PMID- 27764126
OWN - NLM
STAT- MEDLINE
DCOM- 20170606
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 10
DP  - 2016
TI  - Upregulation of HLA Expression in Primary Uveal Melanoma by Infiltrating 
      Leukocytes.
PG  - e0164292
LID - 10.1371/journal.pone.0164292 [doi]
LID - e0164292
AB  - INTRODUCTION: Uveal melanoma (UM) with an inflammatory phenotype, characterized 
      by infiltrating leukocytes and increased human leukocyte antigen (HLA) 
      expression, carry an increased risk of death due to metastases. These tumors 
      should be ideal for T-cell based therapies, yet it is not clear why 
      prognostically-infaust tumors have a high HLA expression. We set out to determine 
      whether the level of HLA molecules in UM is associated with other genetic 
      factors, HLA transcriptional regulators, or microenvironmental factors. METHODS: 
      28 enucleated UM were used to study HLA class I and II expression, and several 
      regulators of HLA by immunohistochemistry, PCR microarray, qPCR and chromosome 
      SNP-array. Fresh tumor samples of eight primary UM and four metastases were 
      compared to their corresponding xenograft in SCID mice, using a PCR microarray 
      and SNP array. RESULTS: Increased expression levels of HLA class I and II showed 
      no dosage effect of chromosome 6p, but, as expected, were associated with 
      monosomy of chromosome 3. Increased HLA class I and II protein levels were 
      positively associated with their gene expression and with raised levels of the 
      peptide-loading gene TAP1, and HLA transcriptional regulators IRF1, IRF8, CIITA, 
      and NLRC5, revealing a higher transcriptional activity in prognostically-bad 
      tumors. Implantation of fresh human tumor samples into SCID mice led to a loss of 
      infiltrating leukocytes, and to a decreased expression of HLA class I and II 
      genes, and their regulators. CONCLUSION: Our data provides evidence for a proper 
      functioning HLA regulatory system in UM, offering a target for T-cell based 
      therapies.
FAU - van Essen, T Huibertus
AU  - van Essen TH
AD  - Department of Ophthalmology, LUMC, Leiden, the Netherlands.
FAU - van Pelt, Sake I
AU  - van Pelt SI
AD  - Department of Medical Statistics, LUMC, Leiden, the Netherlands.
FAU - Bronkhorst, Inge H G
AU  - Bronkhorst IH
AD  - Department of Ophthalmology, LUMC, Leiden, the Netherlands.
FAU - Versluis, Mieke
AU  - Versluis M
AD  - Department of Ophthalmology, LUMC, Leiden, the Netherlands.
FAU - Nemati, Fariba
AU  - Nemati F
AD  - Laboratory of Preclinical Investigation, Translational Research Department, 
      Institut Curie, Paris, France.
FAU - Laurent, Cecile
AU  - Laurent C
AD  - Laboratory of Preclinical Investigation, Translational Research Department, 
      Institut Curie, Paris, France.
FAU - Luyten, Gregorius P M
AU  - Luyten GP
AD  - Department of Ophthalmology, LUMC, Leiden, the Netherlands.
FAU - van Hall, Thorbald
AU  - van Hall T
AD  - Department of Clinical Oncology, LUMC, Leiden, the Netherlands.
FAU - van den Elsen, Peter J
AU  - van den Elsen PJ
AD  - Department of Immunohematology and Blood Transfusion, LUMC, Leiden, the 
      Netherlands.
AD  - Department of Pathology, VU University Medical Center, Amsterdam, the 
      Netherlands.
FAU - van der Velden, Pieter A
AU  - van der Velden PA
AD  - Department of Ophthalmology, LUMC, Leiden, the Netherlands.
FAU - Decaudin, Didier
AU  - Decaudin D
AD  - Laboratory of Preclinical Investigation, Translational Research Department, 
      Institut Curie, Paris, France.
AD  - Department of Clinical Hematology, Institut Curie, Paris France.
FAU - Jager, Martine J
AU  - Jager MJ
AD  - Department of Ophthalmology, LUMC, Leiden, the Netherlands.
LA  - eng
PT  - Journal Article
DEP - 20161020
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (HLA Antigens)
RN  - 0 (Peptides)
RN  - Uveal melanoma
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Animals
MH  - Chromosomes, Human, Pair 3
MH  - Chromosomes, Human, Pair 6
MH  - Female
MH  - HLA Antigens/genetics/*metabolism
MH  - Humans
MH  - Immunohistochemistry
MH  - Lymphocytes, Tumor-Infiltrating/immunology/*metabolism
MH  - Male
MH  - Melanoma/metabolism/*pathology
MH  - Mice
MH  - Mice, SCID
MH  - Middle Aged
MH  - Neoplasm Metastasis
MH  - Peptides/chemistry/metabolism
MH  - Polymorphism, Single Nucleotide
MH  - Transplantation, Heterologous
MH  - Up-Regulation
MH  - Uveal Neoplasms/metabolism/*pathology
PMC - PMC5072555
COIS- The authors have declared that no competing interests exist.
EDAT- 2016/10/21 06:00
MHDA- 2017/06/07 06:00
PMCR- 2016/10/20
CRDT- 2016/10/21 06:00
PHST- 2016/02/20 00:00 [received]
PHST- 2016/09/22 00:00 [accepted]
PHST- 2016/10/21 06:00 [pubmed]
PHST- 2017/06/07 06:00 [medline]
PHST- 2016/10/21 06:00 [entrez]
PHST- 2016/10/20 00:00 [pmc-release]
AID - PONE-D-16-02418 [pii]
AID - 10.1371/journal.pone.0164292 [doi]
PST - epublish
SO  - PLoS One. 2016 Oct 20;11(10):e0164292. doi: 10.1371/journal.pone.0164292. 
      eCollection 2016.