PMID- 16024646
OWN - NLM
STAT- MEDLINE
DCOM- 20050914
LR  - 20210103
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 65
IP  - 14
DP  - 2005 Jul 15
TI  - Immunoselective pressure and human leukocyte antigen class I antigen machinery 
      defects in microsatellite unstable colorectal cancers.
PG  - 6418-24
AB  - In colorectal cancer, the immune response is particularly pronounced against 
      tumors displaying the high microsatellite instability (MSI-H) phenotype. MSI-H 
      tumors accumulate mutations affecting microsatellites located within protein 
      encoding regions (coding microsatellites, cMS), which lead to translational 
      shifts of the respective reading frames. Consequently, novel tumor-specific 
      frameshift-derived neopeptides (FSP) are generated and presented by MSI-H tumor 
      cells, thus eliciting effective cytotoxic immune responses. To analyze whether 
      the immunoselective pressure was reflected by the phenotype of MSI-H colorectal 
      cancer cells, we compared here the expression of antigen processing machinery 
      (APM) components and human leukocyte antigen (HLA) class I antigen subunits in 20 
      MSI-H and 20 microsatellite-stable (MSS) colorectal cancer using a panel of newly 
      developed APM component-specific monoclonal antibodies. In addition, we did a 
      systematic analysis of mutations at cMS located within APM genes and 
      beta2-microglobulin (beta2m). Total HLA class I antigen loss was observed in 12 
      (60.0%) of the 20 MSI-H lesions compared with only 6 (30.0%) of the 20 MSS 
      colorectal cancer lesions. Moreover, total loss of membraneous HLA-A staining was 
      significantly more frequent in MSI-H colorectal cancer (P = 0.0024). Mutations at 
      cMS of beta2m and genes encoding APM components (TAP1 and TAP2) were detected in 
      at least 7 (35.0%) of 20 MSI-H colorectal cancers but in none of the MSS 
      colorectal cancers (P = 0.0002). These data show that defects of HLA class I 
      antigen processing and presentation seem to be significantly more frequent in 
      MSI-H than in MSS colorectal cancer, suggesting that in MSI-H colorectal cancer 
      the immunoselective pressure leads to the outgrowth of cells with defects of 
      antigen presentation.
FAU - Kloor, Matthias
AU  - Kloor M
AD  - Institute of Molecular Pathology, University of Heidelberg, Germany.
FAU - Becker, Christina
AU  - Becker C
FAU - Benner, Axel
AU  - Benner A
FAU - Woerner, Stefan M
AU  - Woerner SM
FAU - Gebert, Johannes
AU  - Gebert J
FAU - Ferrone, Soldano
AU  - Ferrone S
FAU - von Knebel Doeberitz, Magnus
AU  - von Knebel Doeberitz M
LA  - eng
GR  - CA67108/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 2)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 3)
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (HLA-A Antigens)
RN  - 0 (TAP1 protein, human)
RN  - 0 (beta 2-Microglobulin)
RN  - 145892-13-3 (TAP2 protein, human)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 2
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 3
MH  - ATP-Binding Cassette Transporters/immunology
MH  - Antibodies, Monoclonal/immunology
MH  - Antigen Presentation/genetics/immunology
MH  - Colorectal Neoplasms/*genetics/*immunology
MH  - HLA-A Antigens/*genetics/*immunology
MH  - Humans
MH  - Immunohistochemistry
MH  - Microsatellite Repeats/genetics/*immunology
MH  - beta 2-Microglobulin/biosynthesis/genetics/immunology
EDAT- 2005/07/19 09:00
MHDA- 2005/09/15 09:00
CRDT- 2005/07/19 09:00
PHST- 2005/07/19 09:00 [pubmed]
PHST- 2005/09/15 09:00 [medline]
PHST- 2005/07/19 09:00 [entrez]
AID - 65/14/6418 [pii]
AID - 10.1158/0008-5472.CAN-05-0044 [doi]
PST - ppublish
SO  - Cancer Res. 2005 Jul 15;65(14):6418-24. doi: 10.1158/0008-5472.CAN-05-0044.