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Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma
Livnat Jerby-Arnon1,2,3,4, Cyril Neftel3,4,5,6, Marni E Shore3,4,5
1Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Nature Medicine
|January 26, 2021
Summary
Researchers identified a malignant cell state in synovial sarcoma (SyS) that drives immune evasion. Targeting this state with HDAC and CDK4/CDK6 inhibitors can re-sensitize tumors to T cell-mediated killing.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Synovial sarcoma (SyS) is an aggressive cancer characterized by the SS18-SSX fusion gene.
- SyS exhibits limited T cell infiltration, suggesting immune evasion mechanisms are at play.
Purpose of the Study:
- To investigate the cancer-immune interactions in synovial sarcoma.
- To identify therapeutic strategies targeting immune evasion in SyS.
Main Methods:
- Integrative approach combining single-cell RNA sequencing (scRNA-seq), spatial profiling, and genetic/pharmacological perturbations.
- Analysis of 16,872 cells from 12 human SyS tumors.
- Functional assays to assess drug efficacy and immune cell reactivity.
Main Results:
- A distinct malignant subpopulation was identified, associated with immune-deprived niches and poor clinical outcomes.
- The SS18-SSX fusion drives this malignant state, which is suppressed by macrophage and T cell-derived cytokines.
- A combination of HDAC and CDK4/CDK6 inhibitors synergistically targeted this malignant state.
- The drug combination increased tumor immunogenicity and enhanced T cell-mediated killing in SyS models.
Conclusions:
- This study reveals a link between oncogenic fusion proteins and immune evasion in SyS.
- Co-targeting oncogenic pathways and immune evasion presents a promising therapeutic strategy for SyS.
- The findings offer a framework for studying fusion-driven malignancies and their immune microenvironment.
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