Clinically Relevant Cytotoxic Immune Cell Signatures and Clonal Expansion of T-Cell Receptors in High-Risk MYCN-Not-Amplified Human Neuroblastoma.

Wei, JS; Kuznetsov, IB; Zhang, S; Song, YK; Asgharzadeh, S; Sindiri, S; Wen, X; Patidar, R; Najaraj, S; Walton, A; Auvil, JMG; Gerhard, DS; Yuksel, A; Catchpoole, D; Hewitt, SM; Sondel, PM; Seeger, R; Maris, JM; Khan, J

Clinically Relevant Cytotoxic Immune Cell Signatures and Clonal Expansion of T-Cell Receptors in High-Risk MYCN-Not-Amplified Human Neuroblastoma.

Wei, JS Kuznetsov, IB Zhang, S Song, YK Asgharzadeh, S Sindiri, S Wen, X Patidar, R Najaraj, S Walton, A Auvil, JMG Gerhard, DS Yuksel, A Catchpoole, D

Hewitt, SM Sondel, PM Seeger, R Maris, JM Khan, J

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Publisher:: American Association for Cancer Research (AACR)
Publication Type:: Journal Article
Citation:: Clin Cancer Res, 2018, 24, (22), pp. 5673-5684
Issue Date:: 2018-11-15

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Field	Value	Language
dc.contributor.author	Wei, JS
dc.contributor.author	Kuznetsov, IB
dc.contributor.author	Zhang, S
dc.contributor.author	Song, YK
dc.contributor.author	Asgharzadeh, S
dc.contributor.author	Sindiri, S
dc.contributor.author	Wen, X
dc.contributor.author	Patidar, R
dc.contributor.author	Najaraj, S
dc.contributor.author	Walton, A
dc.contributor.author	Auvil, JMG
dc.contributor.author	Gerhard, DS
dc.contributor.author	Yuksel, A
dc.contributor.author	Catchpoole, D https://orcid.org/0000-0001-5836-1413
dc.contributor.author	Hewitt, SM
dc.contributor.author	Sondel, PM
dc.contributor.author	Seeger, R
dc.contributor.author	Maris, JM
dc.contributor.author	Khan, J
dc.date.accessioned	2022-09-03T22:21:58Z
dc.date.available	2018-05-14
dc.date.available	2022-09-03T22:21:58Z
dc.date.issued	2018-11-15
dc.identifier.citation	Clin Cancer Res, 2018, 24, (22), pp. 5673-5684
dc.identifier.issn	1078-0432
dc.identifier.issn	1557-3265
dc.identifier.uri	http://hdl.handle.net/10453/161300
dc.description.abstract	Purpose: High-risk neuroblastoma is an aggressive disease. DNA sequencing studies have revealed a paucity of actionable genomic alterations and a low mutation burden, posing challenges to develop effective novel therapies. We used RNA sequencing (RNA-seq) to investigate the biology of this disease, including a focus on tumor-infiltrating lymphocytes (TIL).Experimental Design: We performed deep RNA-seq on pretreatment diagnostic tumors from 129 high-risk and 21 low- or intermediate-risk patients with neuroblastomas. We used single-sample gene set enrichment analysis to detect gene expression signatures of TILs in tumors and examined their association with clinical and molecular parameters, including patient outcome. The expression profiles of 190 additional pretreatment diagnostic neuroblastomas, a neuroblastoma tissue microarray, and T-cell receptor (TCR) sequencing were used to validate our findings.Results: We found that MYCN-not-amplified (MYCN-NA) tumors had significantly higher cytotoxic TIL signatures compared with MYCN-amplified (MYCN-A) tumors. A reported MYCN activation signature was significantly associated with poor outcome for high-risk patients with MYCN-NA tumors; however, a subgroup of these patients who had elevated activated natural killer (NK) cells, CD8+ T cells, and cytolytic signatures showed improved outcome and expansion of infiltrating TCR clones. Furthermore, we observed upregulation of immune exhaustion marker genes, indicating an immune-suppressive microenvironment in these neuroblastomas.Conclusions: This study provides evidence that RNA signatures of cytotoxic TIL are associated with the presence of activated NK/T cells and improved outcomes in high-risk neuroblastoma patients harboring MYCN-NA tumors. Our findings suggest that these high-risk patients with MYCN-NA neuroblastoma may benefit from additional immunotherapies incorporated into the current therapeutic strategies. Clin Cancer Res; 24(22); 5673-84. ©2018 AACR.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	American Association for Cancer Research (AACR)
dc.relation.ispartof	Clin Cancer Res
dc.relation.isbasedon	10.1158/1078-0432.CCR-18-0599
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Child, Preschool
dc.subject.mesh	Computational Biology
dc.subject.mesh	Cytotoxicity, Immunologic
dc.subject.mesh	Gene Amplification
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Humans
dc.subject.mesh	Infant
dc.subject.mesh	Infant, Newborn
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Neoplasm Staging
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Receptors, Antigen, T-Cell
dc.subject.mesh	T-Lymphocytes
dc.subject.mesh	Transcriptome
dc.subject.mesh	T-Lymphocytes
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Humans
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Receptors, Antigen, T-Cell
dc.subject.mesh	Neoplasm Staging
dc.subject.mesh	Computational Biology
dc.subject.mesh	Cytotoxicity, Immunologic
dc.subject.mesh	Gene Amplification
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Child, Preschool
dc.subject.mesh	Infant
dc.subject.mesh	Infant, Newborn
dc.subject.mesh	Transcriptome
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.title	Clinically Relevant Cytotoxic Immune Cell Signatures and Clonal Expansion of T-Cell Receptors in High-Risk MYCN-Not-Amplified Human Neuroblastoma.
dc.type	Journal Article
utslib.citation.volume	24
utslib.location.activity	United States
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
utslib.copyright.status	closed_access	*
dc.date.updated	2022-09-03T22:21:56Z
pubs.issue	22
pubs.publication-status	Published
pubs.volume	24
utslib.citation.issue	22

Abstract:

Purpose: High-risk neuroblastoma is an aggressive disease. DNA sequencing studies have revealed a paucity of actionable genomic alterations and a low mutation burden, posing challenges to develop effective novel therapies. We used RNA sequencing (RNA-seq) to investigate the biology of this disease, including a focus on tumor-infiltrating lymphocytes (TIL).Experimental Design: We performed deep RNA-seq on pretreatment diagnostic tumors from 129 high-risk and 21 low- or intermediate-risk patients with neuroblastomas. We used single-sample gene set enrichment analysis to detect gene expression signatures of TILs in tumors and examined their association with clinical and molecular parameters, including patient outcome. The expression profiles of 190 additional pretreatment diagnostic neuroblastomas, a neuroblastoma tissue microarray, and T-cell receptor (TCR) sequencing were used to validate our findings.Results: We found that MYCN-not-amplified (MYCN-NA) tumors had significantly higher cytotoxic TIL signatures compared with MYCN-amplified (MYCN-A) tumors. A reported MYCN activation signature was significantly associated with poor outcome for high-risk patients with MYCN-NA tumors; however, a subgroup of these patients who had elevated activated natural killer (NK) cells, CD8+ T cells, and cytolytic signatures showed improved outcome and expansion of infiltrating TCR clones. Furthermore, we observed upregulation of immune exhaustion marker genes, indicating an immune-suppressive microenvironment in these neuroblastomas.Conclusions: This study provides evidence that RNA signatures of cytotoxic TIL are associated with the presence of activated NK/T cells and improved outcomes in high-risk neuroblastoma patients harboring MYCN-NA tumors. Our findings suggest that these high-risk patients with MYCN-NA neuroblastoma may benefit from additional immunotherapies incorporated into the current therapeutic strategies. Clin Cancer Res; 24(22); 5673-84. ©2018 AACR.

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http://hdl.handle.net/10453/161300