National Centre for Scientific Research Demokritos, Agia Paraskevi, Greece.
Department of Pharmacy, University of Patras, Patra, Greece.
Eur J Immunol. 2023 Aug;53(8):e2350449. doi: 10.1002/eji.202350449. Epub 2023 May 15.
ER aminopeptidase 1 (ERAP1) is an ER-resident aminopeptidase that excises N-terminal residues of peptides that then bind onto Major Histocompatibility Complex I molecules (MHC-I) and indirectly modulates adaptive immune responses. ERAP1 contains an allosteric regulatory site that accommodates the C-terminus of at least some peptide substrates, raising questions about its exact influence on antigen presentation and the potential of allosteric inhibition for cancer immunotherapy. We used an inhibitor that targets this regulatory site to study its effect on the immunopeptidome of a human cancer cell line. The immunopeptidomes of allosterically inhibited and ERAP1 KO cells contain high-affinity peptides with sequence motifs consistent with the cellular HLA class I haplotypes but are strikingly different in peptide composition. Compared to KO cells, allosteric inhibition did not affect the length distribution of peptides and skewed the peptide repertoire both in terms of sequence motifs and HLA allele utilization, indicating significant mechanistic differences between the two ways of disrupting ERAP1 function. These findings suggest that the regulatory site of ERAP1 plays distinct roles in antigenic peptide selection, which should be taken into consideration when designing therapeutic interventions targeting the cancer immunopeptidome.
内质网氨肽酶 1（ERAP1）是一种内质网驻留氨肽酶，可切除与主要组织相容性复合体 I 分子（MHC-I）结合的肽的 N 端残基，从而间接调节适应性免疫反应。ERAP1 包含一个变构调节位点，可容纳至少一些肽底物的 C 末端，这引发了对其对抗原呈递的确切影响以及变构抑制在癌症免疫治疗中的潜力的疑问。我们使用靶向该调节位点的抑制剂来研究其对人癌细胞系免疫肽组的影响。变构抑制和 ERAP1 KO 细胞的免疫肽组均含有与细胞 HLA Ⅰ类单倍型一致的高亲和力肽段，但其肽组成却截然不同。与 KO 细胞相比，变构抑制并不影响肽的长度分布，并且在序列基序和 HLA 等位基因利用方面都使肽库发生了倾斜，这表明两种破坏 ERAP1 功能的方式之间存在显著的机制差异。这些发现表明，ERAP1 的调节位点在抗原肽选择中发挥着不同的作用，在针对癌症免疫肽组设计治疗干预措施时应考虑到这一点。
