title: Loss of HLA class I and mismatch repair protein expression in sporadic endometrioid endometrial carcinomas.
abstract: Tumor cells can escape from cytotoxic T-cell responses by downregulation of human leukocyte antigen (HLA) class I molecules expressed at the cell surface which has been associated with a deficient mismatch repair (MMR) system in colorectal carcinomas. Our study investigated the association between expression of MMR proteins and HLA class I in sporadic endometrioid endometrial carcinomas (EC). In a consecutively selected cohort of 486 EC patients, MMR proteins (MLH1, MSH2 and MSH6) and HLA class I (HLA-A, -B, -C or β(2) m) were investigated by immunohistochemistry. Expression levels of MMR proteins and HLA class I were compared between low-grade and high-grade ECs. HLA class I expression was compared between tumors with loss (negative immunostaining of ≥1 MMR protein) and expression of MMR proteins. Associations between previously determined numbers of intratumoral CD8(+)  T-lymphocytes and expression of MMR proteins and HLA class I and the influence on survival was determined. ECs with loss of MMR protein expression (33.5%) more frequently have loss of HLA-B/C (37.3%), compared to ECs with MMR protein expression (25.5%, p = 0.007). Patients with loss of MMR proteins have a worse disease-specific survival compared to patients with expression (p = 0.039). CD8(+)  T-lymphocytes have a positive influence on disease-free and disease-specific survival in the total EC cohort but not in patients with loss of MMR protein expression. In conclusion, our results indicate that loss of MMR protein expression is related to selective downregulation of HLA class I which contributes to immune escape in EC with an abnormal MMR system.
authors.affiliation: Department of Gynecologic Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Renske A
authors.initials: RA
authors.lastname: de Jong
authors.forename: Annemarie
authors.initials: A
authors.lastname: Boerma
authors.forename: H Marike
authors.initials: HM
authors.lastname: Boezen
authors.forename: Marian J E
authors.initials: MJ
authors.lastname: Mourits
authors.forename: Harry
authors.initials: H
authors.lastname: Hollema
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000401:mortality; D005260:Female; D005805:Genes, MHC Class I; D006801:Humans; D007124:Immunoenzyme Techniques; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000378:metabolism*; D060787:Neoplasm Grading; D009687:Nuclear Proteins / Q000378:metabolism*; D011379:Prognosis; D015996:Survival Rate
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein