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Opposing immune and genetic forces shape oncogenic programs in synovial sarcoma
- Publication Year :
- 2019
- Publisher :
- Cold Spring Harbor Laboratory, 2019.
-
Abstract
- Synovial sarcoma is an aggressive mesenchymal neoplasm, driven by the SS18-SSX fusion, and characterized by immunogenic antigens expression and exceptionally low T cell infiltration levels. To study the cancer-immune interplay in this disease, we profiled 16,872 cells from 12 human synovial sarcoma tumors using single-cell RNA-sequencing (scRNA-Seq). Synovial sarcoma manifests antitumor immunity, high cellular plasticity and a core oncogenic program, which is predictive of low immune levels and poor clinical outcomes. Using genetic and pharmacological perturbations, we demonstrate that the program is controlled by the SS18-SSX driver and repressed by cytokines secreted by macrophages and T cells in the tumor microenvironment. Network modeling predicted that SS18-SSX promotes the program through HDAC1 and CDK6. Indeed, the combination of HDAC and CDK4/6 inhibitors represses the program, induces immunogenic cell states, and selectively targets synovial sarcoma cells. Our study demonstrates that immune evasion, cellular plasticity, and cell cycle are co-regulated and can be co-targeted in synovial sarcoma and potentially in other malignancies.
- Subjects :
- 0303 health sciences
Tumor microenvironment
Cell
Cell cycle
Biology
medicine.disease
HDAC1
Synovial sarcoma
3. Good health
03 medical and health sciences
0302 clinical medicine
Immune system
medicine.anatomical_structure
Antigen
030220 oncology & carcinogenesis
medicine
Cancer research
biology.protein
Cyclin-dependent kinase 6
030304 developmental biology
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....e15d6fa81c4c5eeaa50d0c025cdff1e6
- Full Text :
- https://doi.org/10.1101/724302