Cervical Cancer Cells Present HPV-E7 Epitope to CD4+ Tumor Infiltrating Lymphocytes (TIL) in Association with Histocompatibility Leukocyte Antigen (HLA) DR4 - Identification of HPV-peptides by CD4+ T-cells -

Abstract

Purpose: Cellular and humoral immune responses directed against autologous tumor cells in patients with cervical cancer may be directed against proteins provided by human papilloma- virus (HPV) associated products or, alternatively, by yet undefined targets as well. The goal of our study was to evaluate the local cellular immune response in cervical cancer. Methods: From a fresh tumor sample of a patient with cervical carcinoma, tumor-infiltrating lymphocytes (TIL) were generated, expanded and characterized by immunohistochemistry, flow cytometry, cytokine release assays and DNA fragment analysis. Results: We established a MHC class II-restricted CD4+ T-cell line from a patient with cervical cancer which recognizes autologous (HPV35+, HPV59+) tumor cells and the HLA-DR4-matched cervical cancer cell line Me180 (HPV68+) as determined by TNFα secretion. Expression of different HPV-E7 genes in autologous B-cells revealed that this T-cell line defines a DR4-presented T-cell epitope which is shared among the E7 gene of HPV59 and HPV68. Conclusion: Tumor-HPV-specific and MHC-class II-restricted CD4+ T-cells are present within the tumor lesion and can be successfully expanded in the presence of IL-2 and IL-7. MHC class II presented peptides may be implemented to augment T-cell responses directed against autologous tumor cells.