American Association for Cancer Research
10780432ccr180599-sup-197483_2_supp_4733175_p862yg.pdf (8.18 MB)

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

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journal contribution
posted on 2023-03-31, 20:51 authored by Jun S. Wei, Igor B. Kuznetsov, Shile Zhang, Young K. Song, Shahab Asgharzadeh, Sivasish Sindiri, Xinyu Wen, Rajesh Patidar, Sushma Najaraj, Ashley Walton, Jaime M. Guidry Auvil, Daniela S. Gerhard, Aysen Yuksel, Daniel Catchpoole, Stephen M. Hewitt, Paul M. Sondel, Robert Seeger, John M. Maris, Javed Khan

Supplementary Figures S1-S9



Cancer - St. Baldrick's Pediatric Dream Team Translational Research



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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