Immunobiology of Merkel cell carcinoma: implications for immunotherapy of a polyomavirus-associated cancer.

Departments of Medicine/Medical Oncology, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, 98109, USA.
Current Oncology Reports (Impact Factor: 2.87). 09/2011; 13(6):488-97. DOI: 10.1007/s11912-011-0197-5
Source: PubMed

ABSTRACT Merkel cell carcinoma (MCC) is an aggressive skin malignancy with a high mortality rate and an increasing incidence. The recent discovery of Merkel cell polyomavirus has revolutionized our understanding of MCC pathogenesis. Viral oncoproteins appear to play a critical role in tumor progression and are expressed in the majority of MCC tumors. Virus-specific humoral and cellular immune responses are detectable in MCC patients and are linked to the natural history of the disease. Despite persistent expression of immunogenic viral proteins, however, MCC tumors are able to evade the immune system. Understanding of the mechanisms of immune evasion employed by MCC tumors is rapidly increasing and offers opportunities for development of rational immune therapies to improve patient outcomes. Here we review recent discoveries in MCC with a special focus on the pathogenic role of Merkel cell polyomavirus and the immunobiology of this virus-associated disease.

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    ABSTRACT: Due to the implementation of the Montreal Protocol, which has limited, and is now probably reversing, the depletion of the stratospheric ozone layer, only modest increases in solar UV-B radiation at the surface of the Earth have occurred. For many fair-skinned populations, changing behaviour with regard to exposure to the sun over the past half century – more time in the sun, less clothing cover (more skin exposed), and preference for a tan – has probably contributed more to greater levels of exposure to UV-B radiation than ozone depletion. Exposure to UV-B radiation has both adverse and beneficial effects on human health. This report focuses on an assessment of the evidence regarding these outcomes that has been published since our previous report in 2010. The skin and eyes are the organs exposed to solar UV radiation. Excessive solar irradiation causes skin cancer, including cutaneous malignant melanoma and the non-melanoma skin cancers, basal cell carcinoma and squamous cell carcinoma, and contributes to the development of other rare skin cancers such as Merkel cell carcinoma. Although the incidence of melanoma continues to increase in many countries, in some locations, primarily those with strong sun protection programmes, incidence has stabilised or decreased over the past 5 years, particularly in younger age-groups. However, the incidence of non-melanoma skin cancers is still increasing in most locations. Exposure of the skin to the sun also induces systemic immune suppression that may have adverse effects on health, such as through the reactivation of latent viral infections, but also beneficial effects through suppression of autoimmune reactivity. Solar UV-B radiation damages the eyes, causing cataracts and pterygium. UV-B irradiation of the skin is the main source of vitamin D in many geographic locations. Vitamin D plays a critical role in the maintenance of calcium homeostasis in the body; severe deficiency causes the bone diseases, rickets in children and osteomalacia in adults. Although many studies have implicated vitamin D deficiency in a wide range of diseases, such as cancer and cardiovascular disease, more recent evidence is less compelling, with meta-analyses of supplementation trials failing to show a beneficial effect on the health outcomes that have been tested. It continues to be difficult to provide public health messages to guide safe exposure to the sun that are accurate, simple, and can be used by people with different skin types, in different locations, and for different times of the year or day. There is increasing interest in relating sun protection messages to the UV Index. Current sun protection strategies are outlined and assessed. Climatic factors affect the amount of UV radiation received by the skin and eyes, separately from the effect of ozone depletion. For example, cloud cover can decrease or increase the intensity of UV radiation at Earth's surface and warmer temperatures and changes in precipitation patterns may alter the amount of time people spend outdoors and their choice of clothing. The combination of changes in climate and UV radiation may affect the number of pathogenic microorganisms in surface waters, and could have an impact on food security through effects on plant and aquatic systems. It remains difficult to quantify these effects and their possible importance for human health.
    Photochemical and Photobiological Sciences 11/2014; DOI:10.1039/C4PP90033B · 2.94 Impact Factor
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    ABSTRACT: Background: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. Immunosuppression is associated with increased incidence of MCC. Objective: We sought to determine whether solid organ transplant recipients (SOTR) with MCC had decreased progression-free, disease-specific, and overall survival compared with immunocompetent patients. Methods: We conducted a retrospective cohort study examining 8 SOTR with MCC and 89 immunocompetent control subjects. Cox regression models were generated for outcomes of progression, disease-specific death, and death from any cause, adjusted for patient sex, age at diagnosis, and stage at presentation. Results: SOTR had a 4.1-fold increased hazard for progression (95% confidence interval 1.57-10.95, P = .004), a 10.5-fold increased hazard for all-cause mortality (95% confidence interval 3.06-35.98, P < .0001), and an 11.9-fold increased hazard for MCC-specific death (95% confidence interval 2.67-53.08, P = .001), adjusted for sex, age, and stage at presentation. SOTR had decreased 1-year overall survival, 46.8% versus 88.6%, and decreased 1-year MCC-specific survival, 56.3% versus 95.2%. Limitations: This is a single-center study from a tertiary academic care center, and may not be generalizable to all patient populations. Conclusions: SOTR have a significant reduction in overall, MCC-specific, and progression-free survival compared with immunocompetent patients. Further studies will determine whether aggressive treatment may improve outcomes in this high-risk population.
    Journal of the American Academy of Dermatology 06/2014; 71(4). DOI:10.1016/j.jaad.2014.05.054 · 5.00 Impact Factor
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    ABSTRACT: Human oncogenic viruses include Epstein-Barr virus, hepatitis B virus, hepatitis C virus, human papilloma virus, human T-cell lymphotropic virus, Kaposi's associated sarcoma virus, and Merkel cell polyomavirus. It would be expected that during virus-host interaction, the immune system would recognize these pathogens and eliminate them. However, through evolution, these viruses have developed a number of strategies to avoid such an outcome and successfully establish chronic infections. The persistent nature of the infection caused by these viruses is associated with their oncogenic potential. In this article, we will review the latest information on the interaction between oncogenic viruses and the innate immune system of the host. In particular, we will summarize the available knowledge on the recognition by host pattern-recognition receptors of pathogen-associated molecular patterns present in the incoming viral particle or generated during the virus' life cycle. We will also review the data on the recognition of cell-derived danger associated molecular patterns generated during the virus infection that may impact the outcome of the host-pathogen interaction and the development cancer.
    Frontiers in Immunology 07/2014; 5:353. DOI:10.3389/fimmu.2014.00353

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