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ER-aminopeptidase 1 determines the processing and presentation of an immunotherapy-relevant melanoma epitope

Item Type:Article
Title:ER-aminopeptidase 1 determines the processing and presentation of an immunotherapy-relevant melanoma epitope
Creators Name:Textoris-Taube, K. and Cammann, C. and Henklein, P. and Topfstedt, E. and Ebstein, F. and Henze, S. and Liepe, J. and Zhao, F. and Schadendorf, D. and Dahlmann, B. and Uckert, W. and Paschen, A. and Mishto, M. and Seifert, U.
Abstract:Dissecting the different steps of the processing and presentation of tumor-associated antigens is a key aspect of immunotherapies enabling to tackle the immune response evasion attempts of cancer cells. The immunodominant glycoprotein gp100(209-217) epitope, which is liberated from the melanoma differentiation antigen gp100(PMEL17), is part of immunotherapy trials. By analyzing different human melanoma cell lines, we here demonstrate that a pool of N-terminal extended peptides sharing the common minimal epitope is generated by melanoma proteasome subtypes. In vitro and in cellulo experiments indicate that ER-resident aminopeptidase 1 (ERAP1) - but not ERAP2 - defines the processing of this peptide pool thereby modulating the T cell recognition of melanoma cells. By combining the outcomes of our studies and others, we can sketch the complex processing and endogenous presentation pathway of the gp100(209-217)-containing epitope/peptides, which are produced by proteasomes and are translocated to the vesicular compartment through different pathways, where the precursor peptides that reach the endoplasmic reticulum are further processed by ERAP1. The latter step enhances the activation of epitope-specific T lymphocytes, which might be a target to improve the efficiency of anti-melanoma immunotherapy.
Keywords:CD8(+) T Cells, Proteasome, ER-Aminopeptidase, Melanoma, gp100
Source:European Journal of Immunology
ISSN:0014-2980
Publisher:Wiley (U.S.A.)
Date:15 November 2019
Official Publication:https://doi.org/10.1002/eji.201948116
PubMed:View item in PubMed

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