دورية أكاديمية
Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma.
| العنوان: | Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma. |
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| المؤلفون: | Jerby-Arnon, L., Neftel, C., Shore, M.E., Weisman, H.R., Mathewson, N.D., McBride, M.J., Haas, B., Izar, B., Volorio, A., Boulay, G., Cironi, L., Richman, A.R., Broye, L.C., Gurski, J.M., Luo, C.C., Mylvaganam, R., Nguyen, L., Mei, S., Melms, J.C., Georgescu, C., Cohen, O., Buendia-Buendia, J.E., Segerstolpe, A., Sud, M., Cuoco, M.S., Labes, D., Gritsch, S., Zollinger, D.R., Ortogero, N., Beechem, J.M., Petur Nielsen, G., Chebib, I., Nguyen-Ngoc, T., Montemurro, M., Cote, G.M., Choy, E., Letovanec, I., Cherix, S., Wagle, N., Sorger, P.K., Haynes, A.B., Mullen, J.T., Stamenkovic, I., Rivera, M.N., Kadoch, C., Wucherpfennig, K.W., Rozenblatt-Rosen, O., Suvà, M.L., Riggi, N., Regev, A. |
| المصدر: | Nature medicine, vol. 27, no. 2, pp. 289-300 |
| سنة النشر: | 2021 |
| المجموعة: | Université de Lausanne (UNIL): Serval - Serveur académique lausannois |
| مصطلحات موضوعية: | 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, Fusion/genetics, Oncogenes/genetics, RNA-Seq, Sarcoma, Synovial/drug therapy, Synovial/genetics, Synovial/pathology, Single-Cell Analysis |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1078-8956 |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/33495604; info:eu-repo/semantics/altIdentifier/eissn/1546-170X; https://serval.unil.ch/notice/serval:BIB_39EC1C431B02Test; urn:issn:1078-8956 |
| DOI: | 10.1038/s41591-020-01212-6 |
| الإتاحة: | https://doi.org/10.1038/s41591-020-01212-6Test https://serval.unil.ch/notice/serval:BIB_39EC1C431B02Test |
| رقم الانضمام: | edsbas.476BA88A |
| قاعدة البيانات: | BASE |
| تدمد: | 10788956 |
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| DOI: | 10.1038/s41591-020-01212-6 |