Immunogenomic determinants of tumor microenvironment correlate with superior survival in high-risk neuroblastoma

Abstract

BackgroundTumor-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.MethodsA 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.ResultsPatients 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.ConclusionsOur 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.

Deep analysis of neuroblastoma core regulatory circuitries using online databases and integrated bioinformatics shows their pan-cancer roles as prognostic predictors

“…Further to the association of expression of these TFs with patient survival, previous studies have linked their expression with various immune cells in the TME [ 27 ], leading us to address the impact of MES and ADRN TFs on the TME.…”

“…In NB, T-cell infiltration to the tumour microenvironment (TME), correlates with enhanced patient overall survival (OS). Specifically, the expression and activation of MYCN, ASCL1, and SOX11 are inversely correlated with T-cell infiltration in NB and correlate with patient OS [ 27 ], supporting the significance of these TFs in the NB TME. Notably, similar associations between MES and ADRN TFs with the infiltration of cancer-associated fibroblasts (CAFs) of the TME implicate these TFs in pro-tumourigenic remodelling of the TME in cancers [ 28 – 31 ].…”

NAIRscore as a biomarker for the quality of immune response to neoantigens is related with an increased overall survival in multiple myeloma

“… 35 These suggested that a higher cytolytic score resulting from neoantigen load did not yield a better prognosis in MM, although a high neoantigen load and tumor-infiltrating CD8+ T cells have been reported to imply a better survival in some solid tumors, such as melanoma and neuroblastoma. 36 , 37 This might indicate a difference between low- and high-TMB tumors.…”

Clinical Significance of a CD3/CD8-Based Immunoscore in Neuroblastoma Patients Using Digital Pathology

“…showed that tumor-infiltrating T cells, mainly CD3+, CD4+, and CD8+ T cells, improved clinical outcomes of patients with therapy-resistant NB ( 18 ) whereas Riyue et al. demonstrated that patients with high-risk NB showed a better survival when the tumor was T cell inflamed ( 19 ). A detailed description of the phenotypes of all infiltrating T cells, especially CD3+ T cells, CD8+ cytotoxic T cells, and CD45RO+ memory T cells, using a large collection of NB specimens is however currently not available.…”