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1.  Regression of metastatic Merkel cell carcinoma following transfer of polyomavirus-specific T cells and therapies capable of re-inducing HLA class-I 
Cancer immunology research  2013;2(1):27-36.
Merkel cell carcinoma (MCC) is an aggressive skin cancer that typically requires the persistent expression of Merkel cell polyomavirus (MCPyV) oncoproteins that can serve as ideal immunotherapeutic targets. Several immune evasion mechanisms are active in MCC including down-regulation of HLA class-I expression on tumor cells and dysfunctional endogenous MCPyV-specific CD8 T cell responses. To overcome these obstacles, we combined local and systemic immune therapies in a 67-year-old man, who developed metastatic MCPyV-expressing MCC. Intralesional IFNβ-1b or targeted single-dose radiation was administered as a pre-conditioning strategy to reverse the down-regulation of HLA-I expression noted in his tumors and to facilitate the subsequent recognition of tumor cells by T cells. This was followed by the adoptive transfer of ex vivo expanded polyclonal, polyomavirus-specific T cells as a source of reactive antitumor immunity. The combined regimen was well-tolerated and led to persistent up-regulation of HLA-I expression in the tumor and a durable complete response in two of three metastatic lesions. Relative to historical controls, the patient experienced a prolonged period without development of additional distant metastases (535 days compared to historic median of 200 days, 95% confidence interval = 154–260 days). The transferred CD8+ T cells preferentially accumulated in the tumor tissue, remained detectable and functional for >200 days, persisted with an effector phenotype, and exhibited evidence of recent in vivo activation and proliferation. The combination of local and systemic immune stimulatory therapies was well-tolerated and may be a promising approach to overcome immune evasion in virus-driven cancers.
doi:10.1158/2326-6066.CIR-13-0087
PMCID: PMC3888869  PMID: 24432305
2.  Pathogen-Driven Cancers and Emerging Immune Therapeutic Strategies 
Cancer immunology research  2014;2(1):9-14.
Infectious agents play an etiologic role in approximately 20% of cancer cases worldwide. Eleven pathogens (seven viruses, three parasites, and one bacterium) are known to contribute to oncogenesis either directly via the expression of their protein products or indirectly via chronic inflammation. Although prevention of infection and antimicrobial treatments have helped in reducing infection rates and the incidence of associated malignancies, therapies for these cancers remain limited. The importance of immune control over malignant progression is highlighted by the fact that many cancers, particularly those induced by pathogens, occur more frequently among immunosuppressed patients as compared with healthy individuals. Therefore, therapeutic strategies that can elicit a robust immune response and restore tumor detection may be a beneficial approach for treating these cancers. In addition, the study of immune escape mechanisms used by pathogens and their associated cancers may provide insight into the mechanisms of malignant transformation and improved therapies for cancer more generally.
doi:10.1158/2326-6066.CIR-13-0179
PMCID: PMC4135058  PMID: 24778160
3.  p63 expression in Merkel cell carcinoma predicts poorer survival yet may have limited clinical utility 
p63 expression has been identified in several cohorts as a predictor of poorer prognosis in Merkel cell carcinoma. We used multivariate analysis in a large independent cohort to determine the clinical utility of this parameter. Immunohistochemistry was used to determine p63 expression on MCC tumors from 128 patients. Of these, 33% had detectable p63 expression. p63 positivity was associated with an increased risk of death from MCC (hazard ratio 2.05, p = 0.02) in a multivariate Cox regression model considering stage at presentation, age at diagnosis, and gender. Although p63 expression correlated with diminished survival in this largest cohort reported thus far, the effect was weaker than that observed in prior studies. Indeed, within a given stage, p63 status did not predict survival in a clinically or statistically significant manner. It thus remains unclear whether this test should be integrated into routine MCC patient management.
doi:10.1309/AJCPE4PK6CTBNQJY
PMCID: PMC4074520  PMID: 24225752
Merkel cell carcinoma; survival; prognosis; p63
5.  Merkel polyomavirus-specific T cells fluctuate with Merkel cell carcinoma burden and express therapeutically targetable PD-1 and Tim-3 exhaustion markers 
Purpose
The persistent expression of Merkel cell polyomavirus (MCPyV) oncoproteins in Merkel cell carcinoma (MCC) provides a unique opportunity to characterize immune evasion mechanisms in human cancer. We isolated MCPyV-specific T cells and determined their frequency and functional status.
Experimental Design
Multi-parameter flow cytometry panels and HLA/peptide tetramers were used to identify and characterize T cells from tumors (n=7) and blood (n=18) of MCC patients and control subjects (n=10). PD-1 ligand (PD-L1) and CD8 expression within tumors were determined using mRNA profiling (n=35) and immunohistochemistry (n=13).
Results
MCPyV-specific CD8 T cells were detected directly ex vivo from the blood of 7 of 11 (64%) patients with MCPyV-positive tumors. In contrast, 0 of 10 control subjects had detectable levels of these cells in their blood (p<0.01). MCPyV-specific T cells in serial blood specimens increased with MCC disease progression and decreased with effective therapy. MCPyV-specific CD8 T cells and MCC-infiltrating lymphocytes expressed higher levels of therapeutically targetable PD-1 and Tim-3 inhibitory receptors compared to T cells specific to other human viruses (p<0.01). PD-L1 was present in 9 of 13 (69%) MCCs and its expression was correlated with CD8 lymphocyte infiltration.
Conclusions
MCC-targeting T cells expand with tumor burden and express high levels of immune checkpoint receptors PD-1 and Tim-3. Reversal of these inhibitory pathways is therefore a promising therapeutic approach for this virus-driven cancer.
doi:10.1158/1078-0432.CCR-13-0035
PMCID: PMC3790865  PMID: 23922299
6.  Effect of Host, Tumor, Diagnostic, and Treatment Variables on Outcomes in a Large Cohort With Merkel Cell Carcinoma 
JAMA dermatology  2014;150(7):716-723.
IMPORTANCE
Merkel cell carcinoma (MCC) is a rare, aggressive, neuroendocrine-derived skin cancer with high rates of recurrence and associated mortality. Few published studies have used comprehensive patient data and long-term follow-up to examine factors that predict MCC outcomes.
OBJECTIVE
To characterize MCC in a large defined-population cohort and analyze predictors of disease recurrence and survival.
SETTING, DESIGN, AND PARTICIPANTS
Retrospective cohort study of 218 patients with MCC from the cancer registry of Kaiser Permanente Northern California, a large integrated health care delivery system. Patients were diagnosed as having MCC and followed up from January 1, 1995, through December 31, 2009. We examined host (age, sex, race, and immunosuppression), tumor (anatomic site, size, and extent), diagnostic (results of imaging and pathologic nodal evaluation), and treatment (surgery, radiation therapy, and chemotherapy) variables for their association with MCC outcomes.
EXPOSURE
Host, tumor, diagnostic, and treatment factors.
MAIN OUTCOMES AND MEASURES
Recurrence (locoregional and distant) of MCC and patient survival (overall and MCC specific).
RESULTS
We estimated adjusted hazard ratios (AHRs) and 95% CIs for outcomes using Cox proportional hazards regression models. After adjustment for host, tumor, diagnostic, and treatment variables, tumor extent (categorized as local, regional, and distant) remained significantly associated with all outcomes. Immunosuppression was associated with higher MCC-specific mortality (AHR, 4.9 [95% CI, 1.7–14.4]), and an unknown primary site was associated with a lower risk for distant metastasis (0.1 [0.0–0.7]) and improved survival (0.4 [0.2–0.9]). Pathological nodal evaluation was associated with a lower risk for metastasis (AHR, 0.2 [95% CI, 0.0–1.0]) and improved survival. Radiation treatment was associated with a decreased risk for locoregional recurrence (AHR, 0.3 [95% CI, 0.1–0.6]), whereas chemotherapy was not associated with any alteration in outcomes.
CONCLUSIONS AND RELEVANCE
Tumor site and extent, results of pathologic nodal evaluation, and the presence of radiation treatment were associated with MCC recurrence. Immunosuppression, tumor extent, and results of pathologic nodal evaluation were associated with MCC-specific survival, whereas chemotherapy was not associated with any outcomes. Our findings may help to inform diagnostic and therapeutic management of MCCs.
doi:10.1001/jamadermatol.2013.8116
PMCID: PMC4141075  PMID: 24807619
7.  Immunobiology of Merkel cell carcinoma: implications for immunotherapy of a polyomavirus-associated cancer 
Current oncology reports  2011;13(6):488-497.
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.
doi:10.1007/s11912-011-0197-5
PMCID: PMC4112947  PMID: 21953511
Merkel cell carcinoma; immunotherapy; Merkel cell polyomavirus; MCV; MCpyV; cancer virus; viral cancer; immune evasion; immune escape; MHC; tumor immunology; tumor infiltrating lymphocytes; TILs; viral oncoproteins; T-antigen; immune suppression
8.  Inhibition of UVB-induced nonmelanoma skin cancer: A path from tea to caffeine to exercise to decreased tissue fat 
Topics in current chemistry  2013;329:61-72.
Oral administration of green tea, black tea or caffeine (but not the decaffeinated teas) inhibited ultraviolet B radiation (UVB)-induced skin carcino-genesis in SKH-1 mice. Studies with caffeine indicated that its inhibitory effect on the ATR/Chk1 pathway is an important mechanism for caffeine’s inhibition of UVB-induced carcinogenesis. The regular teas or caffeine increased locomotor activity and decreased tissue fat. In these studies, decreased dermal fat thickness was associated with a decrease in the number of tumors per mouse. Administration of caffeine, voluntary exercise and removal of the parametrial fat pads all stimulated UVB-induced apoptosis, inhibited UVB-induced carcinogenesis and stimulated apoptosis in UVB-induced tumors. These results suggest that caffeine administration, voluntary exercise and removal of the parametrial fat pads inhibit UVB-induced carcinogenesis by stimulating UVB-induced apoptosis and by enhancing apoptosis in DNA-damaged precancer cells and in cancer cells. We hypothesize that tissue fat secretes antiapoptotic adipokines that have a tumor promoting effect.
doi:10.1007/128_2012_336
PMCID: PMC4049109  PMID: 22752580
9.  Emerging and Mechanism-Based Therapies for Recurrent or Metastatic Merkel Cell Carcinoma 
Opinion statement
Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer with a disease-specific mortality of approximately 40 %. The association of MCC with a recently discovered polyomavirus, combined with the increased incidence and mortality of MCC among immunocompromised patients, highlight the importance of the immune system in controlling this cancer. Initial management of MCC is summarized within the NCCN guidelines and in recently published reviews. The high rate of recurrent and metastatic disease progression in MCC, however, presents a major challenge in a cancer that lacks mechanism-based, disease-specific therapies. Traditional treatment approaches have focused on cytotoxic chemotherapy that, despite frequent initial efficacy, rarely provides durable responses and has high morbidity among the elderly. In addition, the immunosuppressive nature of chemotherapy is of concern when treating a virus-associated cancer for which survival is unusually tightly linked to immune function. With a median survival of 9.6 months after development of an initial metastasis (n=179, described herein), and no FDA-approved agents for this cancer, there is an urgent need for more effective treatments. We review diverse management options for patients with advanced MCC, with a focus on emerging and mechanism-based therapies, some of which specifically target persistently expressed viral antigens. These treatments include single-dose radiation and novel immunotherapies, some of which are in clinical trials. Due to their encouraging efficacy, low toxicity, and lack of immune suppression, these therapies may offer viable alternatives to traditional cytotoxic chemotherapy.
doi:10.1007/s11864-013-0225-9
PMCID: PMC3651762  PMID: 23436166
Merkel cell carcinoma; Skin cancer; Immunotherapy; Merkel cell polyomavirus; Pazopanib; Octreotide; Somatostatin; Neuroendocrine carcinoma; Adoptive T cell therapy; Single-dose radiation therapy; PD-1; Survival
10.  Vascular E-selectin expression correlates with CD8 lymphocyte infiltration and improved outcome in Merkel cell carcinoma 
Merkel cell carcinoma (MCC) is an aggressive, polyomavirus-linked skin cancer. While CD8 lymphocyte infiltration into the tumor is strongly correlated with improved survival, these cells are absent or sparse in most MCCs. We investigated whether specific mechanisms of T-cell migration may be commonly disrupted in MCC tumors with poor CD8 lymphocyte infiltration. Intratumoral vascular E-selectin, critical for T-cell entry into skin, was downregulated in the majority (52%) of MCCs (n=56), and its loss was associated with poor intratumoral CD8 lymphocyte infiltration (p<0.05; n=45). Importantly, survival was improved in MCC patients whose tumors had higher vascular E-selectin expression (p<0.05). Local nitric oxide (NO) production is one mechanism of E-selectin downregulation and it can be tracked by quantifying nitrotyrosine, a stable biomarker of NO-induced reactive nitrogen species (RNS). Indeed, increasing levels of nitrotyrosine within MCC tumors were associated with low E-selectin expression (p<0.05; n=45) and decreased CD8 lymphocyte infiltration (p<0.05, n=45). These data suggest that one mechanism of immune evasion in MCC may be restriction of T cell entry into the tumor. Existing therapeutic agents that modulate E-selectin expression and/or RNS generation may restore T cell entry and could potentially synergize with other immune-stimulating therapies.
doi:10.1038/jid.2013.36
PMCID: PMC3644376  PMID: 23353989
Merkel cell carcinoma; T cell immune evasion; E-selectin; Nitrotyrosine
11.  Tumor-specific T cells in human Merkel cell carcinomas: a possible role for Tregs and T cell exhaustion in reducing T cell responses 
Merkel cell carcinomas (MCC) are rare but highly malignant skin cancers associated with a novel polyomavirus. MCC tumors were infiltrated by T cells, including effector, central memory and regulatory T cells. Infiltrating T cells showed markedly reduced activation as evidenced by reduced expression of CD69 and CD25. Treatment of MCC tumors in vitro with IL-2 and IL-15 led to T cell activation, proliferation, enhanced cytokine production and loss of viable tumor cells from cultures. Expanded tumor-infiltrating lymphocytes showed TCR repertoire skewing and upregulation of CD137. MCC tumors implanted into immunodeficient mice failed to grow unless human T cells in the tumor grafts were depleted with denileukin diftitox, suggesting tumor-specific T cells capable of controlling tumor growth were present in MCC. Both CD4+ and CD8+ FOXP3+ regulatory T cells were frequent in MCC. 50% of non-activated T cells in MCC expressed PD-1, a marker of T-cell exhaustion, and PD-L1 and PD-L2 were expressed by a subset of tumor dendritic cells and macrophages. In summary, we observed tumor-specific T cells with suppressed activity in MCC tumors. Agents that stimulate T cell activity, block Treg function or inhibit PD-1 signaling may be effective in the treatment of this highly malignant skin cancer.
doi:10.1038/jid.2013.75
PMCID: PMC3691077  PMID: 23419694
Merkel cell carcinoma; immune evasion; T cell dysfunction; PD-1
12.  Merkel Cell Polyomavirus Large T Antigen Has Growth-Promoting and Inhibitory Activities 
Journal of Virology  2013;87(11):6118-6126.
Merkel cell carcinoma (MCC) is a rare and aggressive form of skin cancer. In at least 80% of all MCC, Merkel cell polyomavirus (MCPyV) DNA has undergone clonal integration into the host cell genome, and most tumors express the MCPyV large and small T antigens. In all cases of MCC reported to date, the integrated MCPyV genome has undergone mutations in the large T antigen. These mutations result in expression of a truncated large T antigen that retains the Rb binding or LXCXE motif but deletes the DNA binding and helicase domains. However, the transforming functions of full-length and truncated MCPyV large T antigen are unknown. We compared the transforming activities of full-length, truncated, and alternatively spliced 57kT forms of MCPyV large T antigen. MCPyV large T antigen could bind to Rb but was unable to bind to p53. Furthermore, MCPyV-truncated large T antigen was more effective than full-length and 57kT large T antigen in promoting the growth of human and mouse fibroblasts. In contrast, expression of the MCPyV large T antigen C-terminal 100 residues could inhibit the growth of several different cell types. These data imply that the deletion of the C terminus of MCPyV large T antigen found in MCC serves not only to disrupt viral replication but also results in the loss of a distinct growth-inhibitory function intrinsic to this region.
doi:10.1128/JVI.00385-13
PMCID: PMC3648111  PMID: 23514892
14.  Systemic immune suppression as a stage-independent predictor of diminished Merkel cell carcinoma-specific survival 
Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy linked to a contributory virus (Merkel cell polyomavirus/MCPyV). Multiple epidemiologic studies have established an increased incidence of MCC among persons with systemic immune suppression. Several forms of immune suppression are associated with increased MCC incidence, including hematologic malignancies, HIV/AIDS, and immunosuppressive medications for autoimmune disease or transplant. Indeed, immune suppressed persons represent approximately 10% of the MCC patients, a significant over-representation relative to the general population. We hypothesized that immune suppressed patients may have a poorer MCC-specific prognosis and examined a cohort of 471 patients with a combined follow-up of 1427 years (median 2.1 years). Immune suppressed persons (n=41) demonstrated reduced MCC-specific survival (40% at 3 years) compared to persons with no known systemic immune suppression (n=430; 74% MCC-specific survival at 3 years). By competing risk regression analysis, immune suppression was a stage-independent predictor of worsened MCC-specific survival (hazard ratio 3.8, p < 0.01). Immune-suppressed persons thus have both an increased chance of developing MCC and poorer MCC-specific survival. It may be appropriate to follow these higher-risk individuals more closely, and, when clinically feasible, there may be benefit of diminishing iatrogenic systemic immune suppression.
doi:10.1038/jid.2012.388
PMCID: PMC3570636  PMID: 23190897
15.  Mechanisms of Caffeine-Induced Inhibition of UVB Carcinogenesis 
Frontiers in Oncology  2013;3:144.
Sunlight-induced non-melanoma skin cancer is the most prevalent cancer in the United States with more than two million cases per year. Several studies have shown an inhibitory effect of caffeine administration on UVB-induced skin cancer in mice, and these studies are paralleled by epidemiology studies that indicate an inhibitory effect of coffee drinking on non-melanoma skin cancer in humans. Strikingly, decaffeinated coffee consumption had no such inhibitory effect. Mechanism studies indicate that caffeine has a sunscreen effect that inhibits UVB-induced formation of thymine dimers and sunburn lesions in the epidermis of mice. In addition, caffeine administration has a biological effect that enhances UVB-induced apoptosis thereby enhancing the elimination of damaged precancerous cells, and caffeine administration also enhances apoptosis in tumors. Caffeine administration enhances UVB-induced apoptosis by p53-dependent and p53-independent mechanisms. Exploration of the p53-independent effect indicated that caffeine administration enhanced UVB-induced apoptosis by inhibiting the UVB-induced increase in ATR-mediated formation of phospho-Chk1 (Ser345) and abolishing the UVB-induced decrease in cyclin B1 which resulted in caffeine-induced premature and lethal mitosis in mouse skin. In studies with cultured primary human keratinocytes, inhibition of ATR with siRNA against ATR inhibited Chk1 phosphorylation and enhanced UVB-induced apoptosis. Transgenic mice with decreased epidermal ATR function that were irradiated chronically with UVB had 69% fewer tumors at the end of the study compared with irradiated littermate controls with normal ATR function. These results, which indicate that genetic inhibition of ATR (like pharmacologic inhibition of ATR via caffeine) inhibits UVB-induced carcinogenesis support the concept that ATR-mediated phosphorylation of Chk1 is an important target for caffeine’s inhibitory effect on UVB-induced carcinogenesis.
doi:10.3389/fonc.2013.00144
PMCID: PMC3683821  PMID: 23785666
sunlight-induced skin cancer; sunscreen; ATR inhibition; upregulation of p53; coffee
16.  Identification and validation of a novel mature microRNA encoded by the Merkel cell polyomavirus in human Merkel cell carcinomas 
Background
Merkel cell polyomavirus (MCPyV) is present in approximately 80% of human Merkel cell carcinomas (MCCs). A previous in silico prediction suggested MCPyV encodes a microRNA (miRNA) that may regulate cellular and viral genes.
Objectives
To determine the presence and prevalence of a putative MCPyV-encoded miRNA in human MCC tumors.
Study Design
Over 30 million small RNAs from 7 cryopreserved MCC tumors and 1 perilesional sample were sequenced. 45 additional MCC tumors were examined for expression of an MCPyV-encoded mature miRNA by reverse transcription real-time PCR.
Results
An MCPyV-encoded mature miRNA, “MCV-miR-M1-5p”, was detected by direct sequencing in 2 of 3 MCPyV-positive MCC tumors. Although a precursor miRNA, MCV-miR-M1, had been predicted in silico and studied in vitro by Seo et al., no MCPyV-encoded miRNAs have been directly detected in human tissues. Importantly, the mature sequence of MCV-miR-M1 found in vivo was identical in all 79 reads obtained but differed from the in silico predicted mature miRNA by a 2-nucleotide shift, resulting in a distinct seed region and a different set of predicted target genes. This mature miRNA was detected by real-time PCR in 50% of MCPyV-positive MCCs (n=38) and in 0% of MCPyV-negative MCCs (n=13).
Conclusions
MCV-miR-M1-5p is expressed at low levels in 50% of MCPyV-positive MCCs. This virus-encoded miRNA is predicted to target genes that may play a role in promoting immune evasion and regulating viral DNA replication.
doi:10.1016/j.jcv.2011.08.012
PMCID: PMC3196837  PMID: 21907614
MCV-miR-M1; Merkel cell polyomavirus; Merkel cell carcinoma; microRNA
17.  Merkel cell polyomavirus-specific CD8+ and CD4+ T-cell responses identified in Merkel cell carcinomas and blood 
PURPOSE
Merkel cell polyomavirus (MCPyV) is prevalent in the general population, integrates into most Merkel cell carcinomas (MCCs) and encodes oncoproteins required for MCC tumor growth. We sought to characterize T-cell responses directed against viral proteins that drive this cancer as a step toward immunotherapy.
METHODS
Intracellular cytokine cytometry, IFN-γ-ELISPOT, and a novel HLA-A*2402-restricted MCPyV tetramer were used to identify and characterize T-cell responses against MCPyV oncoproteins in tumors and blood of MCC patients and control subjects.
RESULTS
We isolated virus-reactive CD8 or CD4 T cells from MCPyV-positive MCC tumors (2 of 6), but not from virus-negative tumors (0 of 4). MCPyV-specific T-cell responses were also detected in the blood of MCC patients (14 of 27) and control subjects (5 of 13). These T cells recognized a broad range of peptides derived from capsid proteins (2 epitopes) and oncoproteins (24 epitopes). HLA-A*2402-restricted MCPyV oncoprotein processing and presentation by mammalian cells led to CD8-mediated cytotoxicity. Virus-specific CD8 T cells were markedly enriched among tumor-infiltrating lymphocytes as compared to blood, implying intact T-cell trafficking into the tumor. While tetramer-positive CD8 T cells were detected in the blood of 2 of 5 HLA-matched MCC patients, these cells failed to produce IFN-γ when challenged ex vivo with peptide.
CONCLUSIONS
Our findings suggest that MCC tumors often develop despite the presence of T cells specific for MCPyV T-Ag oncoproteins. The identified epitopes may be candidates for peptide-specific vaccines and tumor- or virus-specific adoptive immunotherapies to overcome immune evasion mechanisms in MCC patients.
doi:10.1158/1078-0432.CCR-11-1513
PMCID: PMC3207011  PMID: 21908576
18.  Correction: Diagnostic Biopsy Does Not Commonly Induce Intratumoral CD8 T Cell Infiltration in Merkel Cell Carcinoma 
PLoS ONE  2012;7(10):10.1371/annotation/c4df91b0-618f-464d-a613-d99758de3f3d.
doi:10.1371/annotation/c4df91b0-618f-464d-a613-d99758de3f3d
PMCID: PMC3525679
19.  Diagnostic Biopsy Does Not Commonly Induce Intratumoral CD8 T Cell Infiltration in Merkel Cell Carcinoma 
PLoS ONE  2012;7(7):e41465.
Background
Merkel cell carcinoma is a polyomavirus-associated cancer that is strongly linked with T lymphocyte immune suppression in epidemiologic studies. CD8+ T cell infiltration into MCC tumors (intratumoral) has recently been shown to be strongly predictive of improved survival. In contrast, the presence of CD8+ T cells at the border of the tumor (peritumoral) had no independent prognostic value. Spontaneous regression has been reported for MCC approximately one thousand times more often than would be expected given the frequency of this cancer. Many of these events began shortly after biopsy, and in some cases lymphocytic infiltration was described.
Methodology/Principal Findings
To determine whether CD8+ lymphocyte infiltration in MCC tumors is commonly altered by biopsy.33 MCC patients who had microscopic confirmation of MCC on both an initial biopsy and a re-excision specimen were included in this study. Intratumoral and peritumoral CD8 lymphocyte infiltration was quantitated using immunohistochemistry and compared using the paired t-test in biopsy versus re-excision samples. There was a trend toward increased CD8 infiltration after biopsy in a peritumoral (‘stalled’) pattern (p = 0.08), however, biopsy was not associated with a significant increase in CD8 T cells in the clinically more important intratumoral location (p = 0.58).
Conclusions/Significance
The initial diagnostic biopsy for MCC does not commonly alter intratumoral CD8+ T cell infiltration, suggesting it does not directly induce immunologic recognition of this cancer. Because CD8 infiltration is typically stable after biopsy, this parameter may be useful to assess the efficacy of future immune therapies for this virus-associated, immunogenic, often-lethal cancer.
doi:10.1371/journal.pone.0041465
PMCID: PMC3409202  PMID: 22859987
20.  Asymmetric lateral distribution of melanoma and Merkel cell carcinoma in the United States 
Background
A recent report suggested a trend towards more UV-linked skin cancers arising on the left rather than the right side of the body in the United States.
Objective
To test whether the reported incidences of two UV-linked skin cancers, malignant melanoma (MM) and Merkel cell carcinoma (MCC), are greater on the left than the right in the US.
Methods
MMs (n = 82,587) and MCCs (n = 2,384) occurring on the left or right side of the face, arm or leg that were reported in the SE*ER registry between 1986–2006 were included for analysis.
Results
MM and MCC were significantly more likely to present on the left than the right (p < 0.01 for both MM and MCC). 53% of arm melanomas, 51% of facial melanomas, and 52% of leg melanomas presented on the left. 55% of arm MCCs, and 52% of facial MCCs presented on the left, while leg MCCs were equally distributed.
Limitations
National registry data did not provide information regarding sun exposure or driving habits. No equivalent registry data were available for basal or squamous cell carcinoma.
Conclusions
Both melanoma and MCC are significantly more likely to arise on the left than the right, and this effect was most prominent on the arm. Driver’s-side automobile UV exposure (approximately 20-fold stronger on the left than right arm) is a likely contributing factor. It may be prudent to remind skin cancer-prone individuals to take appropriate sun precautions when driving in an automobile.
doi:10.1016/j.jaad.2010.05.026
PMCID: PMC3117975  PMID: 21514002
Merkel cell carcinoma; melanoma; ultraviolet; asymmetric; presentation; automobile
21.  Caffeine decreases phospho-Chk1 (Ser317) and increases mitotic cells with cyclin B1 and caspase 3 in tumors from UVB treated mice 
Oral administration of caffeine to mice inhibits UVB-induced carcinogenesis, and these results are paralleled by epidemiology studies indicating that caffeinated coffee and tea intake (but not decaffeinated beverage intake) is associated with decreased incidence of nonmelanoma skin cancer. Topical applications of caffeine to the skin of SKH-1 mice that had previously been treated with UVB inhibited subsequent skin tumor development and stimulated apoptosis in tumors but not in non-tumor areas of the epidermis. The present study sought to determine the basis of these differential effects on tumor vs non-tumor sites that can be induced by caffeine long after all UVB treatment has ceased. The activation status of the ATR/Chk1 pathway in UVB-induced tumors and uninvolved skin was determined by quantitating phospho-Chk1 (Ser317) and induction of lethal mitosis in vivo in the presence and absence of topical caffeine treatment. In the absence of caffeine, we found that UVB-induced tumors often had islands of phospho-Chk1 (Ser317) staining cells that were not present in non-tumor areas of the epidermis. Treatment of mice with topical caffeine significantly diminished phospho-Chk1 (Ser317) staining and increased the number of mitotic cells that expressed cyclin B1 and caspase 3 in tumors, consistent with caffeine-induced lethal mitosis selectively in tumors. We hypothesize that compared to adjacent uninvolved skin, UVB-induced skin tumors have elevated activation of, and dependence on, the ATR/Chk1 pathway long after UVB exposure has ceased and that caffeine can induce apoptosis selectively in tumors by inhibiting this pathway and promoting lethal mitosis.
doi:10.1158/1940-6207.CAPR-11-0116
PMCID: PMC3353410  PMID: 21505179
sunlight-induced skin cancer; cancer chemoprevention; enhanced lethal mitosis
22.  Transcriptome-Wide Studies of Merkel Cell Carcinoma and Validation of Intratumoral CD8+ Lymphocyte Invasion As an Independent Predictor of Survival 
Journal of Clinical Oncology  2011;29(12):1539-1546.
Purpose
Merkel cell carcinoma (MCC) is a polyomavirus-associated skin cancer that is frequently lethal and lacks established prognostic biomarkers. This study sought to identify biomarkers that improve prognostic accuracy and provide insight into MCC biology.
Patients and Methods
Gene expression profiles of 35 MCC tumors were clustered based on prognosis. The cluster of genes overexpressed in good-prognosis tumors was tested for biologic process enrichment. Relevant mRNA expression differences were confirmed by quantitative polymerase chain reaction and immunohistochemistry. An independent set of 146 nonoverlapping MCC tumors (median follow-up, 25 months among 116 living patients) was employed for biomarker validation. Univariate and multivariate Cox regression analyses were performed.
Results
Immune response gene signatures were prominent in patients with good prognoses. In particular, genes associated with cytotoxic CD8+ lymphocytes were overexpressed in tumors from patients with favorable prognoses. In the independent validation set, cases with robust intratumoral CD8+ lymphocyte infiltration had improved outcomes (100% MCC-specific survival, n = 26) compared with instances characterized by sparse infiltration (60% survival, n = 120). Only stage and intratumoral CD8 infiltration (but not age, sex, or CD8+ lymphocytes localized to the tumor-stroma interface) were significant in both univariate and multivariate Cox regression analyses. Notably, traditional histologic identification of tumor-infiltrating lymphocytes was not a significant independent predictor of survival.
Conclusion
Intratumoral CD8+ lymphocyte infiltration can be readily assessed on paraffin-embedded tissue, is independently associated with improved MCC-specific survival, and therefore, may provide prognostic information that enhances established MCC staging protocols.
doi:10.1200/JCO.2010.30.6308
PMCID: PMC3082974  PMID: 21422430
23.  Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: Analysis of 5,823 cases as the basis of the first consensus staging system for this cancer 
Background
The management of Merkel cell carcinoma (MCC) has been complicated by a lack of detailed prognostic data and by the presence of conflicting staging systems.
Objective
To determine the prognostic significance of tumor size, clinical vs pathologic nodal evaluation, and extent of disease at presentation and thereby derive the first consensus staging/prognostic system for MCC.
Methods
5,823 prospectively enrolled MCC cases from the National Cancer Data Base (NCDB) had follow-up data (median 64 months) and were used for prognostic analyses.
Results
At 5 years, overall survival was 40% and relative survival (compared to age- and sex-matched population data) was 54%. Among all MCC cases, 66% presented with local, 27% with nodal and 7% with distant metastatic disease. For cases presenting with local disease only, smaller tumor size was associated with better survival (stage I: ≤2cm: 66% relative survival at five years; stage II: >2cm: 51%; p<0.0001). Patients with clinically local-only disease and pathologically proven negative nodes had better outcome (76% at five years) than those who only underwent clinical nodal evaluation (59%, p<0.0001).
Limitations
The NCDB does not capture disease-specific survival. Overall survival for MCC patients was therefore used to calculate relative survival based on matched population data.
Conclusion
Although the majority (68%) of MCC patients in this nationwide cohort did not undergo pathologic nodal evaluation, this procedure may be indicated in many cases as it improves prognostic accuracy and has important treatment implications for those found to have microscopic nodal involvement.
doi:10.1016/j.jaad.2010.02.056
PMCID: PMC2956767  PMID: 20646783
Merkel cell carcinoma; neuroendocrine carcinoma of the skin; staging; prognosis; sentinel lymph node biopsy; clinical staging; pathologic staging
24.  Antibodies to Merkel cell polyomavirus T-antigen oncoproteins reflect tumor burden in Merkel cell carcinoma patients 
Cancer research  2010;70(21):8388-8397.
Merkel cell polyomavirus (MCPyV) is a common infectious agent that is likely involved in the etiology of most Merkel cell carcinomas (MCCs). Serum antibodies recognizing the MCPyV capsid protein, VP1, are detectable at high titer in nearly all MCC patients, and remain stable over time. Although antibodies to the viral capsid indicate prior MCPyV infection, they provide limited clinical insight into MCC because they are also detected in more than half of the general population. We investigated whether antibodies recognizing MCPyV large and small tumor-associated antigens (T-Ags) would be more specifically associated with MCC. Among 530 population control subjects, these antibodies were present in only 0.9% and were of low titer. In contrast, among 205 MCC cases, 40.5% had serum IgG antibodies that recognize a portion of T-Ag shared between small and large T-Ags. Among cases, titers of T-Ag antibodies fell rapidly (approximately 8 fold/year) in patients whose cancer did not recur, while they rose rapidly in those with progressive disease. Importantly, in several patients who developed metastases, the rise in T-Ag titer preceded clinical detection of disease spread. These results suggest that antibodies recognizing T-Ag are relatively specifically associated with MCC, do not effectively protect against disease progression, and may serve as a clinically useful indicator of disease status.
doi:10.1158/0008-5472.CAN-10-2128
PMCID: PMC2970647  PMID: 20959478
Merkel cell carcinoma; Merkel cell polyomavirus; MCPyV; antibody; biomarker
25.  Merkel cell carcinoma associated with HIV: review of 14 patients 
AIDS (London, England)  2011;25(1):119-121.
doi:10.1097/QAD.0b013e328340a19c
PMCID: PMC3191109  PMID: 21119325

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