High-Risk HPV Oncoproteins and PD-1/PD-L1 Interplay in Human Cervical Cancer: Recent Evidence and Future Directions

Allouch, Soumaya; Malki, Ahmed; Allouch, Asma; Gupta, Ishita; Vranić, Semir; Moustafa, Ala‐Eddin Al

doi:10.3389/fonc.2020.00914

Cited by 51 publications

(47 citation statements)

References 105 publications

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“…We have previously shown that therapeutic vaccination with an HPV16 L2E7E6 fusion protein, TA-CIN, in the TC-1 tumor model upregulated PD-L1 on tumor cells and PD-1 on circulating CD8 1 T cells (47). Other groups have also reported that HPV-associated cancers tend to be associated with upregulated PD-L1 and enhanced responses to immune checkpoint blockades (35,(48)(49)(50). Furthermore, PD-1/PD-L1 blockade has been used in conjunction with other cancer vaccines to improve therapeutic effects (51,52).…”

Section: Discussionmentioning

confidence: 99%

Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody

Peng

Gaillard

Wang

et al. 2021

mBio

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Immunotherapy for cervical cancer should target high-risk human papillomavirus types 16 and 18, which cause 50% and 20% of cervical cancers, respectively. Here, we describe the construction and characterization of the pBI-11 DNA vaccine via the addition of codon-optimized human papillomavirus 18 (HPV18) E7 and HPV16 and 18 E6 genes to the HPV16 E7-targeted DNA vaccine pNGVL4a-SigE7(detox)HSP70 (DNA vaccine pBI-1). Codon optimization of the HPV16/18 E6/E7 genes in pBI-11 improved fusion protein expression compared to that in DNA vaccine pBI-10.1 that utilized the native viral sequences fused 3′ to a signal sequence and 5′ to the HSP70 gene of Mycobacterium tuberculosis. Intramuscular vaccination of mice with pBI-11 DNA better induced HPV antigen-specific CD8+ T cell immune responses than pBI-10.1 DNA. Furthermore, intramuscular vaccination with pBI-11 DNA generated stronger therapeutic responses for C57BL/6 mice bearing HPV16 E6/E7-expressing TC-1 tumors. The HPV16/18 antigen-specific T cell-mediated immune responses generated by pBI-11 DNA vaccination were further enhanced by boosting with tissue-antigen HPV vaccine (TA-HPV). Combination of the pBI-11 DNA and TA-HPV boost vaccination with PD-1 antibody blockade significantly improved the control of TC-1 tumors and extended the survival of the mice. Finally, repeat vaccination with clinical-grade pBI-11 with or without clinical-grade TA-HPV was well tolerated in vaccinated mice. These preclinical studies suggest that the pBI-11 DNA vaccine may be used with TA-HPV in a heterologous prime-boost strategy to enhance HPV 16/18 E6/E7-specific CD8+ T cell responses, either alone or in combination with immune checkpoint blockade, to control HPV16/18-associated tumors. Our data serve as an important foundation for future clinical translation. IMPORTANCE Persistent expression of high-risk human papillomavirus (HPV) E6 and E7 is an obligate driver for several human malignancies, including cervical cancer, wherein HPV16 and HPV18 are the most common types. PD-1 antibody immunotherapy helps a subset of cervical cancer patients, and its efficacy might be improved by combination with active vaccination against E6 and/or E7. For patients with HPV16+ cervical intraepithelial neoplasia grade 2/3 (CIN2/3), the precursor of cervical cancer, intramuscular vaccination with a DNA vaccine targeting HPV16 E7 and then a recombinant vaccinia virus expressing HPV16/18 E6-E7 fusion proteins (TA-HPV) was safe, and half of the patients cleared their lesions in a small study (NCT00788164). Here, we sought to improve upon this therapeutic approach by developing a new DNA vaccine that targets E6 and E7 of HPV16 and HPV18 for administration prior to a TA-HPV booster vaccination and for application against cervical cancer in combination with a PD-1-blocking antibody.

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Section: Discussionmentioning

confidence: 99%

Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody

Peng

Gaillard

Wang

et al. 2021

mBio

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“…In summary, suppression of HOXD9 in cervical cancer can simultaneously suppress the HPV oncogenes E6 and E7, arrest cell proliferation, and induce cell death. Moreover, it has been recently pointed out that E6/E7 oncoproteins of high-risk HPV can upregulate the programmed cell death-1/programmed cell death-tligand 1 (PD-1/PD-L1) axis [33]. Upregulated levels of PD-L1 in cervical cancer are associated with poorer disease-free and disease-specific survival rates in comparison to those with normal or low PD-L1 levels [34,35].…”

Section: Discussionmentioning

confidence: 99%

“…Human papillomavirus (HPV) is detected in more than 90% of CC cases and is considered the most important cause of cervical carcinogenesis. There are approximately 40 types of HPV that infect the female genital organs, 20 types of which, HPV16, 18,26,31,33,35,39,45,51,52,56,58,59, 66, 67, 68, 70, 73 and 82, are considered carcinogenic and classified as high-risk types [2]. HPV16 is the most frequently detected type in CC, accounting for approximately 50% of cases, followed by HPV18, accounting for 20% [3].…”

Section: Introductionmentioning

confidence: 99%

Transcription Factor Homeobox D9 Drives the Malignant Phenotype of HPV18-Positive Cervical Cancer Cells via Binding to the Viral Early Promoter

Hayashi

Iwata

Imagawa

et al. 2021

Cancers

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Persistent infections with two types of human papillomaviruses (HPV), HPV16 and HPV18, are the most common cause of cervical cancer (CC). Two viral early genes, E6 and E7, are associated with tumor development, and expressions of E6 and E7 are primarily regulated by a single viral promoter: P97 in HPV16 and P105 in HPV18. We previously demonstrated that the homeobox D9 (HOXD9) transcription factor is responsible for the malignancy of HPV16-positive CC cell lines via binding to the P97 promoter. Here, we investigated whether HOXD9 is also involved in the regulation of the P105 promoter using two HPV18-positive CC cell lines, SKG-I and HeLa. Following the HOXD9 knockdown, cell viability was significantly reduced, and E6 expression was suppressed and was accompanied by increased protein levels of P53, while mRNA levels of TP53 did not change. E7 expression was also downregulated and, while mRNA levels of RB1 and E2F were unchanged, mRNA levels of E2F-target genes, MCM2 and PCNA, were decreased, which indicates that the HOXD9 knockdown downregulates E7 expression, thus leading to an inactivation of E2F and the cell-cycle arrest. Chromatin immunoprecipitation and promoter reporter assays confirmed that HOXD9 is directly associated with the P105 promoter. Collectively, our results reveal that HOXD9 drives the HPV18 early promoter activity to promote proliferation and immortalization of the CC cells.

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“…The majority of cases of cervical cancer are associated with high-risk HPV (16 or 18) which encode E5, E6 and E7 proteins that drive malignant transformation. These proteins are implicated in the PD1/PDL1 pathway leading to increased PD-L1 expression [ 14 ] potentially propagating immune evasion.…”

Section: Immune Response To Cancer and Immune Checkpoint Inhibition: Rationale For Immunotherapy In Cervical Cancermentioning

confidence: 99%

The Role of Immunotherapy in the Treatment of Advanced Cervical Cancer: Current Status and Future Perspectives

Walsh

Tan

2021

JCM

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Cervical cancer remains one of the most common cancers in women around the world however therapeutic options in the advanced and recurrent setting are limited. Immune checkpoint inhibitors (ICI) have been considered an attractive option given the viral etiology of cervical cancer although the majority of patients do not benefit from their use. This review summarises current knowledge and use of immune checkpoint blockade in cervical cancer as well as discussing the challenges faced in their clinical application, namely, the role of biomarker-driven ICI use, potential mechanisms of resistance, strategies to overcome such resistance and additional immunotherapy options beyond ICI.

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High-Risk HPV Oncoproteins and PD-1/PD-L1 Interplay in Human Cervical Cancer: Recent Evidence and Future Directions

Cited by 51 publications

References 105 publications

Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody

Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody

Transcription Factor Homeobox D9 Drives the Malignant Phenotype of HPV18-Positive Cervical Cancer Cells via Binding to the Viral Early Promoter

The Role of Immunotherapy in the Treatment of Advanced Cervical Cancer: Current Status and Future Perspectives

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