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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?

Authors' Affiliations: Departments of ¹ Pathology, ² Gynecology, and ³ Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands and ⁴ Academic Department of Clinical Oncology, Institute of Infection, Immunity and Inflammation, University of Nottingham, City Hospital, Nottingham, United Kingdom

Requests for reprints: Arko Gorter, Department of Pathology, Leiden University Medical Center, L1Q, P1-32, Albinusdreef 2, 2333ZA Leiden, the Netherlands. Phone: 31-71-5266631; Fax: 31-71-5248158; E-mail: a.gorter{at}lumc.nl.

Purpose: 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.

Experimental Design: 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).

Conclusion: 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.