Laginestra Maria Antonella, Tripodo Claudio, Agostinelli Claudio, Motta Giovanna, Hartmann Sylvia, Döring Claudia, Rossi Maura, Melle Federica, Sapienza Maria Rosaria, Tabanelli Valentina, Pileri Alessandro, Fuligni Fabio, Gazzola Anna, Mannu Claudia, Sagramoso Carlo Alberto, Lonardi Silvia, Lorenzi Luisa, Bacci Francesco, Sabattini Elena, Borges Anita, Simonitsch-Klupp Ingrid, Cabecadas Jose, Campo Elias, Rosai Juan, Hansmann Martin-Leo, Facchetti Fabio, Pileri Stefano Aldo
Haematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
Tumour Immunology Unit, Department of Health Science, Human Pathology Section University of Palermo School of Medicine, Palermo, Italy.
Mol Cancer Res. 2017 May;15(5):541-552. doi: 10.1158/1541-7786.MCR-16-0301. Epub 2017 Jan 27.
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 ( = 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 (T) and T regulatory (T) cell populations, as confirmed 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 Here, it is demonstrated for the first time the transcriptional relationship of FDC sarcomas with nonmalignant FDCs and their distinction from other mesenchymal tumors. The current study provides evidence of a peculiar immune microenvironment associated with FDC sarcomas that may have clinical utility. .
滤泡树突状细胞（FDC）肉瘤是一种罕见的间充质肿瘤，具有多样的临床、形态学和表型特征。对多个FDC肉瘤进行了转录组分析，并与其他间充质肿瘤、显微切割的Castleman FDC和正常成纤维细胞进行了比较。通过无监督分析，FDC肉瘤与显微切割的FDC聚集在一起，与其他间充质肿瘤和成纤维细胞不同。通过应用显微切割的FDC与成纤维细胞之间差异表达基因（n = 1289）的基因特征，FDC肉瘤中FDC相关基因表达程序的特定禀赋得以显现。将FDC肉瘤与显微切割的FDC和其他间充质肿瘤进行的监督分析分别鉴定出370个和2927个差异表达的转录本，并基于信号转导、染色质组织和细胞外基质组织程序的通路富集分析。由于FDC肉瘤的转录组与FDC保持相似性，通过将CIBERSORT算法应用于FDC肉瘤和非FDC间充质肿瘤，研究了FDC肉瘤的免疫格局，结果表明FDC肉瘤在T滤泡辅助（TFH）细胞和T调节（Treg）细胞群体中富集，免疫组化证实了这一点。特定T细胞亚群的富集促使研究抑制性免疫受体PD-1及其配体PD-L1和PD-L2的mRNA表达，发现与其他间充质肿瘤相比，FDC肉瘤中这些基因显著上调，这一发现也得到了证实。在此首次证明了FDC肉瘤与非恶性FDC的转录关系及其与其他间充质肿瘤的区别。当前研究提供了与FDC肉瘤相关的特殊免疫微环境的证据，这可能具有临床应用价值。
