High Number of Intraepithelial CD8+ Tumor-Infiltrating Lymphocytes Is Associated with the Absence of Lymph Node Metastases in Patients with Large Early-Stage Cervical Cancer

Abstract

In a prospective study, we have examined the tumor-specific immune response in a group of 59 patients with human papillomavirus (HPV) 16-positive (HPV16 + )-induced or HPV18 + -induced cervical cancer. Local antitumor immunity was analyzed by the enumeration of tumor-infiltrating dendritic cells and CD4 + , CD8 + , and regulatory T cells as well as by calculation of the ratio of CD8 + /CD4 + T cells and CD8 + / regulatory T cells. Systemic tumor-specific immunity was assessed by determination of the HPV E6-and/or E7-specific T-cell response in the blood of these patients. Finally, these variables were evaluated with respect to known histopathologic prognostic variables, including the absence (LN À ) or presence (LN + ) of lymph node metastases. Stratification according to the lymph node status of patients revealed a significantly stronger CD8 + T-cell tumor infiltration, a higher CD8 + /CD4 + T-cell ratio, and higher CD8 + /regulatory T-cell ratio in the group of patients in which the tumor failed to metastasize to the tumor-draining lymph node. Subdivision according to the presence (IR + ) or absence (IR À

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

“…The proportion of CD4 1 T cells was significantly lower in tumors from patients with lymph node metastases than in those from patients without lymph node metastases, as was the reversed CD4/ CD8 ratio. Similarly, Piersma et al 31 found a significantly stronger CD8 1 T-cell tumor infiltration, a higher CD8 1 /CD4 1 T-cell ratio, and a higher CD8 1 /Tregs ratio in patients with tumors that failed to metastasize to the tumor-draining lymph node. Loddenkemper et al, 27 in a comparison study of high-grade CIN (CIN III) and cervical carcinoma with colon cancer, skin melanoma and bronchial carcinoma, revealed that HPV-derived lesions have a significantly higher number of infiltrating lymphocytes and FOXP3 1 Tregs as compared with three other common tumor types.…”

“…A significant difference was observed between the survival rates of patients with high and low CD4 1 /CD8 1 T-cell ratios (82.4% versus 44.4%, P50.029) (Figure 6). 31 observed that the presence of intratumoral CD8 1 T cells in cervical cancer was correlated with the lack of pelvic lymph node spread and was, therefore, correlated indirectly with prognosis. A high number of tumor-infiltrating CD8 1 T lymphocytes were observed as a favorable prognostic factor for survival in some studies of human cancers, including endometrial cancer, 32 ovarian cancer, 8 colorectal cancer, 33 esophageal cancer 34 and urothelial carcinoma.…”

Low density of CD3+, CD4+ and CD8+ cells is associated with increased risk of relapse in squamous cell cervical cancer

“…It is expressed on cytotoxic T cells that have the capability of killing tumour cells. In a recent study by Piersma et al (2007) the presence of intratumoural CD8 þ cells in cervical cancer correlated with the lack of pelvic lymph node spread and therefore correlated indirectly with prognosis. Also in other cancer types as ovarian cancer (Sato et al, 2005), endometrial cancer (Kondratiev et al, 2004), colon cancer (Guidoboni et al, 2001) and lung cancer (Eerola et al, 2000) have intratumoural CD8 þ cells that have been correlated to improved prognosis.…”

Infiltrating regulatory T cell numbers is not a factor to predict patient's survival in oesophageal squamous cell carcinoma

“…Around the same time, Diederichsen Axel et al (2003) reported that a high CD8/CD4 ratio is associated with a better prognosis in colorectal cancer. Furthermore, Piersma et al (2007)also reported that a higher CD8/ CD4 ratio is associated with the lack of tumour metastases in the draining lymph nodes of cervical cancer patients. Therefore, it is obvious that the balance of CD4 þ T cell and CD8 þ T cell is critical for prognosis of patients with cancer.…”