Abstract 1267: Identification of HPV-derived CD4+ T-helper epitopes for improving therapeutic anti-HPV vaccine potency.

Abstract

Abstract Persistent infection with high-risk types of human papillomavirus (HPV) can lead to malignant transformation and the development of various human malignancies, such as cervical cancer, anal cancer or a subset of oropharyngeal carcinomas. Fortunately, most HPV infections are successfully eradicated by the immune system. Accumulating evidence suggests that both CD8+ and CD4+ T cell responses play a pivotal role in the clearance and control of HPV infection. Up to now, therapeutic anti-HPV vaccines have mostly been developed to elicit CD8+T cell responses. The exclusive targeting of HLA class I-restricted HPV epitopes might be insufficient, as HLA class I surface expression may be reduced as a result of HPV immune evasion strategies. In contrast, HLA class II molecules are expressed in high-grade cervical lesions and cervical cancer. Therefore in this study, we aim to identify novel E2-, E5-, E6- and E7-derived CD4+ T cell epitopes that bind to multiple HLA class II alleles, are naturally processed and presented, and immunogenic. We started with in silico epitope predictions using several web-based prediction algorithms. 15-mer candidate epitopes from the HPV16 E2, E5, E6 and E7 proteins were determined for seven HLA class II alleles - DRB1*0101 (DR1), DRB1*0301 (DR3), DRB1*0401 (DR4), DRB1*0701 (DR7), DRB1*1101 (DR11), DRB1*1501 (DR2b), and DRB1*0901 (DR9); together providing >90% population coverage. To identify promiscuous epitopes, the average binding score to multiple HLA-DR alleles was calculated and peptides ranked accordingly. To assess immunogenicity of HPV-derived candidate peptides, IFN-γ-ELISPOT assays were conducted with lymphocytes isolated from healthy donors. T cells isolated from the majority of healthy donors responded to at least one HPV-derived peptide. The most reactive HPV-derived peptides were further investigated in long-term T cell cultures. Significant production of IFN-γ as well as T cell proliferation was observed in nearly 100% of tested individuals against this panel of epitopes. As the above immunoreactivities most likely represent memory responses that led to viral clearance in healthy donors, we conclude that the identified CD4+ T-helper epitopes are candidates for the development of comprehensive epitope-specific HPV immunotherapy approaches. Citation Format: Agnieszka K. Grabowska, Stephanie Hoppe, Renata Blatnik, Angelika B. Riemer. Identification of HPV-derived CD4+ T-helper epitopes for improving therapeutic anti-HPV vaccine potency. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1267. doi:10.1158/1538-7445.AM2013-1267