E6 and E7 Gene Silencing and Transformed Phenotype of Human Papillomavirus 16-Positive Oropharyngeal Cancer Cells

Ράμπιας, Θεόδωρος; Sasaki, Clarence T.; Weinberger, Paul M.; Psyrri, Amanda

doi:10.1093/jnci/djp017

Cited by 236 publications

(176 citation statements)

References 46 publications

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“…The three relapsing vaccine + α4-1BB-treated mice were killed at day 38 and RT-PCR analysis confirmed that their relapses were not due to loss of E6 or E7 expression, which are essential for maintenance of the transformed state in human cervical cancer (Fig. S1) (16). CTLA-4 blockade with vaccination promoted tumor regression in 2/10 mice; however, none of these regressions were durable.…”

Section: Intranasal Vaccination With Hpv E6/e7 Peptides In Combinatiomentioning

confidence: 86%

Unique potential of 4-1BB agonist antibody to promote durable regression of HPV ⁺ tumors when combined with an E6/E7 peptide vaccine

Bartkowiak

Singh

Yang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Antibody modulation of T-cell coinhibitory (e.g., CTLA-4) or costimulatory (e.g., 4-1BB) receptors promotes clinical responses to a variety of cancers. Therapeutic cancer vaccination, in contrast, has produced limited clinical benefit and no curative therapies. The E6 and E7 oncoproteins of human papilloma virus (HPV) drive the majority of genital cancers, and many oropharyngeal tumors. We discovered 15-19 amino acid peptides from HPV-16 E6/E7 for which induction of T-cell immunity correlates with disease-free survival in patients treated for high-grade cervical neoplasia. We report here that intranasal vaccination with these peptides and the adjuvant alpha-galactosylceramide elicits systemic and mucosal T-cell responses leading to reduced HPV + TC-1 tumor growth and prolonged survival in mice. We hypothesized that the inability of these T cells to fully reject established tumors resulted from suppression in the tumor microenvironment which could be ameliorated through checkpoint modulation. Combining this E6/E7 peptide vaccine with checkpoint blockade produced only modest benefit; however, coadministration with a 4-1BB agonist antibody promoted durable regression of established genital TC-1 tumors. Relative to other therapies tested, this combination of vaccine and α4-1BB promoted the highest CD8 + versus regulatory FoxP3 + T-cell ratios, elicited 2-to 5-fold higher infiltration by E7-specific CTL, and evoked higher densities of highly cytotoxic TcEO (T cytotoxic Eomesodermin) CD8 (>70-fold) and ThEO (T helper Eomesodermin) CD4 (>17-fold) T cells. These findings have immediate clinical relevance both in terms of the direct clinical utility of the vaccine studied and in illustrating the potential of 4-1BB antibody to convert therapeutic E6/E7 vaccines already in clinical trials into curative therapies.C ervical cancer is the second most common malignancy in women worldwide and continues to cause significant morbidity and mortality in the developing world, where screening and prevention programs remain rudimentary (1). The E6 and E7 oncoproteins of human papilloma virus (HPV) drive cervical cancer formation and are critical for maintenance of the transformed state (2). Beyond cervical cancer, HPV infection underlies 40% or greater of cases of oropharyngeal, anal, penile, vaginal, and vulvar cancers (3).The immunologically foreign nature of the HPV E6 and E7 proteins, coupled with their critical role in maintaining the oncogenic state, makes them ideal target antigens for therapeutic cancer vaccination. Whereas peptide-, protein-, viral-and DNAbased vaccines targeting E6 and E7 have been studied both preclinically and in clinical trials, most fail to induce regression of established HPV + tumors (4). To some degree, all of these vaccines succeed in eliciting peripheral E6/E7-specific T-cell responses; however, not all are proven to generate T cells capable of trafficking to the genital mucosa where cervical cancer develops. Whereas a number of these vaccines extend survival, few can induce regression of establishe...

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Section: Intranasal Vaccination With Hpv E6/e7 Peptides In Combinatiomentioning

confidence: 86%

Unique potential of 4-1BB agonist antibody to promote durable regression of HPV ⁺ tumors when combined with an E6/E7 peptide vaccine

Bartkowiak

Singh

Yang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Expression of viral E6 and E7 encoded by the HPV genome respectively inactivate the tumor-suppressors TP53 and RB, and are necessary for malignant behavior of HPV-positive tumors [6].…”

Section: Introductionmentioning

confidence: 99%

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

Saba

Wilson

Doho

et al. 2014

Head and Neck Pathol

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The role of molecular methods in the diagnosis of head and neck cancer is rapidly evolving and holds great potential for improving outcomes for all patients who suffer from this diverse group of malignancies. However, there is considerable debate as to the best clinical approaches, particularly for Next Generation Sequencing (NGS). The choices of NGS methods such as whole exome, whole genome, whole transcriptomes (RNA-Seq) or multiple gene resequencing panels, each have strengths and weakness based on data quality, the size of the data, the turnaround time for data analysis, and clinical actionability. There have also been a variety of gene expression signatures established from microarray studies that correlate with relapse and response to treatment, but none of these methods have been implemented as standard of care for oropharyngeal squamous cell carcinoma (OPSCC). Because many genomic methodologies are still far from the capabilities of most clinical laboratories, we chose to explore the use of a combination of off the shelf targeted mutation analysis and gene expression analysis methods to complement standard anatomical pathology methods. Specifically, we have used the Ion Torrent AmpliSeq cancer panel in combination with the NanoString nCounter Human Cancer Reference Kit on 8 formalin-fixed paraffin embedded (FFPE) OPSCC tumor specimens, (4) HPVpositive and (4) HPV-negative. Differential expression analysis between HPV-positive and negative groups showed that expression of several genes was highly likely to correlate with HPV status. For example, WNT1, PDGFA and OGG1 were all over-expressed in the positive group. Our results show the utility of these methods with routine FFPE clinical specimens to identify potential therapeutic targets which could be readily applied in a clinical trial setting for clinical laboratories lacking the instrumentation or bioinformatics infrastructure to support comprehensive genomics workflows. To the best of our knowledge, these preliminary experiments are among the earliest to combine both mutational and gene expression profiles using Ion Torrent and NanoString technologies. This reports serves as a proof of principle methodology in OPSCC.Electronic supplementary material The online version of this article

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“…The abrogation of functional p53 is required for promoting transformation and maintaining the malignant phenotype (Pathirana et al, 2009). Thus, restoration of p53 function by blocking this degradation pathway has been reported as an attractive strategy to ensure an effective intervention (Hietanen et al, 2000;Rampias et al, 2009). Interestingly, beside the abrogation of p53, HPV 18 infection increases Cdk1/cyclin B1-associated activity by stabilizing cyclin B1 mRNA through the upregulation of HuR protein in HPV 18-infected cervical lesions (Cho et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Restoration of the tumor suppressor p53 by downregulating cyclin B1 in human papillomavirus 16/18-infected cancer cells

et al. 2010

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Abrogation of functional p53 is responsible for malignant cell transformation and the maintenance of malignant state of human papillomavirus-infected cancer cells. Thus, restoration of p53 has been regarded as an important strategy for molecular intervention combating papillomavirus-associated malignancies. We show here that depleting cyclin B1 stabilizes and reactivates p53 in papillomavirusinfected cervical cancer cell lines HeLa and CaSki. HeLa cells depleted of cyclin B1 exhibit mitotic defects in spindle formation and chromosome alignment. Downregulation of cyclin B1 increases p14 alternative reading frame of p16, the positive regulator of p53, and decreases phosphorylation of Ser315 in p53. Whereas RO-3306, a selective inhibitor of cyclin-dependent kinase 1 (Cdk1), suppresses this phosphorylation at Ser315 of p53, ZM447439, targeting Aurora A/B kinases, shows no effect. Further analyses in HeLa cells and HCT116 p53(À/À) cells suggest that the Ser315 phosphorylation by Cdk1 regulates negatively the protein stability and the function of p53. Moreover, increased p53 in HeLa cells is functional by showing its increased downstream effectors p21, mouse double minute 2 and Bax. Restoration of p53 and silencing cyclin B1 render cervical carcinoma cells more susceptible to DNA damage agent camptothecin. Taken together, targeting cyclin B1 might be an attractive strategy for preventing and treating papillomavirus-associated cancer by reactivating p53 and by reducing the Cdk1 activity.

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E6 and E7 Gene Silencing and Transformed Phenotype of Human Papillomavirus 16-Positive Oropharyngeal Cancer Cells

Abstract: Repression of E6 and E7 oncogenes results in restoration of p53 and pRb suppressor pathways and induced apoptosis in HPV16-positive oropharyngeal squamous cell cancer cell lines.

Cited by 236 publications

References 46 publications

Unique potential of 4-1BB agonist antibody to promote durable regression of HPV ⁺ tumors when combined with an E6/E7 peptide vaccine

Unique potential of 4-1BB agonist antibody to promote durable regression of HPV ⁺ tumors when combined with an E6/E7 peptide vaccine

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

Restoration of the tumor suppressor p53 by downregulating cyclin B1 in human papillomavirus 16/18-infected cancer cells

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E6 and E7 Gene Silencing and Transformed Phenotype of Human Papillomavirus 16-Positive Oropharyngeal Cancer Cells

Abstract: Repression of E6 and E7 oncogenes results in restoration of p53 and pRb suppressor pathways and induced apoptosis in HPV16-positive oropharyngeal squamous cell cancer cell lines.

Cited by 236 publications

References 46 publications

Unique potential of 4-1BB agonist antibody to promote durable regression of HPV + tumors when combined with an E6/E7 peptide vaccine

Unique potential of 4-1BB agonist antibody to promote durable regression of HPV + tumors when combined with an E6/E7 peptide vaccine

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

Restoration of the tumor suppressor p53 by downregulating cyclin B1 in human papillomavirus 16/18-infected cancer cells

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About

Unique potential of 4-1BB agonist antibody to promote durable regression of HPV ⁺ tumors when combined with an E6/E7 peptide vaccine

Unique potential of 4-1BB agonist antibody to promote durable regression of HPV ⁺ tumors when combined with an E6/E7 peptide vaccine