Induction of robust cellular immunity against HPV6 and HPV11 in mice by DNA vaccine encoding for E6/E7 antigen

Shin, Taehoon; Pankhong, Panyupa; Yan, Jian; Khan, Amir S.; Sardesai, Niranjan Y.; Weiner, David B.

doi:10.4161/hv.19180

Cited by 18 publications

(12 citation statements)

References 25 publications

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“…Vaccination in C57BL/6 mice with three doses of 20 μg of the DNA plasmid, followed by intramuscular injection and CELLECTRA ® electroporation, at 14 day intervals elicited strong T cell responses [7]. After characterization of the vaccine-induced T cell responses, the authors identified an E6aa40-54 immunodominant peptide, which supported our prior findings [8].…”

Section: Discussionsupporting

confidence: 76%

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

Peng

Mattox

Best

et al. 2016

Cancer Immunol Immunother

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Recurrent Respiratory Papillomatosis (RRP) 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 -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/-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.

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Section: Discussionsupporting

confidence: 76%

“…The majority of efforts in developing therapeutic HPV vaccines have focused on the oncogenic HPV types, types 16 and 18, and have resulted in various human clinical trials. Only recently have efforts begun to expand to include the low risk HPV types 6 and 11 [7]. …”

Section: Introductionmentioning

confidence: 99%

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

Peng

Mattox

Best

et al. 2016

Cancer Immunol Immunother

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“…Their care was in accordance with the guidelines of NIH and University of Pennsylvania Institutional Animal Care and Use Committee (IACUC). Mice were divided into two groups and immunized with 50 ug of hTERT DNA by intramuscular injection (IM) into the quadriceps followed by electroporation (EP) using the CELLECTRA® adaptive constant current device (Inovio Pharmaceuticals Inc.)(33). The mice received 4 immunizations, 2 weeks apart.…”

Section: Mice Studiesmentioning

confidence: 99%

“…Intracellular cytokine staining was performed as described previously (33). Briefly, splenocytes from vaccinated and naïve mice were stimulated with hTERT peptides, stained with FITC anti-mouse CD107a, and followed by ViViD Dye (Invitrogen).…”

Section: Mice Studiesmentioning

confidence: 99%

Highly Optimized DNA Vaccine Targeting Human Telomerase Reverse Transcriptase Stimulates Potent Antitumor Immunity

Yan

Pankhong

Shin

et al. 2013

Cancer Immunology Research

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High levels of human Telomerase Reverse Transcriptase (hTERT) are detected in over 85% of human cancers. Immunological analysis supports hTERT is a widely applicable target recognized by T cells and can be potentially studied as a broad cancer immune therapeutic, or a unique line of defense against tumor recurrence. There remains an urgent need to develop more potent hTERT vaccines. Here, a synthetic highly optimized full-length hTERT DNA vaccine (phTERT) was designed and the induced immunity was examined in mice and non-human primates. When delivered by electroporation, phTERT elicited strong, broad hTERT-specific CD8 responses including induction of T-cells expressing CD107a, IFN-γ and TNF-α in mice. The ability of phTERT to overcome tolerance was evaluated in a NHP model, whose TERT is 96% homologous to that of hTERT. Immunized monkeys exhibited robust (average 1834 SFU/106 PBMCs), diverse (multiple immunodominant epitopes) IFN-γ responses and antigen-specific perforin release (average 332 SFU/106 PBMCs), suggesting phTERT breaks tolerance and induces potent cytotoxic responses in this human relevant model. Moreover, in an HPV16-associated tumor model, vaccination of phTERT slows tumor growth and improves survival rate in both prophylactic and therapeutic studies. Lastly, in vivo cytotoxicity assay confirmed that phTERT-induced CD8 T cells exhibited specific CTL activity, capable of eliminating hTERT-pulsed target cells. These findings support that this synthetic EP-delivered DNA phTERT may have a role as a broad therapeutic cancer vaccine candidate.

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“…HPV-16 and HPV-18 are the most prevalent high-risk genotypes that induce cervical cancer (2). Infections with low-risk genotypes, including HPV-6 and HPV-11, cause benign or low-grade cervical tissue changes and genital warts (3). The molecular mechanisms that underlie the oncogenic potential of high-risk HPVs have been extensively studied and it has been determined that the HPV-E6 protein acts as an oncoprotein that interacts with tumor suppressor p53, leading to the transformation and dysregulated proliferation of transfected cells (4).…”

Section: Introductionmentioning

confidence: 99%

Low risk HPV‑6E6 induces apoptosis in bone marrow‑derived dendritic cells

Sun

Zhao

et al. 2017

Oncol Lett

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Abstract. The present study assessed the subcellular localization and apoptotic potential of low-risk human papilloma virus 6E6 (HPV-6E6), expressed in bone marrow-derived dendritic cells (DCs). DCs were obtained from C57BL/6 mice and transfected with a pGFP-6E6 plasmid. The subcellular localization of E6 was determined by tracing green fluorescent protein (GFP) using fluorescence microscopy. Apoptosis was assessed by staining nuclei with DAPI and performing an apoptosis-based flow cytometry assay. The co-localization of E6 and p53 was also investigated using confocal microscopy. In addition, the expression of apoptosis-associated proteins was analyzed using immunoblotting. The results of the present study demonstrated that low-risk HPV-6E6 is predominantly localized in the cytoplasm of DCs. Furthermore, p53 was upregulated in DCs transfected with pGFP-6E6 and co-localized with GFP-6E6 in the cytoplasm. DCs transfected with a control pGFP plasmid did not undergo apoptosis, whereas cells transfected with pGFP-6E6 did, as indicated by the presence of cell debris and condensation of the nuclei. Furthermore, the expression of apoptosis-associated proteins, including p53, BCL2 associated X apoptosis regulator (Bax), BCL2 homologous antagonist/killer (Bak) and cytochrome c, were significantly higher in DCs expressing low-risk E6 than in control cells. Therefore, the current study demonstrated that low-risk HPV-6E6 is predominantly located in the cytoplasm of DCs and induces apoptosis. This may be an important mechanism that explains why low-risk HPV is unable to induce malignant transformation.

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Induction of robust cellular immunity against HPV6 and HPV11 in mice by DNA vaccine encoding for E6/E7 antigen

Cited by 18 publications

References 25 publications

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

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

Highly Optimized DNA Vaccine Targeting Human Telomerase Reverse Transcriptase Stimulates Potent Antitumor Immunity

Low risk HPV‑6E6 induces apoptosis in bone marrow‑derived dendritic cells

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