HPV-16 E7 but not E6 oncogenic protein triggers both cellular immunosuppression and angiogenic processes

doi:10.1016/S0753-3322(99)80122-X

Biomedicine & Pharmacotherapy

Volume 53, Issue 9, October 1999, Pages 424-431

https://doi.org/10.1016/S0753-3322(99)80122-X Get rights and content

Summary

HPV-16 E6 and E7 oncoproteins impair the cell cycle in human uterine cervix carcinoma cells (HUCC) by acting on p53 and retinoblastoma proteins, respectively. We recently reported that E7 released into the extracellular compartment by HUCC SiHa cells could inhibit immune T-cell response to recall and alloantigens by a mechanism involving an overproduction of the immunosuppressive IFNα by antigen presenting cells (APCs). In this study, we found that besides E7, E6 protein and the vascular endothelium growth factor (VEGF) were released into the SiHa cell supernatants, and we further showed that extracellular E7 but not E6 oncoprotein 1) inhibits the immune cell response to recall and alloantigens, and 2) enhances the release of angiogenic cytokines, including TNFα, IL-1β and IL-6 by macrophages and/or dendritic cells. VEGF unexpectedly released by cancer cells could also contribute to angiogenesis. Thus in HUCC the same E7 oncoprotein which contributes to controlling the cancer cell cycle has the means in its extracellular configuration to contribute to microenvironmental immunosuppressive and angiogenic processes. Neutralizing anti-E7 antibodies either passively administered or induced by active immunization could represent a new immunotherapeutic endeavour to combat the immunosuppression and/or neoangiogenesis effects of extracellular E7 protein.

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Corresponding with the decrease in tobacco use in the United States, the incidence rate of OSCC has declined over the past two decades; however, the incidence of a subgroup of OSCC, squamous cell carcinomas of the oropharynx (SCCOP), has increased in recent years, particularly in young adults and never-smokers and never-drinkers. The rising incidence of SCCOP in the United States is likely a consequence of persistent infection with human papillomavirus (HPV), predominantly high-risk HPV type 16 (HPV-16) [2]. The overall rise in SCCOP incidence from 1984 to 2004 is largely explained by the increasing incidence of HPV-positive cancers, whereas the incidence of HPV-negative cancers declined.
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These results suggest that IL-1α 3′ UTR rs3783553 polymorphism may be functional and influence susceptibility to HPV16-associated OSCC, particularly for SCCOP. Validation of our findings is warranted.
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Additionally, in non-small cell lung cancer cells, the overexpression of both HPV16 E6 and E7 oncoproteins is associated with the promotion of angiogenesis both in vitro and in vivo, and is due to enhanced HIF-1α, as well as downstream VEGF mRNA and protein expression (Li et al., 2011). These studies align with others that have found high-risk HPV oncoproteins capable of inducing pro-angiogenic factors that are transcriptional targets of HIF-1 (Le Buanec et al., 1999; Bequet-Romero and López-Ocejo, 2000; López-Ocejo et al., 2000). Not surprisingly, pathology studies reveal a similar trend—expression of multiple VEGF isoforms are significantly increased coincidently with the grade of cervical intraepithelial neoplasia (Branca et al., 2006; Baritaki et al., 2007).
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Citation Excerpt :
Some other viruses which establish persistent infections develop similar immunosuppressive strategies to protect infected cells from the host immune system. In HPV16-dependent pathologies, including cervical cancer, as with the Tat protein, the E7 protein is released from infected cells and markedly enhances the release of IFN-α and TNF-α by APCs (Le Buanec et al., 1999a,b). Further, some herpes viruses, including EBV and CMV, encode a viral homologue of IL-10 (Kanegane et al., 1997; Spencer et al., 2002).
Anticytokine (AC) immune therapies derived from vaccine procedures aim at enhancing natural immune defense mechanisms ineffective to contain abnormally produced cytokines and counteract their pathogenic effects. Given their short half-life, cytokines, the production of which by effector immune cells (T and B lymphocytes, antigen-presenting cells (APCs), natural killer (NK) and endothelial cells) is inducible and controlled by negative feedback regulation, (1) exert locally their signaling to paracrine/autocrine target responder cells carrying high-affinity membrane receptors and (2) are commonly present at minimal concentration in the body fluid (lymph, serum). Aberrant signaling triggered by cytokines, uncontrolly released by effector immune cells or produced by cancer and other pathologic cells, contribute to the pathogenesis of chronic diseases including cancer, viral infections, allergy, and autoimmunity. To block these ectopic cytokine signaling and prevent their pathogenic effects, AC Abs supplied either by injections (passive AC immune therapy) or elicited by immunization with cytokine-derived immunogenes called Kinoids (active AC immune therapy) proved to be experimentally effective and safe. In this review, we detailed the rationale and the requirements for the use of AC immunotherapies in humans, the proof of efficacy of these medications in animal disease models, and their current clinical development and outcome, including adverse side effects they may generate. We particularly show that, to date, the benefit:risk ratio of AC immune therapies is highly positive.
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Host immune status is an important determinant of disease progression. Infections in the genital tract may alter the immunity in the particular site and hence affect the production of local cytokines. We performed this study to determine whether HIV in association with cervical HPV and CT/GC infections influences the production of local cytokines. Cervical secretions from 100 women with or without HIV infection were collected for measuring IL-1β, -6, -10 and -12 concentrations by ELISA. Cervical HPV and CT/GC DNA were detected by HCII test. Significant elevations of IL-6 and IL-10 were observed in patients having HIV infection. Although cervical HPV infection increased the concentrations of both IL-6 and IL-1β but HPV induced abnormal cervical smear was associated only with increased IL-6 concentrations significantly. Double infection had marked relation with IL-6 and IL-10. CT/GC had no direct effect on any of these cytokines but in association with HIV and HPV, these bacterial pathogens elevated the concentrations of IL-6 significantly. Thus, our results suggest that the presence of HIV and other STAs in the genital tract can cause imbalance of local cytokine levels which in turn may facilitate other opportunistic infections.
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Allergy, autoimmunity and the pathogenesis of some chronic diseases are dependent on host innate and adaptative immune responses. Both responses are associated with abnormal cytokine production within pathologic tissues. Over the past two decades, the availability of purified cytokines and cytokine antibodies (Abs) has prompted a therapeutic approach that aims to supply neutralizing Abs against deleterious cytokines, through either passive immunization (administration of large quantities of high affinity Abs, prepared ex vivo) or active immunization (induction of specific Abs, using immunogenic cytokine derivatives). Both passive and active immunization can safely, transiently and effectively be used, as has been documented by animal experimentation and confirmed by clinical trials. Novel anti-cytokine therapeutic compounds, based on passive Ab immunization, are now available to treat rheumatoid arthritis (RA) and have been shown to help control neoangiogenesis in cancer patients. Clinical trials using Abs to treat allergic disorders are also underway. However, the induction of anti-idiotypic Abs may restrict the long-term use of anti-cytokine immunotherapy using allogenic or humanized/chimeric Abs. We propose that greater consideration should be given to active immunization protocols.
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Original articleHPV-16 E7 but not E6 oncogenic protein triggers both cellular immunosuppression and angiogenic processes

Summary

Cell

J Biol Chem

Biochem Biophys Res Commun

Exp Cell Res

Mol Cell Probes