Immunoselective pressure and human leukocyte antigen class I antigen machinery defects in microsatellite unstable colorectal cancers.

Abstract

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.

• Authors: Matthias Kloor, Christina Becker, Axel Benner, Stefan M Woerner, Johannes Gebert, Soldano Ferrone, Magnus von Knebel Doeberitz
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 14 Pg. 6418-24 (Jul 15 2005) ISSN: 0008-5472 [Print] United States
• PMID: 16024646 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 2
• ATP Binding Cassette Transporter, Subfamily B, Member 3
• ATP-Binding Cassette Transporters
• Antibodies, Monoclonal
• HLA-A Antigens
• TAP1 protein, human
• beta 2-Microglobulin
• TAP2 protein, human

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 2
• ATP Binding Cassette Transporter, Subfamily B, Member 3
• ATP-Binding Cassette Transporters (immunology)
• Antibodies, Monoclonal (immunology)
• Antigen Presentation (genetics, immunology)
• Colorectal Neoplasms (genetics, immunology)
• HLA-A Antigens (genetics, immunology)
• Humans
• Immunohistochemistry
• Microsatellite Repeats (genetics, immunology)
• beta 2-Microglobulin (biosynthesis, genetics, immunology)