RESUMO
Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I-low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of several class I antigen presentation genes. To systematically identify regulators of HLA-I loss in MCC, we performed parallel, genome-scale, gain- and loss-of-function screens in a patient-derived MCPyV-positive cell line and identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. We observed physical interaction of MYCL with the MCPyV small T viral antigen, supporting a mechanism of virally mediated HLA-I suppression. We further identify the PRC1.1 component USP7 as a pharmacologic target to restore HLA-I expression in MCC.
Assuntos
Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Neoplasias Cutâneas , Antígenos Virais de Tumores/genética , Antígenos Virais de Tumores/metabolismo , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/patologia , Epigênese Genética , Humanos , Poliomavírus das Células de Merkel/genética , Poliomavírus das Células de Merkel/metabolismo , Infecções por Polyomavirus/genética , Neoplasias Cutâneas/patologia , Peptidase 7 Específica de Ubiquitina/metabolismoRESUMO
BACKGROUND: Risk stratification for patients undergoing hepatectomy can be attempted using established models. This study compares the platelet-albumin-bilirubin (PALBI) score with albumin-bilirubin (ALBI) and model for end-stage liver disease sodium (MELD-Na) for predicting posthepatectomy liver failure (PHLF) and 30-day mortality. METHODS: The 2014-2018 NSQIP database was queried for patients who underwent elective hepatectomy. Multivariable logistic regressions assessed associations of posthepatectomy outcomes with patient and clinical characteristics. Predictive accuracy of the grading systems was evaluated using receiver operator characteristic (ROC) curves and calculating area under the curve (AUC). RESULTS: Severe PHLF (Grade B/C) and mortality were present in 2.58% (N = 369) and 1.2% (N = 171) of patients who underwent hepatectomy (N = 13 925), respectively. ALBI Grade 2/3 had a stronger association with severe PHLF (odds ratio [OR] = 1.62, p < 0.01) and mortality (OR = 2.06, p < 0.005) than PALBI Grade 2/3 (OR = 1.14, p = 0.43 for PHLF and OR = 2.01, p < 0.005 for mortality) or MELD-Na ≥10 (OR = 1.29, p = 0.25 for PHLF and OR = 1.84, p < 0.03). ALBI had a higher AUC (0.671) than PALBI (0.625) and MELD-Na (0.627) for predicting severe PHLF. ALBI had a higher AUC (0.695) than PALBI (0.642) for predicting 30-day mortality. CONCLUSIONS: ALBI was a more accurate predictor of severe PHLF and 30-day mortality than MELD-Na and PALBI for patients who underwent hepatectomy.