Year: 2014
Type: article
Abstract: Merkel cell carcinoma (MCC) is an aggressive, polyomavirus-associated skin cancer. Robust cellular immune responses are associated with excellent outcomes in patients with MCC, but these responses are typically absent. We determined the prevalence and reversibility of major histocompatibility complex class I (MHC-I) downregulation in MCC, a potentially reversible immune-evasion mechanism. Cell-surface MHC-I expression was assessed on five MCC cell lines using flow cytometry as well as immunohistochemistry on tissue microarrays representing 114 patients. Three additional patients were included who had received intralesional IFN treatment and had evaluable specimens before and after treatment. mRNA expression analysis of antigen presentation pathway genes from 35 MCC tumors was used to examine the mechanisms of downregulation. Of note, 84% of MCCs (total n = 114) showed reduced MHC-I expression as compared with surrounding tissues, and 51% had poor or undetectable MHC-I expression. Expression of MHC-I was lower in polyomavirus-positive MCCs than in polyomavirus-negative MCCs (P < 0.01). The MHC-I downregulation mechanism was multifactorial and did not depend solely on HLA gene expression. Treatment of MCC cell lines with ionizing radiation, etoposide, or IFN resulted in MHC-I upregulation, with IFNs strongly upregulating MHC-I expression in vitro, and in 3 of 3 patients treated with intralesional IFNs. MCC tumors may be amenable to immunotherapy, but downregulation of MHC-I is frequently present in these tumors, particularly those that are positive for polyomavirus. This downregulation is reversible with any of several clinically available treatments that may thus promote the effectiveness of immune-stimulating therapies for MCC.
Source: Cancer Immunology Research
Authors: Kelly G. Paulson, Andrew Tegeder, Christoph Willmes, Jayasri G. Iyer, Olga K. Afanasiev, David Schrama, Shinichi Koba, Renee Thibodeau, Kotaro Nagase, William T. Simonson, Aaron Seo, David M. Koelle, Margaret Madeleine, Shailender Bhatia, Hideki Nakajima, Shigetoshi Sano, James S. Hardwick, Mary L. Disis, Michele A. Cleary, Jürgen C. Becker, Paul Nghiem
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences, National Center for Research Resources, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1182743350, G1288141453, G1389856746, Pathogenetics of Merkel cell cancer: a disease linked to UV damage & a new virus, G1705396944, Institute of Translational Health Sciences, G2771302539, Targeting MCPyV to Overcome Immune Evasion in Merkel Cell Carcinoma, Humoral and cellular immunity in polyomavirus-linked Merkel cell carcinoma, Institute of Translational Health Sciences, Pathogenetic and prognostic studies for improved therapy of Merkel cell carcinoma, Viral oncoprotein targeted immune therapy for Merkel cell carcinoma, G6150049968, G616001722, G75133467, G863835797, Cancer Center Support Grant, Interdisciplinary Training in Cancer Research
OpenAlex ID: W2041546512