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
- CRI
- NCI [1U24CA180922, R33-CA202820]
- Koch Institute NCI Support (core) grant [P30-CA14051]
- Ludwig Centers at Harvard and MIT
- AMRF
- Broad Institute
- Howard Goodman Fellowship at MGH
- Merkin Institute Fellowship at the Broad Institute of MIT and Harvard
- Swiss National Science Foundation Sinergia grant [CRSII5_177266]
- Center for Cancer Systems Pharmacology at Harvard Medical School [CA225088]
- Burroughs Wellcome Fund Career Award for Medical Scientists
- Louis V. Gerstner, Jr. Scholars Program
- Velocity Fellow Program
- Swiss National Science Foundation Professorship grant [PP00P3-157468/1, PP00P3_183724]
- Swiss Cancer League [KFS-3973-08-2016]
- Fond'Action Contre le Cancer grant
- FORCE grant
- American Cancer Society [PF-17-042-01-LIB]
- NIH - NCI [L30 CA231679-01]
- Thomas and Diana Ryan MGH Research Scholar Award
- Klarman Cell Observatory
- STARR cancer consortium
- Scientific Interface from BWF
- [K08CA222663]
- [R37CA245523]
- 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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