Human Viruses and Cancer

Morales-Sánchez, Abigail; Fuentes‐Pananá, Ezequiel M.

doi:10.3390/v6104047

Cited by 186 publications

(145 citation statements)

References 192 publications

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“…Also distinct etiologies of HNC such as HPV +/− disease, with such dramatically different prognoses (37), provided an unparalleled window on this potential biomarker. HPV + HNC represents a unique cancer subset (38), given its location in lymphoepithelial tissue with specific immunological properties (39), virally associated immune evasion properties (40) and yet better clinical prognosis than non-HPV associated HNC (37). Therefore, we investigated immunological properties like ICR expression of both patient subgroups in antigen specific cells from peripheral blood and tumor tissue.…”

Section: Discussionmentioning

confidence: 99%

PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer

et al. 2017

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Improved understanding of expression of immune checkpoint receptors (ICR) on tumor-infiltrating lymphocytes (TIL) may facilitate more effective immunotherapy in head and neck cancer (HNC) patients. A higher frequency of PD-1+ TIL has been reported in human papillomavirus (HPV)+ HNC patients, despite the role of PD-1 in T cell exhaustion. This discordance led us to hypothesize that the extent of PD-1 expression more accurately defines T cell function and prognostic impact, since PD-1high T cells may be more exhausted than PD-1low T cells and may influence clinical outcome and response to anti-PD-1 immunotherapy. In this study, PD-1 expression was indeed upregulated on HNC patient TIL, and the frequency of these PD-1+ TIL was higher in HPV+ patients (p = 0.006), who nonetheless experienced significantly better clinical outcome. However, PD-1high CD8+ TIL were more frequent in HPV− patients and represented a more dysfunctional subset with compromised IFN-γ secretion. Moreover, HNC patients with higher frequencies of PD-1high CD8+ TIL showed significantly worse disease free survival (DFS) and higher hazard ratio for recurrence (p<0.001), while higher fractions of PD-1low T cells associated with HPV positivity and better outcome. In a murine HPV+ HNC model, anti-PD-1 mAb therapy differentially modulated PD-1high/low populations, and tumor rejection associated with loss of dysfunctional PD-1high CD8+ T cells and a significant increase in PD-1low TIL. Thus, the extent of PD-1 expression on CD8+ TIL provides a potential biomarker for anti-PD-1 based immunotherapy.

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Section: Discussionmentioning

confidence: 99%

PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer

et al. 2017

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“…Recently, we have preliminarily discovered the role of CpG island methylation in PTEN inactivation [5], but its molecular mechanism is still unknown. It is established that viral infections contribute to 15-20% of all human cancers [24, 25]. EBV, a human gamma herpes virus, is widespread throughout the world [26].…”

Section: Discussionmentioning

confidence: 99%

Higher methylation intensity induced by EBV LMP1 via NF-κB/DNMT3b signaling contributes to silencing of PTEN gene

et al. 2016

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Phosphatase and tensin homolog (PTEN) is a major tumor suppressor and usually silenced via the deletion, insertion and mutation. We previously discovered its inactivation via aberrant CpG island methylation. Here, we provide further evidence that EBV latent membrane protein 1(LMP1) can induce a higher intensity of DNA methylation at PTEN CpG islands, inactivating PTEN at the cellular and molecular level. Initially, increased methylation intensity of PTEN CpG islands was observed in EBV-infected nasopharyngeal carcinoma (NPC) cells, accompanied by decreased PTEN expression. In NPC tissue samples showing the methylation at PTEN promoter, LMP1 was highly expressed in higher methylation intensity group relative to lower intensity group, and DNA methyltransferase 3b (DNMT3b) expression was positively correlated with LMP1 expression. Moreover, transfection of LMP1 gene into EBV-negative NPC cells demonstrated that LMP1 up-regulated DNMT3b expression, leading to a higher intensity of PTEN CpG island methylation. Mechanistically, computational prediction and luciferase reporter assay identified a functional NF-κB binding site on DNMT3b promoter and the mutated NF-κB binding site abolished LMP1-mediated DNMT3b activation. Chromatin immunoprecipitation displayed that NF-κB p65 subunit constitutively bound to DNMT3b promoter, supporting the activation of DNMT3b by EBV LMP1 via NF-κB signaling. Furthermore, the expression level of DNMT3b was observed to be increased in the nuclei of LMP1-expressing NPC cells, and a NF-κB inhibitor, PDTC, counteracted LMP1-mediated DNMT3b overexpression. Thus, this study first reports that LMP1-mediated NF-κB can up-regulate DNMT3b transcription, thereby leading to relatively higher methylation intensity at PTEN CpG islands, and ultimately silencing major tumor suppressor PTEN.

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“…erpesviruses are double-stranded DNA (dsDNA), enveloped viruses that cause lifelong latent infections and ailments ranging in severity from skin lesions to blindness, encephalitis, and cancer (1,2). A unique feature of all herpesviruses is a multiprotein tegument layer between the capsid and the envelope.…”

mentioning

confidence: 99%

The Unusual Fold of Herpes Simplex Virus 1 UL21, a Multifunctional Tegument Protein

Metrick

Chadha

Heldwein

2015

J Virol

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bUL21 is a conserved protein in the tegument of alphaherpesviruses and has multiple important albeit poorly understood functions in viral replication and pathogenesis. To provide a roadmap for exploration of the multiple roles of UL21, we determined the crystal structure of its conserved N-terminal domain from herpes simplex virus 1 to 2.0-Å resolution, which revealed a novel sail-like protein fold. Evolutionarily conserved surface patches highlight residues of potential importance for future targeting by mutagenesis. Herpesviruses are double-stranded DNA (dsDNA), enveloped viruses that cause lifelong latent infections and ailments ranging in severity from skin lesions to blindness, encephalitis, and cancer (1, 2). A unique feature of all herpesviruses is a multiprotein tegument layer between the capsid and the envelope. Besides being necessary for viral assembly, tegument proteins also play critical roles at early stages of the viral replication cycle, in which some are released to regulate expression of viral (3) or cellular genes (4) while others remain bound to the capsid and mediate its trafficking (5-7). The involvement of tegument proteins at multiple stages during viral replication makes them attractive antiviral targets, yet few have been characterized in detail.Herpes simplex virus 1 (HSV-1) UL21 is a 535-amino-acid tegument protein that is conserved within the Alphaherpesvirus subfamily (8) and may have analogs among other herpesviruses. UL21 is important for replication in culture because UL21-null mutants of HSV-1 and pseudorabies virus (PRV) show reductions in titer and small plaques (9, 10), whereas HSV-2 cannot replicate without UL21 (8). A lack of UL21 also leads to defects in pathogenesis of PRV in mice and pigs (11)(12)(13)(14). UL21 is involved in secondary envelopment (15) and cell-cell spread of mature virions (16) through binding of the tegument proteins UL16 (15, 17) and UL11 (16,17). The UL21-UL16-UL11 heterotrimer binds the cytoplasmic domain of glycoprotein E (gE), a viral glycoprotein required for viral cell spread (18, 19) and cell-cell fusion of infected cells (20), and regulates these functions (16). UL21 may also have a role in cytosolic capsid transport through association with microtubules (21). In the absence of UL21, expression of viral genes is delayed, possibly due to lower mRNA levels (8, 10). Finally, capsids of UL21-null HSV-2 are unable to undergo nuclear egress (8), suggesting a potential nuclear function for UL21, which localizes not only to the cytoplasm but also to the nucleus (17, 21), specifically the nuclear rim (8, 9, 16).Although UL21 clearly plays multiple roles in the viral replication cycle, little is known about it due to the lack of sequence Citation Metrick CM, Chadha P, Heldwein EE. 2015. The unusual fold of herpes simplex virus 1 UL21, a multifunctional tegument protein.

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Human Viruses and Cancer

Cited by 186 publications

References 192 publications

PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer

PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer

Higher methylation intensity induced by EBV LMP1 via NF-κB/DNMT3b signaling contributes to silencing of PTEN gene

The Unusual Fold of Herpes Simplex Virus 1 UL21, a Multifunctional Tegument Protein

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