PMID- 19274709
OWN - NLM
STAT- MEDLINE
DCOM- 20090624
LR  - 20220317
IS  - 1096-9896 (Electronic)
IS  - 0022-3417 (Linking)
VI  - 218
IP  - 2
DP  - 2009 Jun
TI  - Reduced human leukocyte antigen expression in advanced-stage Ewing sarcoma: 
      implications for immune recognition.
PG  - 222-31
LID - 10.1002/path.2537 [doi]
AB  - Ewing sarcoma (EWS) is a tumour most commonly arising in bone, although on 
      occasion in soft tissue, with a poor prognosis in patients with refractory or 
      relapsed disease, despite multimodal therapy. Immunotherapeutic strategies based 
      on tumour-reactive T and/or natural killer cells may improve the treatment of 
      advanced-stage EWS. Since cellular immune recognition critically depends on human 
      leukocyte antigen (HLA) expression, knowledge about HLA expression in EWS is 
      crucial in the design of cellular immunotherapeutic strategies. Constitutive and 
      IFNgamma-induced HLA class I expression was analysed in EWS cell lines (n = 6) by 
      flow cytometry, using antibodies against both monomorphic and allele-specific 
      antigens. Expression of antigen processing pathway components and beta-2 
      microglobulin (beta2m) was assessed by western blot. Expression of class II 
      transactivator (CIITA), and its contribution to HLA class II expression, was 
      evaluated by qRT-PCR, transduction assays, and flow cytometry. beta2m/HLA class I 
      and class II expression was validated in EWS tumours (n = 67) by 
      immunofluorescence. Complete or partial absence of HLA class I expression was 
      observed in 79% of EWS tumours. Lung metastases consistently lacked HLA class I 
      and sequential tumours demonstrated a tendency towards decreased expression upon 
      disease progression. Together with absent or low constitutive expression levels 
      of specific HLA class I loci and alleles, and differential induction of identical 
      alleles by IFNgamma in different cell lines, these results may reflect the 
      existence of an immune escape mechanism. Inducible expression of TAP-1/-2, 
      tapasin, LMP-2/-7, and the beta2m/HLA class I complex by IFNgamma suggests that 
      regulatory mechanisms are mainly responsible for heterogeneity in constitutive 
      class I expression. EWSs lack IFNgamma-inducible HLA class II, due to lack of 
      functional CIITA. The majority of EWS tumours, particularly if advanced-stage, 
      exhibit complete or partial absence of both classes of HLA. This knowledge will 
      be instrumental in the design of cellular immunotherapeutic strategies for 
      advanced-stage EWS.
FAU - Berghuis, Dagmar
AU  - Berghuis D
AD  - Department of Pathology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - de Hooge, Alfons S K
AU  - de Hooge AS
FAU - Santos, Susy J
AU  - Santos SJ
FAU - Horst, Danielle
AU  - Horst D
FAU - Wiertz, Emmanuel J
AU  - Wiertz EJ
FAU - van Eggermond, Marja C
AU  - van Eggermond MC
FAU - van den Elsen, Peter J
AU  - van den Elsen PJ
FAU - Taminiau, Antonie H M
AU  - Taminiau AH
FAU - Ottaviano, Laura
AU  - Ottaviano L
FAU - Schaefer, Karl-Ludwig
AU  - Schaefer KL
FAU - Dirksen, Uta
AU  - Dirksen U
FAU - Hooijberg, Erik
AU  - Hooijberg E
FAU - Mulder, Arend
AU  - Mulder A
FAU - Melief, Cornelis J M
AU  - Melief CJ
FAU - Egeler, R Maarten
AU  - Egeler RM
FAU - Schilham, Marco W
AU  - Schilham MW
FAU - Jordanova, Ekaterina S
AU  - Jordanova ES
FAU - Hogendoorn, Pancras C W
AU  - Hogendoorn PC
FAU - Lankester, Arjan C
AU  - Lankester AC
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Pathol
JT  - The Journal of pathology
JID - 0204634
RN  - 0 (Biomarkers)
RN  - 0 (HLA-DR Antigens)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 0 (MHC class II transactivator protein)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Trans-Activators)
RN  - 0 (beta 2-Microglobulin)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Adolescent
MH  - Antigen Presentation
MH  - Biomarkers/analysis
MH  - Blotting, Western
MH  - Bone Neoplasms/*immunology/mortality/secondary
MH  - Cell Line, Tumor
MH  - Flow Cytometry
MH  - HLA-DR Antigens/genetics
MH  - Histocompatibility Antigens Class I/*analysis
MH  - Histocompatibility Antigens Class II/genetics
MH  - Humans
MH  - Immunization
MH  - Immunohistochemistry
MH  - Interferon-gamma/pharmacology
MH  - Kaplan-Meier Estimate
MH  - Nuclear Proteins/genetics
MH  - Sarcoma, Ewing/*immunology/mortality/secondary
MH  - Statistics, Nonparametric
MH  - Trans-Activators/genetics
MH  - Tumor Cells, Cultured
MH  - Tumor Escape
MH  - beta 2-Microglobulin/analysis
EDAT- 2009/03/11 09:00
MHDA- 2009/06/25 09:00
CRDT- 2009/03/11 09:00
PHST- 2009/03/11 09:00 [entrez]
PHST- 2009/03/11 09:00 [pubmed]
PHST- 2009/06/25 09:00 [medline]
AID - 10.1002/path.2537 [doi]
PST - ppublish
SO  - J Pathol. 2009 Jun;218(2):222-31. doi: 10.1002/path.2537.