title: The detection of circulating human papillomavirus-specific T cells is associated with improved survival of patients with deeply infiltrating tumors.
abstract: A detailed analyses of HPV-specific immunity was performed in a large group of patients with HPV-induced cervical cancer (CxCa) in relation to HLA-types and prognostic factors. Patients were HLA-typed and HPV16/18-specific T-cell immunity was assessed by proliferation assay and cytometric bead array using freshly isolated PBMC and by phenotypic analysis of HPV-specific T cells. The results were analyzed in relation to known disease-related HLA-types (DR7, DR13, DR15/DQ06), invasion-depth and size of tumor, lymph node (LN) status and disease free survival. In total 119 HLA-typed patients with CxCa were analyzed. Patients expressing the HLA-DR13 haplotype were underrepresented as compared to the Dutch population (p = 0.014), whereas HLA-DR7 was overrepresented in patients with HPV16+ CxCa (p = 0.006). In 29 of 94 patients (31%) from whom blood could be tested, a proliferative response to HPV16/18 was detected, which was associated with increased numbers of HPV-specific CD4+CD25+ (activated) T cells (p = 0.03) and HPV-specific CD4+CD25+FoxP3-positive T cells (p = 0.04). The presence of both FoxP3-positive and negative HPV-specific CD4+CD25+ T cells was significantly correlated (p = 0.01). Interestingly, the detection of HPV-specific proliferation was associated with invasion depth (p = 0.020) but not with HLA type, tumor size nor LN status. Moreover, the detection of HPV-specific immunity was associated with an improved disease free survival (p = 0.04) in patients with deeply infiltrating tumors. In conclusion, HPV-specific proliferative T-cell response, comprising higher percentages of HPV-specific CD25+ and CD25+FoxP3-positive CD4+T cells, are more frequently detected in patients with deep infiltrating CxCa tumors and associated with an improved survival.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Moniek
authors.initials: M
authors.lastname: Heusinkveld
authors.forename: Marij J P
authors.initials: MJ
authors.lastname: Welters
authors.forename: Mariette I E
authors.initials: MI
authors.lastname: van Poelgeest
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: van der Hulst
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.forename: Gert Jan J
authors.initials: GJ
authors.lastname: Fleuren
authors.forename: Gemma G
authors.initials: GG
authors.lastname: Kenter
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
mesh_terms: D000328:Adult; D000368:Aged; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005802:Genes, MHC Class II; D006801:Humans; D008875:Middle Aged; D027383:Papillomaviridae / Q000276:immunology*; D016016:Proportional Hazards Models; D011446:Prospective Studies; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000401:mortality
chemical_list: D016207:Cytokines