Identification and functional analysis of HPV-16 E7 HLA-DR restricted epitopes in patients with cervical neoplasia or cancer.

摘要

To generate an effective cellular immune response, it is necessary to elicit both antigen-specific CTL (CD8+) and Th (CD4 +) T cell recognition. The design of an effective therapeutic vaccine must incorporate means by which to generate novel T cell responses or enhance existing responses of a clinically-preferred functional type. In the cancer setting, one vaccine strategy is to target the immune system to specifically recognize tumor-associated antigens (TAAs). TAAs can be sub-categorized in many ways (i.e. onco-viral, mutated self-proteins, overexpressed and fetal-like proteins). Thus far, in part based on the historical prioritization applied to epitope searches, the number of defined CTL epitopes greatly outnumbers that of Th epitopes. Our goal in the current studies was to define and then characterize functional CD4+ T cell responses directed against the HPV-16 E7 oncoprotein in patients with cervical intraepithelial neoplasia (CIN) or cancer using dendritic cell (DC)-based vaccine strategies.; The importance of this work stems from the unequivocal linkage between oncogenic HPV-infection and the development of cervical carcinoma. Over 50% of all cervical carcinomas are HPV-16 positive, making it the most salient HPV type for integration into therapeutic vaccine designs. For cellular transformation to occur and be maintained, expression of the HPV early region gene products E6 and E7 is mandatory. Due to this unique requirement for sustained expression of the E6 and E7 proteins in transformed cells, these proteins make excellent candidates for protective or therapeutic vaccinations. While numerous HPV-16 E7-derived CTL epitopes have been identified over the past several years, surprisingly, only a single Th epitope has been reported thus far. In this thesis, I have defined three novel, naturally-processed and -presented epitopes derived from the HPV-16 E7 oncoprotein that are recognized by CD4+ T helper cells in patients with cervical intraepithelial neoplasia (CIN) or cervical carcinoma. Since the functional polarization state of the E7-specific CD4+ T cells remains of the Th1-type until the development of cancer in situ in these patients, DC-based vaccines that include E7-derived peptides or the whole E7 protein, and which are capable of selectively maintaining or enhancing Type-1 immunity may prove clinically beneficial in preventing or treating HPV-16+ malignancies, including cervical cancer.