title: RNA fingerprints provide direct evidence for the inhibitory role of TGFbeta and PD-1 on CD4+ T cells in Hodgkin lymphoma.
abstract: A hallmark of various human malignancies is the expression of immunoinhibitory factors within the tumor microenvironment. There is indirect evidence based on in vitro experiments that tumor-infiltrating T cells in human malignancies are suppressed by such factors. Still, direct evidence of the influence of individual inhibitory factors on immune cells in human cancer in vivo is lacking. To address this question, we used Hodgkin lymphoma (HL) as a model because histopathological characteristics of HL are thought to be due mostly to the effects of a wide variety of cytokines, including TGFbeta or membrane-bound receptors such as PD-1 that are suspected to contribute to immune evasion of tumor cells. Using a genome-wide transcriptional approach, we established specific RNA fingerprints of TGFbeta and PD-1 signaling in human T cells in vitro. Applying these specific fingerprints, we directly demonstrate that CD4+ T cells in HL--but not in follicular lymphoma (FL)--are under the inhibitory influence of both TGFbeta and PD-1 in vivo. This approach can be easily generalized to provide direct evidence of the impact of any given soluble or cell-bound factor on any cell type within diseased tissue.
authors.affiliation: Molecular Tumor Biology and Tumor Immunology, Department of Internal Medicine I, University of Cologne, Kerpener Strasse 62, 50924 Cologne, Germany.
authors.forename: Jens M
authors.initials: JM
authors.lastname: Chemnitz
authors.forename: Daniela
authors.initials: D
authors.lastname: Eggle
authors.forename: Julia
authors.initials: J
authors.lastname: Driesen
authors.forename: Sabine
authors.initials: S
authors.lastname: Classen
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
authors.forename: Svenja
authors.initials: S
authors.lastname: Debey-Pascher
authors.forename: Marc
authors.initials: M
authors.lastname: Beyer
authors.forename: Alexey
authors.initials: A
authors.lastname: Popov
authors.forename: Thomas
authors.initials: T
authors.lastname: Zander
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
mesh_terms: D015703:Antigens, CD / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006689:Hodgkin Disease / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009710:Nucleotide Mapping; D020411:Oligonucleotide Array Sequence Analysis; D061026:Programmed Cell Death 1 Receptor; D012313:RNA / Q000032:analysis*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016212:Transforming Growth Factor beta; D012313:RNA