4.8 Article

Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma

Journal

NATURE MEDICINE
Volume 27, Issue 2, Pages 289-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41591-020-01212-6

Keywords

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Funding

  1. CRI
  2. NCI [1U24CA180922, R33-CA202820]
  3. Koch Institute NCI Support (core) grant [P30-CA14051]
  4. Ludwig Centers at Harvard and MIT
  5. AMRF
  6. Broad Institute
  7. Howard Goodman Fellowship at MGH
  8. Merkin Institute Fellowship at the Broad Institute of MIT and Harvard
  9. Swiss National Science Foundation Sinergia grant [CRSII5_177266]
  10. Center for Cancer Systems Pharmacology at Harvard Medical School [CA225088]
  11. Burroughs Wellcome Fund Career Award for Medical Scientists
  12. Louis V. Gerstner, Jr. Scholars Program
  13. Velocity Fellow Program
  14. Swiss National Science Foundation Professorship grant [PP00P3-157468/1, PP00P3_183724]
  15. Swiss Cancer League [KFS-3973-08-2016]
  16. Fond'Action Contre le Cancer grant
  17. FORCE grant
  18. American Cancer Society [PF-17-042-01-LIB]
  19. NIH - NCI [L30 CA231679-01]
  20. Thomas and Diana Ryan MGH Research Scholar Award
  21. Klarman Cell Observatory
  22. STARR cancer consortium
  23. Scientific Interface from BWF
  24. [K08CA222663]
  25. [R37CA245523]
  26. Swiss National Science Foundation (SNF) [PP00P3_183724, CRSII5_177266, PP00P3_157468] Funding Source: Swiss National Science Foundation (SNF)

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Single-cell transcriptional profiling of primary human synovial sarcoma tumors suggests that combinatorial treatment with HDAC and CDK4/CDK6 inhibitors could enhance tumor immunogenicity. The study demonstrates an interplay between immune evasion and oncogenic processes in SyS that can be co-targeted for potential therapeutic interventions in other malignancies.
Single-cell transcriptional profiling of primary human synovial sarcoma tumors suggests that combinatorial treatment with HDAC and CDK4/CDK6 inhibitors could enhance tumor immunogenicity. 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.

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