HPV16 E5 Mediates Resistance to PD-L1 Blockade and Can Be Targeted with Rimantadine in Head and Neck Cancer

Miyauchi, Sayuri; Sanders, P. Dominick; Guram, Kripa; Kim, Sangwoo S.; Paolini, Francesca; Venuti, Aldo; Cohen, Ezra E.W.; Gutkind, J. Silvio; Califano, Joseph A.; Sharabi, Andrew B.

doi:10.1158/0008-5472.can-19-1771

Cited by 41 publications

(38 citation statements)

References 65 publications

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“…Overexpression of E5 in HNSCC cell lines renders them resistant to immune-checkpoint blockade (ICB), likely through the acquired loss of antigen presentation. Interestingly, this effect can be reversed with rimantadine, an antiviral medication that inhibits E5 and upregulates MHC class I in vitro (25). figure 1.…”

Section: Downregulation Of Mhc Molecules To Prevent Cytotoxic T-and Nmentioning

confidence: 99%

Tumor Immunity and Immunotherapy for HPV-Related Cancers

et al. 2021

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Human papillomavirus (HPV) infection drives tumorigenesis in the majority of cervical, oropharyngeal, anal, and vulvar cancers. Genetic and epidemiologic evidence has highlighted the role of immunosuppression in the oncogenesis of HPV-related malignancies. Here we review how HPV modulates the immune microenvironment and subsequent therapeutic implications. We describe the landscape of immunotherapies for these cancers with a focus on findings from early-phase studies exploring antigen-specific treatments, and discuss future directions. Although responses across these studies have been modest to date, a deeper understanding of HPV-related tumor biology and immunology may prove instrumental for the development of more efficacious immunotherapeutic approaches.Significance: HPV modulates the microenvironment to create a protumorigenic state of immune suppression and evasion. Our understanding of these mechanisms has led to the development of immunomodulatory treatments that have shown early clinical promise in patients with HPV-related malignancies. This review summarizes our current understanding of the interactions of HPV and its microenvironment and provides insight into the progress and challenges of developing immunotherapies for HPV-related malignancies.

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Section: Downregulation Of Mhc Molecules To Prevent Cytotoxic T-and Nmentioning

confidence: 99%

Tumor Immunity and Immunotherapy for HPV-Related Cancers

et al. 2021

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“…Recent data has suggested a potential role for E5 viroporin activity in the modulation of the host immune response. In a mouse model of HNSCC, HPV16 E5 expression resulted in a downregulation of MHC class I and this provided resistance to anti-programmed death-ligand 1 (anti-PD-L1) immunotherapy [ 98 ]. However, co-treatment with the viroporin inhibitor rimantadine sensitized tumours to anti-PD-L1 treatment, suggesting that E5 viroporin activity is responsible for the resistance to these therapies and could hence be therapeutically targeted using the currently available inhibitors [ 98 ].…”

Section: The E5 Oncoproteinmentioning

confidence: 99%

The human papillomavirus oncoproteins: a review of the host pathways targeted on the road to transformation

Scarth

Patterson

Morgan

et al. 2021

Journal of General Virology

115

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Persistent infection with high-risk human papillomaviruses (HR-HPVs) is the causal factor in over 99 % of cervical cancer cases, and a significant proportion of oropharyngeal and anogenital cancers. The key drivers of HPV-mediated transformation are the oncoproteins E5, E6 and E7. Together, they act to prolong cell-cycle progression, delay differentiation and inhibit apoptosis in the host keratinocyte cell in order to generate an environment permissive for viral replication. The oncoproteins also have key roles in mediating evasion of the host immune response, enabling infection to persist. Moreover, prolonged infection within the cellular environment established by the HR-HPV oncoproteins can lead to the acquisition of host genetic mutations, eventually culminating in transformation to malignancy. In this review, we outline the many ways in which the HR-HPV oncoproteins manipulate the host cellular environment, focusing on how these activities can contribute to carcinogenesis.

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“…HPV-induced transformation is primarily driven by three virus-expressed oncogenes: E5, E6 and E7. HPV E5 functions as an ion channel, induces EGFR signalling and promotes resistance to anti-PD-L1 immunotherapy [3][4][5][6]. E6 and E7 are the primary drivers of viral oncogenesis; in addition to their well-characterised inactivation of the p53 and pRb tumour suppressors [7,8], they regulate a multitude of signalling pathways that contribute to transformation [9][10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

E6-mediated activation of JNK drives EGFR signalling to promote proliferation and viral oncoprotein expression in cervical cancer

et al. 2020

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Human papillomaviruses (HPV) are a major cause of malignancy worldwide, contributing to ~5% of all human cancers including almost all cases of cervical cancer and a growing number of ano-genital and oral cancers. HPV-induced malignancy is primarily driven by the viral oncogenes, E6 and E7, which manipulate host cellular pathways to increase cell proliferation and enhance cell survival, ultimately predisposing infected cells to malignant transformation. Consequently, a more detailed understanding of viral-host interactions in HPV-associated disease offers the potential to identify novel therapeutic targets. Here, we identify that the c-Jun N-terminal kinase (JNK) signalling pathway is activated in cervical disease and in cervical cancer. The HPV E6 oncogene induces JNK1/2 phosphorylation in a manner that requires the E6 PDZ binding motif. We show that blockade of JNK1/2 signalling using small molecule inhibitors, or knockdown of the canonical JNK substrate c-Jun, reduces cell proliferation and induces apoptosis in cervical cancer cells. We further demonstrate that this phenotype is at least partially driven by JNK-dependent activation of EGFR signalling via increased expression of EGFR and the EGFR ligands EGF and HB-EGF. JNK/c-Jun signalling promoted the invasive potential of cervical cancer cells and was required for the expression of the epithelial to mesenchymal transition (EMT)-associated transcription factor Slug and the mesenchymal marker Vimentin. Furthermore, JNK/c-Jun signalling is required for the constitutive expression of HPV E6 and E7, which are essential for cervical cancer cell growth and survival. Together, these data demonstrate a positive feedback loop between the EGFR signalling pathway and HPV E6/E7 expression, identifying a regulatory mechanism in which HPV drives EGFR signalling to promote proliferation, survival and EMT. Thus, our study has identified a novel therapeutic target that may be beneficial for the treatment of cervical cancer.

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HPV16 E5 Mediates Resistance to PD-L1 Blockade and Can Be Targeted with Rimantadine in Head and Neck Cancer

Cited by 41 publications

References 65 publications

Tumor Immunity and Immunotherapy for HPV-Related Cancers

Tumor Immunity and Immunotherapy for HPV-Related Cancers

The human papillomavirus oncoproteins: a review of the host pathways targeted on the road to transformation

E6-mediated activation of JNK drives EGFR signalling to promote proliferation and viral oncoprotein expression in cervical cancer

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