Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma.

Détails

ID Serval
serval:BIB_39EC1C431B02
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma.
Périodique
Nature medicine
Auteur(s)
Jerby-Arnon L., Neftel C., Shore M.E., Weisman H.R., Mathewson N.D., McBride M.J., Haas B., Izar B., Volorio A., Boulay G., Cironi L., Richman A.R., Broye L.C., Gurski J.M., Luo C.C., Mylvaganam R., Nguyen L., Mei S., Melms J.C., Georgescu C., Cohen O., Buendia-Buendia J.E., Segerstolpe A., Sud M., Cuoco M.S., Labes D., Gritsch S., Zollinger D.R., Ortogero N., Beechem J.M., Petur Nielsen G., Chebib I., Nguyen-Ngoc T., Montemurro M., Cote G.M., Choy E., Letovanec I., Cherix S., Wagle N., Sorger P.K., Haynes A.B., Mullen J.T., Stamenkovic I., Rivera M.N., Kadoch C., Wucherpfennig K.W., Rozenblatt-Rosen O., Suvà M.L., Riggi N., Regev A.
ISSN
1546-170X (Electronic)
ISSN-L
1078-8956
Statut éditorial
Publié
Date de publication
02/2021
Peer-reviewed
Oui
Volume
27
Numéro
2
Pages
289-300
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18-SSX fusion, and is characterized by low T cell infiltration. Here, we studied the cancer-immune interplay in SyS using an integrative approach that combines single-cell RNA sequencing (scRNA-seq), spatial profiling and genetic and pharmacological perturbations. scRNA-seq of 16,872 cells from 12 human SyS tumors uncovered a malignant subpopulation that marks immune-deprived niches in situ and is predictive of poor clinical outcomes in two independent cohorts. Functional analyses revealed that this malignant cell state is controlled by the SS18-SSX fusion, is repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/CDK6 inhibitors. This drug combination enhanced malignant-cell immunogenicity in SyS models, leading to induced T cell reactivity and T cell-mediated killing. Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.
Mots-clé
Carcinogenesis/genetics, Cell Line, Tumor, Cyclin-Dependent Kinase 4/antagonists & inhibitors, Histone Deacetylase Inhibitors/therapeutic use, Histone Deacetylases/genetics, Histone Deacetylases/therapeutic use, Humans, Molecular Targeted Therapy, Oncogene Proteins, Fusion/antagonists & inhibitors, Oncogene Proteins, Fusion/genetics, Oncogenes/genetics, RNA-Seq, Sarcoma, Synovial/drug therapy, Sarcoma, Synovial/genetics, Sarcoma, Synovial/pathology, Single-Cell Analysis
Pubmed
Web of science
Création de la notice
27/01/2021 13:10
Dernière modification de la notice
07/07/2021 5:36
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