Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 50, Issue 2, Pages 270-283Publisher
WILEY
DOI: 10.1002/eji.201948116
Keywords
CD8(+) T cells; proteasome; ER-aminopeptidase; melanoma; gp100
Categories
Funding
- Deutsche Forschungsgemeinschaft [SFB-TR36]
- Deutsche Krebshilfe [106861]
- Berliner Krebsgesellschaft e.V. [Z:SEFF200907]
- AICE FIRE Onlus Emilia Romagna
- KCL-Monash collaboration award 2018
- Cancer Research UK King's Health Partners Centre at King's College London
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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.
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