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Cancer Cell. 2019 Dec 9;36(6):597-612.e8. doi: 10.1016/j.ccell.2019.10.008. Epub 2019 Nov 7.

Clonally Expanded T Cells Reveal Immunogenicity of Rhabdoid Tumors.

Author information

1
PSL Research University, Institut Curie Research Center, INSERM U830, Paris, France; PSL Research University, Institut Curie Research Center, Translational Research Department, Paris, France; SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France.
2
PSL Research University, Institut Curie Research Center, Translational Research Department, Paris, France; PSL Research University, Institut Curie Research Center, INSERM U932, Paris, France.
3
Sainte-Anne Hospital, Department of Neuropathology, Paris, France.
4
PSL Research University, Institut Curie Research Center, Translational Research Department, Paris, France; SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France.
5
AP-HP, Necker Hospital, Department of Neurosurgery, Paris, France.
6
PSL Research University, Institut Curie Research Center, INSERM U900, Paris, France; MINES ParisTech, PSL Research University, CBIO-Centre for Computational Biology, Paris, France.
7
PSL Research University, Institut Curie Research Center, INSERM U932, Paris, France.
8
PSL Research University, Institut Curie Hospital, Laboratory of Somatic Genetics, Paris, France.
9
PSL Research University, Institut Curie Research Center, INSERM U830, Paris, France; SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France.
10
PSL Research University, Institut Curie Genomics of Excellence (ICGex) Platform, Paris, France.
11
PSL Research University, Institut Curie Research Center, CNRS UMR 3347, INSERM U1021, Orsay, France.
12
AP-HP, Armand Trousseau Hospital, Department of Pathology, Paris, France.
13
AP-HP, Necker Hospital, Department of Pathology, Paris, France.
14
PSL Research University, Institut Curie Research Center, INSERM U830, Paris, France; PSL Research University, Institut Curie Research Center, Translational Research Department, Paris, France. Electronic address: joshua.waterfall@curie.fr.
15
PSL Research University, Institut Curie Research Center, Translational Research Department, Paris, France; PSL Research University, Institut Curie Research Center, INSERM U932, Paris, France. Electronic address: eliane.piaggio@curie.fr.
16
PSL Research University, Institut Curie Research Center, INSERM U830, Paris, France; PSL Research University, Institut Curie Research Center, Translational Research Department, Paris, France; SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France. Electronic address: franck.bourdeaut@curie.fr.

Abstract

Rhabdoid tumors (RTs) are genomically simple pediatric cancers driven by the biallelic inactivation of SMARCB1, leading to SWI/SNF chromatin remodeler complex deficiency. Comprehensive evaluation of the immune infiltrates of human and mice RTs, including immunohistochemistry, bulk RNA sequencing and DNA methylation profiling studies showed a high rate of tumors infiltrated by T and myeloid cells. Single-cell RNA (scRNA) and T cell receptor sequencing highlighted the heterogeneity of these cells and revealed therapeutically targetable exhausted effector and clonally expanded tissue resident memory CD8+ T subpopulations, likely representing tumor-specific cells. Checkpoint blockade therapy in an experimental RT model induced the regression of established tumors and durable immune responses. Finally, we show that one mechanism mediating RTs immunogenicity involves SMARCB1-dependent re-expression of endogenous retroviruses and interferon-signaling activation.

KEYWORDS:

AT/RT; SMARCB1; SWI/SNF; T cell receptor; endogenous retrovirus; immunotherapy; pediatric cancer; rhabdoid tumor; single-cell RNA sequencing; tumor immunology

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