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

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.Cervical cancer is the second most frequent cancer in women worldwide (1). The development of cervical cancer is a multistep process initiated by persistent infection with highrisk human papillomavirus (HPV; ref. 2). After high-risk HPV infection, in a limited number of patients, cervical lesions progress via cervical intraepithelial neoplasia I to cervical intraepithelial neoplasia III to cervical cancer. Cervical carcinoma cells constitutively express the HPV-encoded E6 and E7 oncoproteins. Therefore, peptides derived from these viral antigens can be generated and presented in the context of human leukocyte antigen (HLA) class I to cytotoxic T cells. The presence of substantial numbers of lymphocytes in cervical carcinomas as previously reported by our group and others suggests the presence of a cellular antitumor response (3 -6). Indeed, HPV-specific CD4 + and CD8 + T cells can be isolated from cervical tumors and CD8 + T-cell clones are able to kill cervical cancer cells in vitro (7 -10). However, this does not seem to be sufficient to eradicate the tumor. During tumor development, cancer cells have acquired several strategies to avoid eradication by cytotoxic T cells and natural killer (NK) cells. Among these mechanisms are down-regulation of HLA class I, down-regulation of MHC class I chain-related molecule A (MICA; a cytotoxic T-cell and NK cell ligand), production of immunosuppressive cytokines such as transforming growth factor-h, and the induction of i...

Success or failure of vaccination for HPV16-positive vulvar lesions correlates with kinetics and phenotype of induced T-cell responses

“…These Foxp3 + cells likely comprise HPV-specific suppressor cells, because similar populations of CD4 + CD25 high T cells stably expressing (≥7 d) Foxp3 after stimulation with cytomegalovirus or tetanus toxoid were suppressive in vitro (27). Moreover, we also documented that suppressive T cells in cervical cancer patients had the CD4 + CD25 high Foxp3 + phenotype (23) and that, as in many malignancies, their presence impaired tumor immunity as reflected in worse patient survival (28). In contrast to the antigen-specific stimulation used here, strong mitogenic agents were reported to induce Foxp3 expression in nonsuppressive T cells (29,30).…”

Systemic and local human papillomavirus 16‐specific T‐cell immunity in patients with head and neck cancer

“…5,33 Similarly, in HPV16 induced genital malignancies the presence of FoxP3 positive as well as FoxP3 negative HPV16 specific regulatory T cells in tumor and LN is described 30,36,38 and a low CD8/Treg T-cell ratio is associated with worse outcome. 39 While the regulatory function of the CD4þCD25þFoxp3þ T cells present in TILs needs to be confirmed, at least one of our isolated clones clearly exerted regulatory function. The expression of CD39 and CD73 has been found on CD4þ T cells as well as on the great majority of regulatory T cells in HNSCC, and has been implicated as a mechanism for T cell suppression.…”

“…The presence of HPV in the diluted samples was determined by genotyping the samples that demonstrated 65 basepair PCR amplimers on a 3% agarose gel using an INNOLiPA Genotyping Extra test (Innogenetics, Ghent, Belgium), according to the manufacturer's instruction. This assay allows the detection of the following HPV types: HPV 6,11,16,18,26,31,33,35,39,40,43,44,45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69/71, 73 and 74. Hybridization patterns were visually inspected and interpreted using a grid.…”

Human FOXP3 and cancer

“…Meanwhile, another team administered metronomic low dose oral cyclophosphamide for patients with hormone-resistant prostate cancer. (Gobert et al, 2009) 191 Unfavorable Colorectal carcinoma (Salama et al, 2009) 967 Favorable Cervix carcinoma (Jordanova et al, 2008) 115 Unfavorable Esophagus carcinoma (Yoshioka et al, 2008) 122 Not significant Gastric carcinoma (Mizukami et al, 2008) 80 Unfavorable (*) Head & neck carcinoma (Badoual et al, 2006) 84 Favorable Hepatocellular carcinoma (Gao et al, 2007) 302 Unfavorable Kidney carcinoma (Siddiqui et al, 2007) 170 Not significant Lymphoma (B cell) (Carreras et al, 2006) 98 Favorable Lymphoma (Hodgkin) (Alvaro et al, 2005) 257 Favorable Ovary carcinoma (Curiel et al, 2004) 104 Unfavorable Pancreatic carcinoma (Hiraoka et al, 2006) 198 Unfavorable…”