely regulated pathway, such as in virally infected or transformed cells, can affect immunosurveillance by cytotoxic T cells and even NK responses ( 26 – 31 ). Furthermore, understanding how this cross-modulatory behavior is affected by different haplotypes of ERAP1 or alternative isoforms of ERAP2 whose function has not been yet characterized ( 32 ), will be a fruitful area of future investigation.…”

Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment

“…Natural killer cells (NKs) in the immune microenvironment of osteosarcoma NKs, considered nonspecific cytotoxic immune cells, are able to nonspecifically destroy infected abnormal cells (such as cancer cells) without prior activation or sensitization. [75][76][77] They generally express suppressive surface receptors, such as killer-cell immu noglobulin-like receptors (KIRs), that can identify specific HLA class I molecules, including CD94/NK group 2 member A (NKG2A) and HLA-A, B and C. [78][79][80] Moreover, they can be trained to lyse cancer cells with low expression of MHC class I produced from host cells. 81,82 Their activated surface receptors generally include NKG2D and natural cytotoxic receptors (NCRs), which can recognize stress proteins on the surface of cancer cells, such as MHC class I peptide A/B (MICA/B), UL16-binding proteins (ULBPs), and the Fcg receptor CD16, which induces ADCC by recognizing the Fc portion of antibodies on opsonized cells.…”