Immunogenomic determinants of tumor microenvironment correlate with superior survival in high-risk neuroblastoma
Background Tumor-infiltrating CD8+ T cells and neoantigens are predictors of a favorable prognosis and response to immunotherapy with checkpoint inhibitors in many types of adult cancer, but little is known about their role in pediatric malignancies. Here, we analyzed the prognostic strength of T ce...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2021-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/7/e002417.full |
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| author | Ami V Desai Stefani Spranger Thomas F Gajewski Yuanyuan Zha Jason J Luke Peter Pytel Kyle Hernandez Samuel L Volchenboum Susan L Cohn |
| author_facet | Ami V Desai Stefani Spranger Thomas F Gajewski Yuanyuan Zha Jason J Luke Peter Pytel Kyle Hernandez Samuel L Volchenboum Susan L Cohn |
| author_sort | Ami V Desai |
| collection | DOAJ |
| description | Background Tumor-infiltrating CD8+ T cells and neoantigens are predictors of a favorable prognosis and response to immunotherapy with checkpoint inhibitors in many types of adult cancer, but little is known about their role in pediatric malignancies. Here, we analyzed the prognostic strength of T cell-inflamed gene expression and neoantigen load in high-risk neuroblastoma. We also compared transcriptional programs in T cell-inflamed and non-T cell-inflamed high-risk neuroblastomas to investigate possible mechanisms of immune exclusion.Methods A defined T cell-inflamed gene expression signature was used to categorize high-risk neuroblastomas in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program (n=123), and the Gabriella Miller Kids First (GMKF) program (n=48) into T cell-inflamed, non-T cell-inflamed, and intermediate groups. Associations between the T cell-inflamed and non-T cell-inflamed group, MYCN amplification, and survival were analyzed by Cox proportional hazards models. Additional survival analysis was conducted after integrating neoantigen load predicted from somatic mutations. Pathways activated in non-T cell-inflamed relative to T cell-inflamed tumors were analyzed using causal network analysis.Results Patients with T cell-inflamed high-risk tumors showed improved overall survival compared with those with non-T cell-inflamed tumors (p<0.05), independent of MYCN amplification status, in both TARGET and GMKF cohorts. Higher neoantigen load was also associated with better event-free and overall survival (p<0.005) and was independent of the T cell-inflamed signature. Activation of MYCN, ASCL1, SOX11, and KMT2A transcriptional programs was inversely correlated with the T cell-inflamed signature in both cohorts.Conclusions Our results indicate that tumors from children with high-risk neuroblastoma harboring a strong T cell-inflamed signature have a more favorable clinical outcome, and neoantigen load is a prognosis predictor, independent of T cell inflammation. Strategies to target SOX11 and other signaling pathways associated with non-T cell-inflamed tumors should be pursued as potential immune-potentiating interventions. |
| format | Article |
| id | doaj-art-b260b4d6e43c4d658b87dc58bb5c263c |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2021-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-b260b4d6e43c4d658b87dc58bb5c263c2025-08-20T02:12:49ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-07-019710.1136/jitc-2021-002417Immunogenomic determinants of tumor microenvironment correlate with superior survival in high-risk neuroblastomaAmi V Desai0Stefani Spranger1Thomas F Gajewski2Yuanyuan Zha3Jason J Luke4Peter Pytel5Kyle Hernandez6Samuel L Volchenboum7Susan L Cohn8Department of Pediatrics, The University of Chicago, Chicago, Illinois, USAKoch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA1 Medicine, The University of Chicago Medicine Comprehensive Cancer Center, Chicago, Illinois, USAComprehensive Cancer Center, University of Chicago, Chicago, Illinois, USA1UPMC Hillman Cancer Center, Pittsburgh, PA, USADepartment of Pathology, The University of Chicago, Chicago, Illinois, USACenter for Translational Data Science, The University of Chicago, Chicago, Illinois, USADepartment of Pediatrics, The University of Chicago, Chicago, Illinois, USADepartment of Pediatrics, The University of Chicago, Chicago, Illinois, USABackground Tumor-infiltrating CD8+ T cells and neoantigens are predictors of a favorable prognosis and response to immunotherapy with checkpoint inhibitors in many types of adult cancer, but little is known about their role in pediatric malignancies. Here, we analyzed the prognostic strength of T cell-inflamed gene expression and neoantigen load in high-risk neuroblastoma. We also compared transcriptional programs in T cell-inflamed and non-T cell-inflamed high-risk neuroblastomas to investigate possible mechanisms of immune exclusion.Methods A defined T cell-inflamed gene expression signature was used to categorize high-risk neuroblastomas in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program (n=123), and the Gabriella Miller Kids First (GMKF) program (n=48) into T cell-inflamed, non-T cell-inflamed, and intermediate groups. Associations between the T cell-inflamed and non-T cell-inflamed group, MYCN amplification, and survival were analyzed by Cox proportional hazards models. Additional survival analysis was conducted after integrating neoantigen load predicted from somatic mutations. Pathways activated in non-T cell-inflamed relative to T cell-inflamed tumors were analyzed using causal network analysis.Results Patients with T cell-inflamed high-risk tumors showed improved overall survival compared with those with non-T cell-inflamed tumors (p<0.05), independent of MYCN amplification status, in both TARGET and GMKF cohorts. Higher neoantigen load was also associated with better event-free and overall survival (p<0.005) and was independent of the T cell-inflamed signature. Activation of MYCN, ASCL1, SOX11, and KMT2A transcriptional programs was inversely correlated with the T cell-inflamed signature in both cohorts.Conclusions Our results indicate that tumors from children with high-risk neuroblastoma harboring a strong T cell-inflamed signature have a more favorable clinical outcome, and neoantigen load is a prognosis predictor, independent of T cell inflammation. Strategies to target SOX11 and other signaling pathways associated with non-T cell-inflamed tumors should be pursued as potential immune-potentiating interventions.https://jitc.bmj.com/content/9/7/e002417.full |
| spellingShingle | Ami V Desai Stefani Spranger Thomas F Gajewski Yuanyuan Zha Jason J Luke Peter Pytel Kyle Hernandez Samuel L Volchenboum Susan L Cohn Immunogenomic determinants of tumor microenvironment correlate with superior survival in high-risk neuroblastoma Journal for ImmunoTherapy of Cancer |
| title | Immunogenomic determinants of tumor microenvironment correlate with superior survival in high-risk neuroblastoma |
| title_full | Immunogenomic determinants of tumor microenvironment correlate with superior survival in high-risk neuroblastoma |
| title_fullStr | Immunogenomic determinants of tumor microenvironment correlate with superior survival in high-risk neuroblastoma |
| title_full_unstemmed | Immunogenomic determinants of tumor microenvironment correlate with superior survival in high-risk neuroblastoma |
| title_short | Immunogenomic determinants of tumor microenvironment correlate with superior survival in high-risk neuroblastoma |
| title_sort | immunogenomic determinants of tumor microenvironment correlate with superior survival in high risk neuroblastoma |
| url | https://jitc.bmj.com/content/9/7/e002417.full |
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