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?
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.
Jordanova
Ekaterina S
ES
Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
Gorter
Arko
A
Ayachi
Ouissam
O
Prins
Frans
F
Durrant
Lindy G
LG
Kenter
Gemma G
GG
van der Burg
Sjoerd H
SH
Fleuren
Gert Jan
GJ
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*
D014408:Biomarkers, Tumor; D015234:HLA-A Antigens; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A