title: Distinctive Histogenesis and Immunological Microenvironment Based on Transcriptional Profiles of Follicular Dendritic Cell Sarcomas.
abstract: Follicular dendritic cell (FDC) sarcomas are rare mesenchymal tumors with variable clinical, morphologic, and phenotypic characteristics. Transcriptome analysis was performed on multiple FDC sarcomas and compared with other mesenchymal tumors, microdissected Castleman FDCs, and normal fibroblasts. Using unsupervised analysis, FDC sarcomas clustered with microdissected FDCs, distinct from other mesenchymal tumors and fibroblasts. The specific endowment of FDC-related gene expression programs in FDC sarcomas emerged by applying a gene signature of differentially expressed genes (n= 1,289) between microdissected FDCs and fibroblasts. Supervised analysis comparing FDC sarcomas with microdissected FDCs and other mesenchymal tumors identified 370 and 2,927 differentially expressed transcripts, respectively, and on the basis of pathway enrichment analysis ascribed to signal transduction, chromatin organization, and extracellular matrix organization programs. As the transcriptome of FDC sarcomas retained similarity with FDCs, the immune landscape of FDC sarcoma was investigated by applying the CIBERSORT algorithm to FDC sarcomas and non-FDC mesenchymal tumors and demonstrated that FDC sarcomas were enriched in T follicular helper (TFH) and T regulatory (TREG) cell populations, as confirmedin situby immunohistochemistry. The enrichment in specific T-cell subsets prompted investigating the mRNA expression of the inhibitory immune receptor PD-1 and its ligands PD-L1 and PD-L2, which were found to be significantly upregulated in FDC sarcomas as compared with other mesenchymal tumors, a finding also confirmedin situHere, it is demonstrated for the first time the transcriptional relationship of FDC sarcomas with nonmalignant FDCs and their distinction from other mesenchymal tumors.Implications:The current study provides evidence of a peculiar immune microenvironment associated with FDC sarcomas that may have clinical utility.Mol Cancer Res; 15(5); 541-52. ©2017 AACR.
authors.affiliation: Haematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Maria Antonella
authors.initials: MA
authors.lastname: Laginestra
authors.affiliation: Tumour Immunology Unit, Department of Health Science, Human Pathology Section University of Palermo School of Medicine, Palermo, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Tripodo
authors.affiliation: Haematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Agostinelli
authors.affiliation: Unit of Diagnostic Haematopathology, European Institute of Oncology, Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Motta
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Hartmann
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Döring
authors.affiliation: Haematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Unit of Diagnostic Haematopathology, European Institute of Oncology, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Melle
authors.affiliation: Haematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Sapienza
authors.affiliation: Unit of Diagnostic Haematopathology, European Institute of Oncology, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Tabanelli
authors.affiliation: Dermatology Unit, Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pileri
authors.affiliation: Genetics and Genome Biology Paediatric Laboratory Medicine (PLM). The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Fabio
authors.initials: F
authors.lastname: Fuligni
authors.affiliation: Haematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Gazzola
authors.affiliation: Haematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mannu
authors.affiliation: Haematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Sagramoso
authors.affiliation: Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lonardi
authors.affiliation: Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Lorenzi
authors.affiliation: Haematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bacci
authors.affiliation: Haematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Sabattini
authors.affiliation: Histopathology, SRL Diagnostics, Mumbai, India.
authors.forename: Anita
authors.initials: A
authors.lastname: Borges
authors.affiliation: Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Simonitsch-Klupp
authors.affiliation: Department of Pathology, Portuguese Institute of Oncology, Lisbon, Portugal.
authors.forename: Jose
authors.initials: J
authors.lastname: Cabecadas
authors.affiliation: Hematopathology Section, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.affiliation: Centro Diagnostico Italiano, Milano, Italy.
authors.forename: Juan
authors.initials: J
authors.lastname: Rosai
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany.
authors.forename: Martin-Leo
authors.initials: ML
authors.lastname: Hansmann
authors.affiliation: Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.affiliation: Unit of Diagnostic Haematopathology, European Institute of Oncology, Milan, Italy. stefano.pileri@ieo.it/stefano.pileri@unibo.it.|Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: Stefano Aldo
authors.initials: SA
authors.lastname: Pileri
mesh_terms: D000465:Algorithms; D060890:B7-H1 Antigen / Q000235:genetics; D005871:Castleman Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002843:Chromatin / Q000235:genetics / Q000473:pathology; D016000:Cluster Analysis; D054740:Dendritic Cell Sarcoma, Follicular / Q000235:genetics / Q000276:immunology*; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D002843:Chromatin; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor