MHC class-I downregulation in PD-1/PD-L1 inhibitor refractory Merkel cell carcinoma and its potential reversal by histone deacetylase inhibition: a case series

We report four cases of patients with metastatic MCC who did not respond to immunotherapy by PD-1/PD-L1 blockade. Two of the patients received, subsequently, the HDACi panobinostat in combination with PD-1/PD-L1 blockade. Tumor biopsies of the patients were analyzed for cellular and molecular markers of antigen processing and presentation as well as the degree of T-cell infiltration.Results and conclusionLow expression of APM-related genes associated with low HLA class-I surface expression was observed in all MCC patients, progressing on PD-1/PD-L1 blockade. In one evaluable patient, of the two treated with the combination therapy of the HDACi, panobinostat and PD-1/PD-L1 blockade, reintroduction of HLA class-I-related genes, enhanced HLA class-I surface expression, and elevated CD8+ T-cell infiltration into the MCC tumor tissue were observed; however, these changes did not translate into a clinical benefit. Our findings suggest that HDACi may be useful to overcome HLA class-I downregulation as a resistance mechanism against anti-PD-1/PD-L1 antibodies in MCC patients. Prospective clinical trials are needed to evaluate this notion.
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research

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Second primary cancers (SPCs) are becoming a common cancer entity, which may interfere with survival in relatively benign first primary cancers. We wanted to examine the hypothesis that immune dysfunction may contribute to SPCs by assessing SPCs associated with known immune responsive skin cancers, invasive and in situ squamous cell carcinoma (SCC), Kaposi sarcoma (KS) and Merkel cell carcinoma (MCC). Cancers were identified from the Swedish Cancer Registry from the years 1958 through to 2015. Standardized relative risks (RRs) were calculated bi-directionally for any SPC after skin cancer and for skin cancer as SPC.
Source: Journal of Investigative Dermatology - Category: Dermatology Authors: Tags: Original Article Source Type: research
As a general principle, a key indicator of the prognosis of a given primary malignant tumor is its size. Simply put, at the time of cancer diagnosis, it is better to have a small tumor than a large one. The tenet that size matters applies not only to malignant tumors developing in parenchymal organs but also cutaneous cancers. The metastatic potential of squamous cell carcinoma, the second most common cutaneous malignant condition, is highly or directly correlated with tumor size. At sizes smaller than a certain threshold, typically in the range of 2 mm, the risk of secondary spread is negligible. By contrast, metastases a...
Source: JAMA Dermatology - Category: Dermatology Source Type: research
ConclusionsThe guidelines presented here answer clinical questions that arise in routine practice. They can provide dermatologists with a starting point for decision-making, although available resources and patient preferences must always be borne in mind.ResumenAntecedentes y objetivoEl carcinoma de células de Merkel es un tipo de cáncer de piel infrecuente y agresivo. Hay una gran variación en su manejo y las diferentes guías extranjeras que existen cubren parcialmente los problemas identificados como principales. El objetivo de la presente guía es servir de referencia a los dermat&oacu...
Source: Actas Dermo-Sifiliograficas - Category: Dermatology Source Type: research
Conclusions: This supports that KA and MCPyV are not related to each other and MCVyP is not a major factor in the pathogenesis of KA. PMID: 31127879 [PubMed - in process]
Source: Asian Pacific Journal of Cancer Prevention - Category: Cancer & Oncology Tags: Asian Pac J Cancer Prev Source Type: research
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer. Most MCC are virus positive (VP-MCC) and express Merkel cell polyomavirus oncogenes, whereas virus negative MCC (VN-MCC) are associated with abundant UV signature mutations. MCC has characteristic features that differentiate it from other neuroendocrine carcinomas, such as expressing Cytokeratin 20 (CK20). Staining of CK20 and other cytokeratins as a paranuclear dot is highly suggestive of MCC. This aggregation of intermediate filament proteins adjacent to the nucleus has been described as displaying a “Golgi pattern”, but little h...
Source: Journal of Investigative Dermatology - Category: Dermatology Authors: Tags: Carcinogenesis and Cancer Genetics Source Type: research
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer that frequently carries integrated Merkel cell polyomavirus (MCPyV) and expresses viral transforming antigens (TAgs) implicated in tumorigenesis. MCC tumor cells express a complement of signature genes detected in normal, post-mitotic Merkel cells (MCs), including keratins K20 and K8, along with a network of transcription factors governing neuroendocrine cell fate, such as Atoh1. While previous studies showed that MCPyV TAgs drive transformation in vivo, these models have not yet yielded MCC tumors.
Source: Journal of Investigative Dermatology - Category: Dermatology Authors: Tags: Carcinogenesis and Cancer Genetics Source Type: research
Merkel cell carcinoma (MCC) is a rare, but highly malignant skin cancer. Despite its high malignancy, however, a good prognosis, including spontaneous regression, has been reported in some sporadic cases since the first report by O ’Rourke and Bell in 1986. T-cell-mediated immunity is suggested to play an important role in tumor regression, and the expression of programmed death-ligand 1 (PD-L1) in cancer cells correlates with better clinical outcomes in MCC, in contrast to other solid carcinomas, such as malignant melanoma.
Source: Journal of Investigative Dermatology - Category: Dermatology Authors: Tags: Carcinogenesis and Cancer Genetics Source Type: research
Human Polyomaviruses (HPyVs) frequently cause asymptomatic infections in healthy individuals. In rare cases, the Merkel Cell Polyomavirus (MCPyV) contributes to the development of a rare but deadly skin cancer, Merkel Cell Carcinoma (MCC). Why MCPyV promotes tumorigensis while other cutaneous polyomaviruses, like HPyV6 and HPyV7, do not, remains unclear. Here, we describe the functional differences between the small T antigens (ST) of these three cutaneous polyomaviruses. Lentiviral expression of the HPyV6, HPyV7 and MCPyV small T antigens in primary dermal fibroblasts revealed that both HPyV6 and HPyV7 ST induce cellular ...
Source: Journal of Investigative Dermatology - Category: Dermatology Authors: Tags: Innate Immunity, Microbiology, and Microbiome Source Type: research
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Conventional post-operative radiotherapy (cPORT), given in 25-30 fractions (2Gy per fraction) over 5-6 weeks, is associated with improved locoregional control but also with skin toxicity, fibrosis, and wound healing issues. We hypothesized that 1-3 fractions of 8Gy hypofractionated PORT (hPORT), may provide adequate control in the majority of patients with significantly diminished toxicity and a less extensive treatment regimen. 17 patients with locoregional MCC were identified from our prospective registry that received hPORT after an informed discussion th...
Source: Journal of Investigative Dermatology - Category: Dermatology Authors: Tags: Interventional Studies, Clinical and Patient Outcomes Research Source Type: research
Merkel cell carcinoma (MCC) is a rare skin cancer with a ∼40% recurrence rate. The Merkel cell polyomavirus (MCPyV) drives 80% of cases, while 20% are caused by UV-induced mutations. About half of MCC patients produce antibodies to MCPyV oncoproteins. If patients are sero-positive at diagnosis, they can be tracked with a clinical grade MCPyV antibody te st to detect recurrences (titer rises if disease recurs, falls if not). This test is also useful for sero-negative patients since their recurrence risk is 42% higher and they benefit from close surveillance with imaging.
Source: Journal of Investigative Dermatology - Category: Dermatology Authors: Tags: Interventional Studies, Clinical and Patient Outcomes Research Source Type: research
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