Enhanced Cytotoxic CD8 T Cell Priming Using Dendritic Cell-Expressing Human Papillomavirus-16 E6/E7-p16INK4 Fusion Protein with Sequenced Anti-Programmed Death-1

被引:16
|
作者
Garcia-Bates, Tatiana M. [1 ,2 ]
Kim, Eun [3 ]
Concha-Benavente, Fernando [4 ]
Trivedi, Sumita [1 ]
Mailliard, Robbie B. [2 ]
Gambotto, Andrea [3 ]
Ferris, Robert L. [1 ,4 ,5 ]
机构
[1] Univ Pittsburgh, Dept Otolaryngol, Pittsburgh, PA 15232 USA
[2] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Infect Dis & Microbiol, Pittsburgh, PA 15261 USA
[3] Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15232 USA
[4] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA 15232 USA
[5] Univ Pittsburgh, Inst Canc, Canc Immunol Program, Pittsburgh, PA 15213 USA
来源
JOURNAL OF IMMUNOLOGY | 2016年 / 196卷 / 06期
基金
美国国家卫生研究院;
关键词
OROPHARYNGEAL CANCER; IMMUNOTHERAPY; CARCINOMA; VACCINE; E6; ACTIVATION; INFECTION; RESPONSES; GROWTH; HEAD;
D O I
10.4049/jimmunol.1502027
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The incidence of human papillomavirus (HPV)-related head and neck squamous cell carcinoma has increased in recent decades, though HPV prevention vaccines may reduce this rise in the future. HPV-related cancers express the viral oncoproteins E6 and E7. The latter inactivates the tumor suppressor protein retinoblastoma (Rb), which leads to the overexpression of p16(INK4) protein, providing unique Ags for therapeutic HPV-specific cancer vaccination. We developed potential adenoviral vaccines that express a fusion protein of HPV-16 E6 and E7 (Ad.E6E7) alone or fused with p16 (Ad.E6E7p16) and also encoding an anti-programmed death (PD)-1 Ab. Human monocyte-derived dendritic cells (DC) transduced with Ad.E6E7 or Ad.E6E7p16 with or without Ad.alpha PD1 were used to activate autologous CD8 CTL in vitro. CTL responses were tested against naturally HPV-infected head and neck squamous cell carcinoma cells using IFN-gamma ELISPOT and [Cr-51] release assay. Surprisingly, stimulation and antitumor activity of CTL were increased after incubation with Ad.E6E7p16-transduced DC (DC.E6E7p16) compared with Ad.E6E7 (DC.E6E7), a result that may be due to an effect of p16 on cyclin-dependent kinase 4 levels and IL-12 secretion by DC. Moreover, the beneficial effect was most prominent when anti-PD-1 was introduced during the second round of stimulation (after initial priming). These data suggest that careful sequencing of Ad.E6E7.p16 with Ad.alpha PD1 could improve antitumor immunity against HPV-related tumors and that p16 may enhance the immunogenicity of DC, through cyclin-dependent pathways, Th1 cytokine secretion, and by adding a nonviral Ag highly overexpressed in HPV-induced cancers.
引用
收藏
页码:2870 / 2878
页数:9
相关论文
共 24 条
  • [1] Induction of specific CD8+ T-lymphocyte responses using a human papillomavirus-16 E6/E7 fusion protein and autologous dendritic cells
    Murakami, M
    Gurski, KJ
    Marincola, FM
    Ackland, J
    Steller, MA
    CANCER RESEARCH, 1999, 59 (06) : 1184 - 1187
  • [2] Successful induction of specific CD8+ T-lymphocyte responses using an human papillomavirus-16 E6/E7 fusion protein and autologous dendritic cells
    Murakami, M
    Gurski, K
    Marincola, F
    Crowley, J
    Ackland, J
    Steller, M
    17TH INTERNATIONAL CANCER CONGRESS, VOL 1 AND 2, 1998, : 127 - 131
  • [3] HLA class I binding promiscuity of the CD8 T-Cell epitopes of human papillomavirus type 16 E6 protein
    Nakagawa, Mayumi
    Kim, Kevin H.
    Gillam, Tiffany M.
    Moscicki, Anna-Barbara
    JOURNAL OF VIROLOGY, 2007, 81 (03) : 1412 - 1423
  • [4] CD4-positive and CD8-positive cytotoxic T lymphocytes contribute to human papillomavirus type 16 E6 and E7 responses
    Nakagawa, M
    Stites, DP
    Palefsky, JM
    Kneass, Z
    Moscicki, AB
    CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY, 1999, 6 (04) : 494 - 498
  • [5] CD4+T-CELL RESPONSE AGAINST HUMAN PAPILLOMAVIRUS TYPE 16 E6 PROTEIN IS ASSOCIATED WITH A FAVORABLE CLINICAL TREND
    Kim, K. H.
    Greenfield, W. W.
    Cannon, M. J.
    Coleman, H. N.
    Spencer, H. J.
    Nakagawa, M.
    JOURNAL OF INVESTIGATIVE MEDICINE, 2011, 59 (04) : 697 - 697
  • [6] Cytotoxic T Lymphocytes Elicited by Dendritic Cell-Targeted Delivery of Human Papillomavirus Type-16 E6/E7 Fusion Gene Exert Lethal Effects on CaSki Cells
    Wu, Xiang-Mei
    Liu, Xing
    Jiao, Qing-Fang
    Fu, Shao-Yue
    Bu, You-Quan
    Song, Fang-Zhou
    Yi, Fa-Ping
    ASIAN PACIFIC JOURNAL OF CANCER PREVENTION, 2014, 15 (06) : 2447 - 2451
  • [7] Patterns of CD8 T-cell epitopes within the human papillomavirus type 16 (HPV 16) E6 protein among young women whose HPV 16 infection has become undetectable
    Nakagawa, M
    Kim, KH
    Moscicki, AB
    CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY, 2005, 12 (08) : 1003 - 1005
  • [8] INDUCTION OF RAT PROLIFERATIVE CD8+ T-CELL LINES SPECIFIC FOR HUMAN PAPILLOMAVIRUS TYPE-16 E6 AND E7 PROTEINS
    BAGOT, M
    CHARUE, D
    CERNI, C
    REVUZ, J
    MENEGUZZI, G
    JOURNAL OF INVESTIGATIVE DERMATOLOGY, 1994, 103 (03) : 398 - 398
  • [9] CD4+ T-cell response against human papillomavirus type 16 E6 protein is associated with a favorable clinical trend
    Kim, Kevin H.
    Greenfield, William W.
    Cannon, Martin J.
    Coleman, Hannah N.
    Spencer, Horace J.
    Nakagawa, Mayumi
    CANCER IMMUNOLOGY IMMUNOTHERAPY, 2012, 61 (01) : 63 - 70
  • [10] CD4+ T-cell response against human papillomavirus type 16 E6 protein is associated with a favorable clinical trend
    Kevin H. Kim
    William W. Greenfield
    Martin J. Cannon
    Hannah N. Coleman
    Horace J. Spencer
    Mayumi Nakagawa
    Cancer Immunology, Immunotherapy, 2012, 61 : 63 - 70