Format

Send to

Choose Destination
Cancer Immunol Res. 2014 Nov;2(11):1071-9. doi: 10.1158/2326-6066.CIR-14-0005. Epub 2014 Aug 12.

Downregulation of MHC-I expression is prevalent but reversible in Merkel cell carcinoma.

Author information

1
Department of Medicine, Division of Dermatology, University of Washington, Seattle, Washington.
2
Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.
3
Department of Dermatology, University Hospital Würzburg, Würzburg, Germany. Department of Dermatology, Medical University of Graz, Graz, Austria.
4
Department of Pathology, University of Washington, Seattle, Washington. Department of Laboratory Medicine, University of Washington, Seattle, Washington.
5
Department of Laboratory Medicine, University of Washington, Seattle, Washington. Department of Medicine, Division of Infectious Disease, University of Washington, Seattle, Washington. Department of Global Health, University of Washington, Seattle, Washington. Fred Hutchinson Cancer Research Center, Seattle, Washington.
6
Fred Hutchinson Cancer Research Center, Seattle, Washington.
7
Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, Washington.
8
Department of Dermatology, Kochi Medical School, Kochi University, Kochi, Japan.
9
Merck and Co. Inc., West Point, Pennsylvania.
10
Department of Dermatology, Medical University of Graz, Graz, Austria. Department for Translational Dermato-Oncology (DKTK), University Hospital Essen, Essen, Germany.
11
Department of Medicine, Division of Dermatology, University of Washington, Seattle, Washington. Department of Pathology, University of Washington, Seattle, Washington. Fred Hutchinson Cancer Research Center, Seattle, Washington. pnghiem@uw.edu.

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.

PMID:
25116754
PMCID:
PMC4221542
DOI:
10.1158/2326-6066.CIR-14-0005
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center