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Clin Cancer Res. 2018 Nov 15;24(22):5673-5684. doi: 10.1158/1078-0432.CCR-18-0599. Epub 2018 May 21.

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

Author information

1
Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
2
Cancer Research Center and Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, Rensselaer, New York.
3
Division of Hematology/Oncology, the Children's Hospital Los Angeles, Los Angeles, California.
4
Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland.
5
The Tumour Bank, Children's Cancer Research Unit, Kids Research Institute, the Children's Hospital at Westmead, Westmead, New South Wales, Australia.
6
Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
7
Departments of Pediatrics, Human Oncology and Genetics, the University of Wisconsin, Madison, Wisconsin.
8
Department of Pediatrics, University of Pennsylvania and Center for Childhood Cancer Research, the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
9
Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. khanjav@mail.nih.gov.
#
Contributed equally

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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