Cancer Immunology, Immunotherapy

, Volume 65, Issue 3, pp 261–271 | Cite as

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

  • Shiwen Peng
  • Austin Mattox
  • Simon R. Best
  • Anca M. Barbu
  • James A. Burns
  • Belinda Akpeng
  • Jessica Jeang
  • Benjamin Yang
  • Eiichi Ishida
  • Chien-Fu Hung
  • Tzyy-Choou Wu
  • Sara I. Pai
Original Article

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-2Db-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-2Db-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 Vaccine T cell epitope MHC class I Recurrent respiratory papillomatosis Immunotherapy 

Abbreviations

CRT

Calreticulin

HLA

Human leukocyte antigen

HPV

Human papillomavirus

RRP

Recurrent respiratory papillomatosis

Supplementary material

262_2016_1793_MOESM1_ESM.pdf (100 kb)
Supplementary material 1 (PDF 100 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Shiwen Peng
    • 1
  • Austin Mattox
    • 2
  • Simon R. Best
    • 3
  • Anca M. Barbu
    • 4
  • James A. Burns
    • 4
  • Belinda Akpeng
    • 4
  • Jessica Jeang
    • 1
  • Benjamin Yang
    • 1
  • Eiichi Ishida
    • 4
  • Chien-Fu Hung
    • 1
    • 2
  • Tzyy-Choou Wu
    • 1
    • 2
    • 5
    • 6
  • Sara I. Pai
    • 4
  1. 1.Department of PathologyThe Johns Hopkins Medical InstitutionsBaltimoreUSA
  2. 2.Department of OncologyThe Johns Hopkins Medical InstitutionsBaltimoreUSA
  3. 3.Department of Otolaryngology-Head and Neck SurgeryThe Johns Hopkins Medical InstitutionsBaltimoreUSA
  4. 4.Department of SurgeryMassachusetts General HospitalBostonUSA
  5. 5.Department of Obstetrics and GynecologyThe Johns Hopkins Medical InstitutionsBaltimoreUSA
  6. 6.Department of Molecular Microbiology and ImmunologyThe Johns Hopkins Medical InstitutionsBaltimoreUSA

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