A Role for Naturally Occurring Alleles of Endoplasmic Reticulum Aminopeptidases in Tumor Immunity and Cancer Pre-Disposition

Abstract

Endoplasmic reticulum aminopeptidase 1 and 2 (ERAP1 and ERAP2) are key components on the pathway that generates antigenic epitopes for presentation to cytotoxic T-lymphocytes (CTLs). Coding single nucleotide polymorphisms (SNPs) in these enzymes have been associated with pre-disposition to several major human diseases including inflammatory diseases with autoimmune etiology, viral infections, and virally induced cancer. The function of these enzymes has been demonstrated to affect CTL and natural killer cell responses toward healthy and malignant cells as well as the production of inflammatory cytokines. Recent studies have demonstrated that SNPs in ERAP1 and ERAP2 can affect their ability to generate or destroy antigenic epitopes and define the immunopeptidome. In this review, we examine the potential role of these enzymes and their polymorphic states on the generation of cytotoxic responses toward malignantly transformed cells. Given the current state-of-the-art, it is possible that polymorphic variation in these enzymes may contribute to the individual’s pre-disposition to cancer through altered generation or destruction of tumor antigens that can facilitate tumor immune evasion.

Crystal Structures of ERAP2 Complexed with Inhibitors Reveal Pharmacophore Requirements for Optimizing Inhibitor Potency

“…11,12 Unlike humans, mice do not express ERAP2, and as a result, the tractability of ERAP2 inhibition for cancer immunotherapy has not been evaluated yet, but given the variable expression of ERAP2 in human tumors, the possibility that ERAP2 inhibition can lead to enhancement of antitumor responses has been proposed. 13,14 The proposed secondary role of ERAP2 in generating antigenic peptides compared to ERAP1, however, possibly makes ERAP2 a more attractive target for pharmacological intervention since its inhibition is less likely to elicit unwanted side-effects.…”

Crystal Structure of Insulin-Regulated Aminopeptidase with Bound Substrate Analogue Provides Insight on Antigenic Epitope Precursor Recognition and Processing

“…ERAP1 and ERAP2 have been shown to be polymorphic, and several single nucleotide polymorphisms (SNPs) in these enzymes have been associated with predisposition to disease, ranging from viral infections and cancer to autoimmunity. These SNPs have been shown to affect enzymatic activity, Ag generation, and cytotoxic responses [reviewed in (15)(16)(17)] and to form specific disease-associated functionally distinct allotypes (18,19). Recently, two SNPs in IRAP have also been reported to associate with psoriasis and ankylosing spondylitis, suggesting that IRAP polymorphic variation may also contribute to the pathogenesis of autoimmunity (20,21).…”

Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2

“…Coding single nucleotide polymorphisms in these enzymes have been repeatedly associated with predisposition to major human diseases (5,10,11). Particular ERAP1 and ERAP2 haplotypes have been associated with disease often in epistasis with specific MHC alleles and shown to functionally affect antigen processing in model systems (12)(13)(14)(15)(16)(17).…”