Immunohistochemical analysis of CD4+ and CD8+ T-cell subsets in high risk human papillomavirus-associated pre-malignant and malignant lesions of the uterine cervix

Monnier-Benoit, Sylvain; Mauny, Frédéric; Riethmuller, Didier; Guerrini, Jean-Sébastien; Căpîlna, Mihai Emil; Félix, Sophie; Seillès, Estelle; Mougin, Christiane; Prétet, Jean‐Luc

doi:10.1016/j.ygyno.2005.11.039

Cited by 80 publications

(68 citation statements)

References 54 publications

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“…Serial section and co-expression analysis showed that most of the mononuclear cells that were making PD L1 were CD8 cells. It has been documented by other researchers that CD8 cells are the dominant lymphocytic cell type in cervical carcinoma 20 and that CD8 cells may have a role in viral clearance in regressing CINs. 11 Our results are consistent with a key role of CD8 cytotoxic cells in cervical precancer/cancer and suggest that the CD8 activity may be reduced due to the high expression of PD L1.…”

Section: Discussionmentioning

confidence: 94%

Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers

et al. 2015

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Programmed death ligand 1 (PD L1) expression can reduce the immune response in both infectious diseases and cancers. We thus examined PD L1 expression in cervical intraepithelial neoplasias (CINs) and cancers since they each reflect infection by human papillomavirus (HPV). PD L1 protein was not evident by immunohistochemistry in histologically normal cervical epithelia (0/55) even when adjacent to CIN or cancer. PD L1 expression was much increased in CINs (20/21 = 95%) and cervical squamous cell cancer (56/70 = 80%) and localized to the dysplastic/neoplastic squamous cells and mononuclear cells, respectively. There was also a significant increase (each Po0.001) in PD L1 detection in mononuclear cells when comparing cervical squamous cell cancers to endometrial (22/115 = 19%) and ovarian adenocarcinomas (5/40 = 13%). Co-expression analyses showed that the primary inflammatory cell that contained PD L1 was the CD8+ lymphocyte that strongly concentrated around the dysplastic CIN cells and nests of invasive squamous cancer cells. These data show that PD L1 is a solid biomarker of productive HPV infection of the cervix and that it is significantly upregulated in both the carcinoma and surrounding inflammatory cells in cervical cancer when compared with other gynecologic malignancies. This suggests that anti-PD L1 therapy may have a role in the treatment of cervical cancer.

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Section: Discussionmentioning

confidence: 94%

Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers

et al. 2015

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“…35 Other studies on non-small cell lung cancer, 36 anal squamous cell carcinoma 24 and renal cell carcinoma 37 reported that CD8 1 T lymphocytes were a negative prognostic factor. The CD8 1 T-cell subpopulation has been considered to be the effector in the antitumor response; however, when the status of activation was explored, most of the cells were underprimed (CD45RO 1 ) 38 or inactivated (in this study, the GrB/CD8 ratio was 7/48), regardless of the effector/target ratio within the tumor tissue (data not shown). It is unlikely that such a weak functional population could eliminate the tumor burden.…”

Section: Comparative Numbers Of Cd4mentioning

confidence: 85%

A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4+FOXP3+ regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix

et al. 2010

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In this study, 40 biopsy samples collected from cervical cancer patients at the First Affiliated Hospital of Xi'an Jiaotong University, China, were retrospectively assessed using immunohistochemistry for CD4 1 and CD8 1 tumor-infiltrating lymphocytes (TILs) and were analyzed for the expression of FOXP3, OX40, granzyme B (GrB) and perforin (Prf). The proliferating index of the TILs was determined by assessing Ki67 expression. We determined the prognostic value of low and high numbers of TILs on survival by performing KaplanMeier analysis using median values as the cut-off points. Except for the number of CD4 1 FOXP3 1 regulatory T cells (Tregs) and the CD4/ CD8 ratio, none of the CD4 1 , CD8 1 , OX40 1 , GrB 1 or Prf 1 TILs were associated with the overall 5-year survival rate. The 5-year survival rate was significantly lower in patients who had a high percentage of Tregs as compared with the those who had a lower percentage (35.3% versus 88.9%, P50.001), while the 5-year survival rate was significantly higher in patients with a high CD4/CD8 ratio as compared with patients who had a low CD4/CD8 ratio (82.4% versus 44.4%, P50.029). When we considered the deaths and surviving cases as separate groups, we found that both the number of CD4 1 T cells and the CD4/CD8 ratio were significantly lower in patients who died as compared with those who survived (26.33611.80 versus 47.79638.18, P50.023 and 0.6060.25 versus 1.1761.02, P50.019, respectively). In conclusion, decreased proportions of tumor-infiltrating CD4 1 T cells with high percentages of Tregs and reversed CD4/CD8 ratios were significantly associated with the clinical outcome of patients with cervical carcinoma.

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“…It is of interest that elevated ORs were present when comparing SCC with lesions of all grades, suggesting that this is a phenomenon associated with invasion and not with persistent infection or development of precursor lesions. Given the fact that CD8+ cells presented the highest coefficient variation, and that there was lack of agreement when the dispersion of the measurements was compared, we also estimated the ORs using the counting conducted by each pathologist to estimate the average number of cells/mm 2 [14,15,30,31]. However since the confidence intervals were wide, studies with bigger sample size may help to confirm the accuracy of our observation.…”

Section: Discussionmentioning

confidence: 94%

“…Immune response has been considered a cofactor that may play a role in the different stages of the natural history of cervical cancer [13]. Although tumor infiltrates lymphocytes (TILs) have been observed in pre neoplastic and tumor tissues [14][15][16][17], it has been difficult to delineate the role that these immune cells may play in affording the regression of different grades of CIN. Studies have reported an equal proportion of CD4+ and CD8+ cells in the stroma of pre-neoplastic lesions and a low density of CD4+ cells in the epithelium of pre-neoplastic lesions when compared to normal tissues [18].…”

Section: Introductionmentioning

confidence: 99%

“…Even further, in cervical cancer, high number of CD8+ TILs are associated with absence of metastasis [19] and low numbers of immune cell types with relapse [20]. Others have reported that a high number of CD8+ cells are present in invasive cervical cancers [15]. In this study we conducted a thorough statistical analysis of the reproducibility of the counts of three important types of immune cells (CD8+, CD4+) and regulatory T cells (CD25+ Foxp3+) in premalignant and malignant lesions of cervical cancer.…”

Section: Introductionmentioning

confidence: 99%

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Location and Density of Immune Cells in Precursor Lesions and Cervical Cancer

Bedoya

Jaramillo

Baena

et al. 2012

Cancer Microenvironment

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Only a small proportion of women infected with Human Papillomavirus (HPV) develop cervical cancer. Host immune response seems to play a role eliminating the viral infection and preventing progression to cancer. Characterization of tumor infiltrating lymphocytes (TILs) in cervical pre-neoplastic lesions and cervical cancer may be helpful to understand the mechanisms that mediate this protection. The aim of this study was to determine if there are differences in the localization and density (cells/mm 2 ) of CD8+ T-cells, CD4+ T-cells and Tregs (CD25 + Foxp3+) in cervical pre-neoplastic lesions and cervical cancer. Immunohistochemical analysis of sections of 96 (26 CIN1, 21 CIN2, 25 CIN3, and 24 SCC) samples revealed that regardless of CIN grades, CD8+ T-cells are more abundant than CD4+, CD25+ and Foxp3+ cells in both the stroma and epithelium. There was a higher density of CD8+ cells in the stroma of cervical cancer compared to CIN3 (OR 0 4.20, 95% CI 1.2-15), CIN2 (OR 0 7.86, 95% CI 1.7-36.4) and CIN1 (OR 0 4.25, 95% CI 1.1-17). Studies evaluating whether these cells are recruited before or after cancer progression will be helpful to understand the role of these cells in the natural history of HPV-induced lesions.

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Immunohistochemical analysis of CD4+ and CD8+ T-cell subsets in high risk human papillomavirus-associated pre-malignant and malignant lesions of the uterine cervix

Cited by 80 publications

References 54 publications

Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers

Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers

A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4+FOXP3+ regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix

Location and Density of Immune Cells in Precursor Lesions and Cervical Cancer

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