title: 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: Institute of Molecular Pathology, University of Heidelberg, Germany.
authors: Matthias
authors: M
authors: Kloor
authors: Christina
authors: C
authors: Becker
authors: Axel
authors: A
authors: Benner
authors: Stefan M
authors: SM
authors: Woerner
authors: Johannes
authors: J
authors: Gebert
authors: Soldano
authors: S
authors: Ferrone
authors: Magnus
authors: M
authors: von Knebel Doeberitz
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000276:immunology*; D015234:HLA-A Antigens / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D018895:Microsatellite Repeats / Q000235:genetics / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D000911:Antibodies, Monoclonal; D015234:HLA-A Antigens; C073119:TAP1 protein, human; D001613:beta 2-Microglobulin; C071692:TAP2 protein, human