title: PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival.
abstract: Merkel cell carcinoma (MCC) is a lethal, virus-associated cancer that lacks effective therapies for advanced disease. Agents blocking the PD-1/PD-L1 pathway have demonstrated objective, durable tumor regressions in patients with advanced solid malignancies and efficacy has been linked to PD-L1 expression in the tumor microenvironment. To investigate whether MCC might be a target for PD-1/PD-L1 blockade, we examined MCC PD-L1 expression, its association with tumor-infiltrating lymphocytes (TILs), Merkel cell polyomavirus (MCPyV), and overall survival. Sixty-seven MCC specimens from 49 patients were assessed with immunohistochemistry for PD-L1 expression by tumor cells and TILs, and immune infiltrates were characterized phenotypically. Tumor cell and TIL PD-L1 expression were observed in 49% and 55% of patients, respectively. In specimens with PD-L1(+) tumor cells, 97% (28/29) demonstrated a geographic association with immune infiltrates. Among specimens with moderate-severe TIL intensities, 100% (29/29) demonstrated PD-L1 expression by tumor cells. Significant associations were also observed between the presence of MCPyV DNA, a brisk inflammatory response, and tumor cell PD-L1 expression: MCPyV(-) tumor cells were uniformly PD-L1(-). Taken together, these findings suggest that a local tumor-specific and potentially MCPyV-specific immune response drives tumor PD-L1 expression, similar to previous observations in melanoma and head and neck squamous cell carcinomas. In multivariate analyses, PD-L1(-) MCCs were independently associated with worse overall survival (hazard ratio 3.12; 95% CI, 1.28-7.61; p=0.012). These findings suggest that an endogenous immune response promotes PD-L1 expression in the MCC microenvironment when MCPyV is present, and provide a rationale for investigating therapies blocking PD-1/PD-L1 for patients with MCC.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21287.
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Lipson
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21287.
authors.forename: Jeremy G
authors.initials: JG
authors.lastname: Vincent
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21287.
authors.forename: Myriam
authors.initials: M
authors.lastname: Loyo
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21287.
authors.forename: Luciane T
authors.initials: LT
authors.lastname: Kagohara
authors.affiliation: Department of Oncology, Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21287.
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Luber
authors.affiliation: Department of Oncology, Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21287.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21287.
authors.forename: Haiying
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21287.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Nayar
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21287.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21287.
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21287.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21287.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Topalian
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21287.|Department of Dermatology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21287.
authors.forename: Janis M
authors.initials: JM
authors.lastname: Taube
mesh_terms: D000368:Aged; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015266:Carcinoma, Merkel Cell / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D059965:Merkel cell polyomavirus / Q000302:isolation & purification*; D009367:Neoplasm Staging; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D016019:Survival Analysis
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human
keywords: B7-H1; Merkel cell carcinoma; Merkel cell polyomavirus; PD-L1; immunotherapy