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Cancer Immunol Immunother. 2016 Mar;65(3):261-71. doi: 10.1007/s00262-016-1793-x. Epub 2016 Jan 13.

Identification of the murine H-2D(b) and human HLA-A*0201 MHC class I-restricted HPV6 E7-specific cytotoxic T lymphocyte epitopes.

Author information

1
Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
2
Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
3
Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
4
Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA.
5
Department of Obstetrics and Gynecology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
6
Department of Molecular Microbiology and Immunology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
7
Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. sara.pai@mgh.harvard.edu.

Abstract

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.

KEYWORDS:

Human papillomavirus; Immunotherapy; MHC class I; Recurrent respiratory papillomatosis; T cell epitope; Vaccine

PMID:
26759151
PMCID:
PMC5690558
DOI:
10.1007/s00262-016-1793-x
[Indexed for MEDLINE]
Free PMC Article

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