RRC ID 52554
著者 Warthan MD, Washington SL, Franzese SE, Ramus RM, Kim KR, York TP, Stratikos E, Strauss JF 3rd, Lee ED.
タイトル The role of endoplasmic reticulum aminopeptidase 2 in modulating immune detection of choriocarcinoma.
ジャーナル Biol Reprod
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.
巻・号 98(3)
ページ 309-322
公開日 2018-3-1
DOI 10.1093/biolre/ioy001
PII 4794933
PMID 29324974
PMC PMC5939618
MeSH Aminopeptidases / metabolism* Cell Line, Tumor Choriocarcinoma / immunology* Choriocarcinoma / metabolism Female Humans Interferon-gamma / pharmacology Pregnancy Trophoblasts / drug effects Trophoblasts / immunology Trophoblasts / metabolism Uterine Cervical Neoplasms / immunology* Uterine Cervical Neoplasms / metabolism
IF 3.322
引用数 3
リソース情報
ヒト・動物細胞 T3M-3(RCB1018)