Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma

Nat Med. 2021 Feb;27(2):289-300. doi: 10.1038/s41591-020-01212-6. Epub 2021 Jan 25.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Histone Deacetylase Inhibitors
  • Oncogene Proteins, Fusion
  • Cyclin-Dependent Kinase 4
  • Histone Deacetylases