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9 January 2018 The role of endoplasmic reticulum aminopeptidase 2 in modulating immune detection of choriocarcinoma
Michelle D Warthan, Sonya L Washington, Samone E Franzese, Ronald M Ramus, Kyu-Rae Kim, Timothy P York, Efstratios Stratikos, Jerome F Strauss, Eun D Lee
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Abstract

Gestational choriocarcinomas are derived from placental trophoblast cells, with HLA-C being the only class I polymorphic molecule expressed. However, choriocarcinomas have not been profiled for endoplasmic reticulum aminopeptidase 2 (ERAP2) expression. ERAP2 trims peptides presented by human leukocyte antigens (HLA) that have shown to modulate immune response. Over 50% of choriocarcinomas we screened lack ERAP2 expression, which suggests that the absence of ERAP2 expression allows immune evasion of choriocarcinoma cells. We demonstrate that the ability of choriocarcinoma cells to activate lymphocytes was lowest with cells lacking ERAP2 (JEG-3) or HLA-C (JAr). This observation suggests that activation is dependent on expression of both ERAP2 and HLA-C molecules. In addition, an ERAP2 variant in which lysine is changed to asparagine (K392N) results in increased trimming activity (165-fold) for hydrophobic peptides and biologically never been detected. We hypothesize that homozygosity for the N392 ERAP2 variant is prohibited because it modulates the immune recognition of placental trophoblasts. We demonstrate that NK-cell activation and killing were significantly dependent on forced expression of the N392 ERAP2 isoform in JEG-3 cells. Cytotoxicity was confirmed by 7AAD killing assays showing that N392 ERAP2-isoform expressing JEG-3 cells had the highest percentage of apoptotic cells independent of the expression level of CD11a on lymphocytes. This is the first report showing that N392 ERAP2 promotes an immune clearance pathway for choriocarcinoma cells, and provides an explanation for why embryonic homozygosity for the N392 ERAP2 variant is not detected in any population.

Summary Sentence

The N392 ERAP2 isoform expression promotes immune cell activation and apoptotic immune clearance of choriocarcinoma cells.

© The Author(s) 2018. Published by Oxford University Press on behalf of Society for the Study of Reproduction. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
Michelle D Warthan, Sonya L Washington, Samone E Franzese, Ronald M Ramus, Kyu-Rae Kim, Timothy P York, Efstratios Stratikos, Jerome F Strauss, and Eun D Lee "The role of endoplasmic reticulum aminopeptidase 2 in modulating immune detection of choriocarcinoma," Biology of Reproduction 98(3), 309-322, (9 January 2018). https://doi.org/10.1093/biolre/ioy001
Received: 17 March 2017; Accepted: 5 January 2018; Published: 9 January 2018
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