Human papillomavirus E5 suppresses immunity via inhibition of the immunoproteasome and STING pathway

Miyauchi, Sayuri; Kim, Sangwoo S.; Jones, R.N.; Zhang, Lin; Guram, Kripa; Sharma, Sonia; Schoenberger, Stephen P.; Cohen, Ezra E.W.; Califano, Joseph A.; Sharabi, Andrew B.

doi:10.1016/j.celrep.2023.112508

Cited by 18 publications

(19 citation statements)

References 63 publications

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“…To understand the relationship between viral infection and dysregulation of protein translation in metastatic expanding clones, we tested for the relative expression levels of translation-initiating factors and regulatory kinases associated with virally activated translational relief, a process by which virally infected cells escape normal anti-viral mechanisms 29,30 . Under normal circumstances, a cell will downregulate protein translation and upregulate apoptosis once a virus is detected.…”

Section: Resultsmentioning

confidence: 99%

“…Notably, abundant regulatory T-cells are associated with a more unfavourable prognosis 36 . Viral infection generally results in immune evasion via suppression of IFN-stimulated gene transcription 32 and, in HPV-infection, downregulation of the immunoproteasome 30 . Silencing the IFN regulatory pathway has also been demonstrated to be a feature of metastatic cancer cells 37 .…”

Section: Resultsmentioning

confidence: 99%

“…While the mechanisms are not always resolved, it is clear that clonal selection occurs for cell phenotypes that enhance survival and metastatic processes. In the case of HPV+ oropharyngeal cancer, persistent HPV infection leads to alterations in the host immune response 30 , which likely results in significant selection pressure on cells, which shapes the tumour microenvironment 44 . This is evident when observing immune cell microenvironment changes through acute and chronic viral infection phases and pre-cancer and invasive cancer development with HPV infection 36 , highlighting the importance of examining cancer clones in their spatial context.…”

Section: Discussionmentioning

confidence: 99%

“…The immunoproteasome is involved in antigen presentation and is a critical step in the inflammatory response to viral infection and cancer. E5 HPV protein is a powerful negative regulator of the anti-viral immune response by limiting the MHC I antigen repertoire via suppression of the immunoproteasome 30 , allowing infected cells to escape host immune surveillance 55,56 . The importance of the immunoproteasome in antigen recognition is further demonstrated, with high expression being a positive predictive biomarker of immune checkpoint inhibitor blockade response 57 .…”

Section: Discussionmentioning

confidence: 99%

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Protein Translation Dysregulation and Immune Cell Evasion Define Metastatic Clones in HPV-related Cancer of the Oropharynx

Chin,

Muskovic,

McCloy

et al. 2024

Preprint

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Head and neck cancers, representing the seventh most common malignancy globally, have seen a shift in causative factors from traditional smoking and alcohol use to human papillomavirus (HPV) infection, now accounting for up to 80% of oropharyngeal cancers. We identify the cellular and clonal mechanisms underlying immune avoidance and metastasis by analysing single-cell and spatial genomic data from primary and metastatic cancers. We first map the clonal evolution of malignant cells based on the accumulation of mutations. We identify metastasising clones based on mutational similarity scores between cells in the primary and lymph node metastasis. Genomic analysis of metastasising and non-metastasising clones identified virally mediated protein translation relief (P=4.24x10-24) pathway underlying metastatic expansion. We show that in metastatic clones, this process is driven through upregulation of transition-initiating factors, EIF4E (P=1.5x10-13) and EIFG1 (P<2.22x10-16), and suppression of regulatory kinases EIF4EBP1 (P=2.1x10), EIF2AK2 (P<2.22x10-16), and EIF2S1 (P<2.22x10-16). We subsequently identify that metastatic clones have a corresponding downregulation of the JAK/STAT pathway and immunoproteasome genes PSMB8 (P<2.22x10-16) and PSMB9 (P<2.22x10-16), suggesting these clones escape immune surveillance through decreased INF inflammatory response and antigen presentation. We validate these results using spatial RNA-seq data, where metastatic cancer clones show decreased cell-to-cell interactions with CD4 T-effector memory cells (CD4TEM) (P=0.0077), CD8 T-exhausted cells (CD8Ex) (P=0.0191), and innate lymphoid cells (ILC) (P=0.04). Finally, we demonstrate that the upregulation of cap-independent translational drives cell proliferation in metastatic clones through the expression of translation initiation factors (EIF4G1: P<2.22x10-16). Our results provide evidence of the mechanisms by which virally induced cancer clones lead to advanced disease and poor prognosis in patients.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Protein Translation Dysregulation and Immune Cell Evasion Define Metastatic Clones in HPV-related Cancer of the Oropharynx

Chin,

Muskovic,

McCloy

et al. 2024

Preprint

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“…Notably, the oncoprotein E7 of high-risk HPV16, which shares a low degree of homology with HPV18 E7, is also responsible for potently suppressing STING-induced immune activation, but does not directly interact with STING [ 160 ]. Instead, HPV16 E5 was demonstrated to directly bind to STING and subsequently inhibit downstream signaling [ 193 ]. However, the exact mechanism via, which HPV16 E5 antagonizes STING is yet to be fully elucidated.…”

Section: Mechanisms Of Sting-mediated Immune Evasion By Oncogenic Dna...mentioning

confidence: 99%

STINGing Defenses: Unmasking the Mechanisms of DNA Oncovirus-Mediated Immune Escape

Martínez-López,

Muslin,

Kyriakidis

2024

Viruses

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DNA oncoviruses represent an intriguing subject due to their involvement in oncogenesis. These viruses have evolved mechanisms to manipulate the host immune response, facilitating their persistence and actively contributing to carcinogenic processes. This paper describes the complex interactions between DNA oncoviruses and the innate immune system, with a particular emphasis on the cGAS-STING pathway. Exploring these interactions highlights that DNA oncoviruses strategically target and subvert this pathway, exploiting its vulnerabilities for their own survival and proliferation within the host. Understanding these interactions lays the foundation for identifying potential therapeutic interventions. Herein, we sought to contribute to the ongoing efforts in advancing our understanding of the innate immune system in oncoviral pathogenesis.

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Human papillomaviruses: Knowns, mysteries, and unchartered territories

Gelbard,

Munger

2023

Journal of Medical Virology

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There has been an explosion in the number of papillomaviruses that have been identified and fully sequenced. Yet only a minute fraction of these has been studied in any detail. Most of our molecular research efforts have focused on the E6 and E7 proteins of “high‐risk,” cancer‐associated human papillomaviruses (HPVs). Interactions of the high‐risk HPV E6 and E7 proteins with their respective cellular targets, the p53 and the retinoblastoma tumor suppressors, have been investigated in minute detail. Some have thus questioned if research on papillomaviruses remains an exciting and worthwhile area of investigation. However, fundamentally new insights on the biological activities and cellular targets of the high‐risk HPV E6 and E7 proteins have been discovered and previously unstudied HPVs have been newly associated with human diseases. HPV infections continue to be an important cause of human morbidity and mortality and since there are no antivirals to combat HPV infections, research on HPVs should remain attractive to new investigators and biomedical funding agencies, alike.

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Human papillomavirus E5 suppresses immunity via inhibition of the immunoproteasome and STING pathway

Cited by 18 publications

References 63 publications

Protein Translation Dysregulation and Immune Cell Evasion Define Metastatic Clones in HPV-related Cancer of the Oropharynx

Protein Translation Dysregulation and Immune Cell Evasion Define Metastatic Clones in HPV-related Cancer of the Oropharynx

STINGing Defenses: Unmasking the Mechanisms of DNA Oncovirus-Mediated Immune Escape

Human papillomaviruses: Knowns, mysteries, and unchartered territories

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