CEACAM1-3S Drives Melanoma Cells into NK Cell-Mediated Cytolysis and Enhances Patient Survival.
CEACAM1 is a widely expressed multifunctional cell-cell adhesion protein reported to serve as a poor prognosis marker in melanoma patients. In this study, we examine the functional and clinical contributions of the four splice isoforms of CEACAM1. Specifically, we present in vitro and in vivo evidence that they affect melanoma progression and immune surveillance in a negative or positive manner that is isoform specific in action. In contrast with isoforms CEACAM1-4S and CEACAM1-4L, expression of isoforms CEACAM1-3S and CEACAM1-3L is induced during disease progression shown to correlate with clinical stage. Unexpectedly, overall survival was prolonged in patients with advanced melanomas expressing CEACAM1-3S. The favorable effects of CEACAM1-3S related to enhanced immunogenicity, which was mediated by cell surface upregulation of NKG2D receptor ligands, thereby sensitizing melanoma cells to lysis by natural killer cells. Conversely, CEACAM1-4L downregulated cell surface levels of the NKG2D ligands MICA and ULBP2 by enhanced shedding, thereby promoting malignant character. Overall, our results define the splice isoform-specific immunomodulatory and cell biologic functions of CEACAM1 in melanoma pathogenesis.
Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany.
Nico
N
Ullrich
Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany.
Anja
A
Heinemann
Institute of Anatomy, University Hospital, University Duisburg-Essen, Essen, Germany.
Elena
E
Nilewski
Institute for Gastroenterology and Hepatology, Medical Faculty, University Duisburg-Essen, Essen, Germany.
Inka
I
Scheffrahn
Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany.
Joachim
J
Klode
Clinical Epidemiology, Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
André
A
Scherag
Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany.
Dirk
D
Schadendorf
Institute of Anatomy, University Hospital, University Duisburg-Essen, Essen, Germany. iris.helfrich@uk-essen.de bernhard.singer@uk-essen.de.
Bernhard B
BB
Singer
Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany. iris.helfrich@uk-essen.de bernhard.singer@uk-essen.de.
Iris
I
Helfrich
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D018450:Disease Progression; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000401:mortality*; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology; D020033:Protein Isoforms; D014162:Transfection; D015854:Up-Regulation / Q000276:immunology
D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D020033:Protein Isoforms; C423230:ULBP2 protein, human