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RESEARCH PRODUCT

Distinctive Histogenesis and Immunological Microenvironment Based on Transcriptional Profiles of Follicular Dendritic Cell Sarcomas

Luisa LorenziSilvia LonardiElena SabattiniStefano PileriStefano PileriClaudio AgostinelliMaria Antonella LaginestraAnna GazzolaCarlo SagramosoValentina TabanelliFederica MelleFabio FuligniFrancesco BacciJosé CabeçadasFabio FacchettiAlessandro PileriClaudio TripodoClaudia DöringSylvia HartmannMaura RossiAnita BorgesJuan RosaiGiovanna MottaIngrid Simonitsch-kluppMaria Rosaria SapienzaMartin-leo HansmannElias CampoClaudia Mannu

subject

0301 basic medicineAlgorithms; B7-H1 Antigen; Castleman Disease; Chromatin; Cluster Analysis; Dendritic Cell Sarcoma Follicular; Gene Expression Profiling; Gene Expression Regulation Neoplastic; Humans; Programmed Cell Death 1 Ligand 2 Protein; Programmed Cell Death 1 Receptor; Signal Transduction; T-Lymphocytes Helper-Inducer; T-Lymphocytes Regulatory; Up-Regulation; Gene Regulatory Networks; Molecular Biology; Oncology; Cancer ResearchCancer ResearchProgrammed Cell Death 1 ReceptorDendritic Cell Sarcoma FollicularBiologyT-Lymphocytes RegulatoryB7-H1 AntigenTranscriptome03 medical and health sciencesmedicineCluster AnalysisHumansGene Regulatory NetworksMolecular BiologyRegulation of gene expressionCluster AnalysiGene Regulatory NetworkFollicular dendritic cellsCastleman DiseaseGene Expression ProfilingMesenchymal stem cellT-Lymphocytes Helper-InducerProgrammed Cell Death 1 Ligand 2 Proteinmedicine.diseaseChromatinUp-RegulationAlgorithmGene Expression Regulation NeoplasticGene expression profiling030104 developmental biologyOncologyCancer researchImmunohistochemistrySarcomaAlgorithmsHumanSignal TransductionExtracellular matrix organization

description

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 confirmed in situ by 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 confirmed in situ. Here, 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.

yearjournalcountryeditionlanguage
2017-01-01Molecular Cancer Research
https://doi.org/10.1158/1541-7786.mcr-16-0301