title: Human leukocyte antigen class I, MHC class I chain-related molecule A, and CD8+/regulatory T-cell ratio: which variable determines survival of cervical cancer patients?
abstract: OBJECTIVE
  To investigate the effect of intraepithelial tumor-infiltrating lymphocytes (ieTIL) and their ligands expressed by cervical tumor cells on the outcome of cervical cancer patients.
  
  
  METHODS
  The prognostic value of ieTILs was investigated in 115 cases of cervical cancer. T-cell subsets, CD57(+) cells, and regulatory T cells (Treg) were enumerated. The associations of these different ieTIL subtypes with human leukocyte antigen (HLA) class I and MHC class I chain-related molecule A (MICA) expression were determined in relation to clinical variables and patient survival.
  
  
  RESULTS
  Survival analysis showed that a high number of intraepithelial Treg (FoxP3(+)), a low CD8(+)/regulatory T-cell ratio, and a weak HLA-A expression were all associated with worse survival (P=0.034, 0.025, and 0.033, respectively, log-rank test). Further stratification of patient groups based on HLA-A-MICA expression and HLA-A-MICA-CD8(+)/Treg ratio revealed an even poorer survival (P=0.005). In a multivariate Cox analysis, low CD8(+)/Treg ratio (P=0.047), weak HLA-A-MICA expression (P=0.003), and weak HLA-A-MICA expression combined with low CD8(+)/Treg ratio (P=0.002) were all found to be independent unfavorable prognostic predictors in cervical carcinoma (hazard ratios, 2.7, 4.0, and 4.9, respectively).
  
  
  CONCLUSIONS
  Weak HLA-A-MICA expression combined with low CD8(+)/Treg ratio reveals a patient group with the poorest survival in cervical cancer. As a single variable, low CD8(+)/Treg ratio was a significant independent unfavorable prognostic factor.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.forename: Arko
authors.initials: A
authors.lastname: Gorter
authors.forename: Ouissam
authors.initials: O
authors.lastname: Ayachi
authors.forename: Frans
authors.initials: F
authors.lastname: Prins
authors.forename: Lindy G
authors.initials: LG
authors.lastname: Durrant
authors.forename: Gemma G
authors.initials: GG
authors.lastname: Kenter
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Fleuren
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005455:Fluorescent Antibody Technique; D015234:HLA-A Antigens / Q000096:biosynthesis*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000378:metabolism / Q000401:mortality*
chemical_list: D014408:Biomarkers, Tumor; D015234:HLA-A Antigens; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A