title: Broad and Conserved Immune Regulation by Genetically Heterogeneous Melanoma Cells.
abstract: Although mutations drive cancer, it is less clear to what extent genetic defects control immune mechanisms and confer resistance to T-cell-based immunotherapy. Here, we studied the reactions of malignant and benign melanocyte lines to cytotoxic CD8+T cells (CTL) using flow cytometry and gene expression analyses. We found rapid and broad upregulation of immune-regulatory genes, essentially triggered by CTL-derived IFNγ and augmented by TNFα. These reactions were predominantly homogenous, independent of oncogenic driver mutations, and similar in benign and malignant cells. The reactions exhibited both pro- and antitumorigenic potential and primarily corresponded to mechanisms that were conserved, rather than acquired, by mutations. Similar results were obtained from directex vivoanalysis of the tumor microenvironment. Thus, immune regulation in the tumor landscape may often be driven by conserved mechanisms, which may explain why T-cell-based immunotherapy can provide durable benefits with relatively infrequent escape.Cancer Res; 77(7); 1623-36. ©2017 AACR.
authors.affiliation: Ludwig Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Neubert
authors.affiliation: Ludwig Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Laure
authors.initials: L
authors.lastname: Tillé
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Barras
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Soneson
authors.affiliation: Ludwig Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Baumgaertner
authors.affiliation: Ludwig Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Donata
authors.initials: D
authors.lastname: Rimoldi
authors.affiliation: Ludwig Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland.|SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Gfeller
authors.affiliation: Ludwig Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland.|SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: Ludwig Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Silvia A
authors.initials: SA
authors.lastname: Fuertes Marraco
authors.affiliation: Ludwig Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland. doc@dspeiser.ch.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
mesh_terms: D045744:Cell Line, Tumor; D020558:GTP Phosphohydrolases / Q000235:genetics; D018740:Genetic Heterogeneity; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000494:pharmacology; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology* / Q000628:therapy; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019139:Tumor Escape; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human