title: 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-) 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-) of circulating HPV-specific T cells disclosed that the highest number of tumor-infiltrating CD8+ T cells was found in the group of LN- patients displaying a concomitant systemic tumor-specific immune response (LN-IR+). CD8+ T-cell infiltration in LN-IR- patients was comparable with that of LN+ patients. In cervical cancer, the absence of lymph node metastases is strongly associated with a better prognosis. Our data indicate that, especially in a subgroup of LN- patients, a strong and effective interaction between immune system and tumor exists. This subgroup of cervical cancer patients may have the best prognosis.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
authors.forename: Sytse J
authors.initials: SJ
authors.lastname: Piersma
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.forename: Mariëtte I E
authors.initials: MI
authors.lastname: van Poelgeest
authors.forename: Kitty M C
authors.initials: KM
authors.lastname: Kwappenberg
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: van der Hulst
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.forename: Gemma G
authors.initials: GG
authors.lastname: Kenter
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Fleuren
authors.forename: Rienk
authors.initials: R
authors.lastname: Offringa
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology; D052161:Human papillomavirus 18 / Q000276:immunology; D006801:Humans; D008207:Lymphatic Metastasis; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000276:immunology; D011379:Prognosis; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000473:pathology* / Q000821:virology