title: A morphological and immunophenotypic map of the immune response in Merkel cell carcinoma.
abstract: The susceptibility of Merkel cell carcinoma to the host immune response has prompted a search for effective immunotherapy. CD8-positive T lymphocytes are considered key effectors of this response, but the cellular infiltrates also harbor tumor-protective agents. By developing a comprehensive morphological and immunophenotypic map of tumor-infiltrating lymphocytes (TILS) in Merkel cell carcinoma, we aimed to establish a useful template for future studies. Twenty-two cases (mean age, 79years [range, 52-95]; male-female ratio, 10:12) were studied. TILS were categorized as brisk (7), nonbrisk (9), and absent(6). Merkel cell polyomavirus (MCPyV)-positive (16) and -negative (6) cases were included, as were those with pure (18) and combined (4) morphologies. One MCPyV+ case had undergone spontaneous regression. Immunohistochemical markers included CD3, CD4, CD8, CD20, CD68, FoxP3, PD-1, and CD123. Statistical analysis used Fisher exact tests and Spearman correlations. There was a significant correlation between brisk TILs and MCPyV+ status (P=.025). CD8+ T lymphocytes predominated, were present in significantly higher proportions in brisk infiltrates (P=.003), and showed a significant predilection for the intratumoral environment (P=.003). Immune inhibitors including T regulatory cells (FOXP3+) and PD-1+ "exhausted" immunocytes were present in lower proportions. Our findings support (1) the link between a brisk immune response and MCPyV positivity, (2) the supremacy of CD8+ cells in effecting immunity, and (3) the incorporation of immune inhibitors within the global infiltrate. Efforts to therapeutically arm the "effectors" and disarm the "detractors" are well focused. These will likely have the greatest impact on MCPyV-positive cases.
authors.affiliation: Department of Pathology, Queen Elizabeth II Health Sciences Center, Nova Scotia Health Authority (Central Zone), Halifax, Nova Scotia, B3H 1V8, Canada; Dalhousie University, Halifax, Nova Scotia, B3H 1V8, Canada; Department of Medicine, Queen Elizabeth II Health Sciences Center, Nova Scotia Health Authority (Central Zone), Halifax, Nova Scotia, B3H 1V8, Canada. Electronic address: Noreen.walsh@nshealth.ca.
authors.forename: Noreen M
authors.initials: NM
authors.lastname: Walsh
authors.affiliation: Department of Pathology, Queen Elizabeth II Health Sciences Center, Nova Scotia Health Authority (Central Zone), Halifax, Nova Scotia, B3H 1V8, Canada; Dalhousie University, Halifax, Nova Scotia, B3H 1V8, Canada.
authors.forename: Kirsten E
authors.initials: KE
authors.lastname: Fleming
authors.affiliation: Department of Pathology, Queen Elizabeth II Health Sciences Center, Nova Scotia Health Authority (Central Zone), Halifax, Nova Scotia, B3H 1V8, Canada; Dalhousie University, Halifax, Nova Scotia, B3H 1V8, Canada; Department of Medicine, Queen Elizabeth II Health Sciences Center, Nova Scotia Health Authority (Central Zone), Halifax, Nova Scotia, B3H 1V8, Canada.
authors.forename: John G
authors.initials: JG
authors.lastname: Hanly
authors.affiliation: Department of Pathology, Queen Elizabeth II Health Sciences Center, Nova Scotia Health Authority (Central Zone), Halifax, Nova Scotia, B3H 1V8, Canada; Dalhousie University, Halifax, Nova Scotia, B3H 1V8, Canada.
authors.forename: Kelly
authors.initials: K
authors.lastname: Dakin Hache
authors.affiliation: Dalhousie University, Halifax, Nova Scotia, B3H 1V8, Canada; Research Methods Unit, Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, B3H 1V7, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Doucette
authors.affiliation: Anatomic Pathology Unit, Gaetano Rummo Hospital, Benevento, Italy; Research Unit Dermatopathology, Department of Dermatology, Medical University of Graz, Graz, Austria.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ferrara
authors.affiliation: Research Unit Dermatopathology, Department of Dermatology, Medical University of Graz, Graz, Austria.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cerroni
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015266:Carcinoma, Merkel Cell / Q000737:chemistry / Q000276:immunology* / Q000473:pathology / Q000821:virology; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping / Q000379:methods*; D007167:Immunotherapy / Q000379:methods; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000737:chemistry / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008297:Male; D059965:Merkel cell polyomavirus / Q000276:immunology; D008875:Middle Aged; D010641:Phenotype; D012878:Skin Neoplasms / Q000737:chemistry / Q000276:immunology* / Q000473:pathology / Q000821:virology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D019139:Tumor Escape; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor
keywords: Antitumoral immunity; Cutaneous neuroendocrine carcinoma; Merkel cell carcinoma; PD-1/PD-L1 pathway; TILS; Tumor-infiltrating lymphocytes; Tumor-specific CD8+ T cells