Identification of the murine H-2Db and human HLA-A0201 MHC class I-restricted HPV6 E7-specific cytotoxic T lymphocyte epitopes

• Published in: Cancer Immunology, Immunotherapy Vol. 65; no. 3; pp. 261 - 271
• Main Authors: Peng, Shiwen, Mattox, Austin, Best, Simon R., Barbu, Anca M., Burns, James A., Akpeng, Belinda, Jeang, Jessica, Yang, Benjamin, Ishida, Eiichi, Hung, Chien-Fu, Wu, Tzyy-Choou, Pai, Sara I.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2016
• Subjects: Cancer Research; Immunology; Medicine; Medicine & Public Health; Oncology; Original Article; MHC class I; Human papillomavirus; Vaccine; T cell epitope; Recurrent respiratory papillomatosis; Immunotherapy
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-016-1793-x

Recurrent respiratory papillomatosis is caused by human papillomavirus (HPV) infection, most commonly types 6 (HPV-6) and 11 (HPV-11). Due to failed host immune responses, HPV is unable to be cleared from the host, resulting in recurrent growth of HPV-related lesions that can obstruct the lumen of the airway within the upper aerodigestive tract. In our murine model, the HPV-6b and HPV-11 E7 antigens are not innately immunogenic. In order to enhance the host immune responses against the HPV E7 antigen, we linked calreticulin (CRT) to HPV-6b E7 and found that vaccinating C57BL/6 mice with the HPV-6b CRT/E7 DNA vaccine is able to induce a CD8 + T cell response that recognizes an H-2D b -restricted E7aa21-29 epitope. Additionally, vaccination of HLA-A*0201 transgenic mice with HPV-6b CRT/E7 DNA generated a CD8 + T cell response against the E7aa82-90 epitope that was not observed in the wild-type C57BL/6 mice, indicating this T cell response is restricted to HLA-A*0201. In vivo cytotoxic T cell killing assays demonstrated that the vaccine-induced CD8 + T cells are able to efficiently kill target cells. Interestingly, the H-2D b -restricted E7aa21-29 sequence and the HLA-A*0201-restricted E7aa82-90 sequence are conserved between HPV-6b and HPV-11 and may represent shared immunogenic epitopes. The identification of the HPV-6b/HPV-11 CD8 + T cell epitopes facilitates the evaluation of various immunomodulatory strategies in preclinical models. More importantly, the identified HLA-A*0201-restricted T cell epitope may serve as a peptide vaccination strategy, as well as facilitate the monitoring of vaccine-induced HPV-specific immunologic responses in future human clinical trials.