Abstract LB-225: Expression- and immune-profiling of neuroblastoma associated with Opsoclonus-myoclonus-ataxia syndrome (OMAS) to identify features of auto- and tumor immunity

Abstract

Abstract Background: Neuroblastoma (NB) is a pediatric cancer arising from the primordia of the autonomic nervous system. In spite of aggressive treatment, five year survival rates remain around 50% for high risk NB. OMAS is an autoimmune disorder that affects 2-3% of children with NB, causing ataxia, myoclonic jerks, and disordered mood/behavior. In contrast to high risk NB, survival rates among children with OMAS exceed 90%. The OMAS causative antigen is unknown, there are no molecular markers of active disease, and the nature of the immune process is poorly understood. We hypothesize that the distinctive immune response in OMAS patients is responsible for superior NB-tumor outcomes, and that deeper understanding of immune response in OMAS may provide insights into mechanisms of effective anti-NB tumor immunity. Methods: We have undertaken a molecular study of a large cohort of OMAS NB samples that were collected as part of a Children’s Oncology Group clinical trial for OMAS therapy. Fifty four children were enrolled in the trial, from which tumor, blood and cerebrospinal fluid were collected at time of diagnosis. We compared RNAseq gene expression profiles of OMAS NB to low- and high-risk NB without OMAS, to identify differentially expressed genes in OMAS that may drive anti-neuronal reactivity or that improve antitumor immunity. In parallel, we are investigating the immune profile of OMAS, to determine whether any distinctive features of OMAS immunity may be linked to improved tumor outcomes. We used T cell receptor β-chain sequencing of tumor genomic DNA to profile tumor-infiltrating lymphocytes in OMAS NBs and control NBs without OMAS. Results: Initial analysis shows that OMAS samples cluster together, and separately from low- and high-risk NB without OMAS. B and T cell gene signatures dominate the differentially expressed genes and drive the clustering. This strongly implies increased tumor infiltration in OMAS samples. We have identified several intriguing candidate autoantigen genes, which we are now testing for recognition by OMAS patient serum antibody repertoires. While we predicted a clonal, antigen driven response in OMAS patient samples, β-chain repertoires from these patients exhibit no clonal dominance, but rather comprise diverse repertoires, suggesting that the antitumor response may not be dominated by the OMAS associated antigen. Nevertheless, comparison of CDR3 amino acid sequence repertoires using Jaccard Index reveals detectable similarity of OMAS T-cell repertoires. Conclusion: We find the strongest feature of OMAS NB so far to be its immune signal. Current work aims to determine the activation state and subtype of tumor infiltrating T cells in OMAS, and to test whether candidates from RNAseq affect T cell activation and differentiation. Furthermore, B cells are essential for OMAS, since treatment with anti-CD20+ monoclonal antibody is crucially beneficial in achieving remission from OMAS. Autoantibody production is presumed essential. However, recent work on other autoimmune diseases, like lupus and multiple sclerosis, supports a critical cellular function for B cells as antigen presenting cells (APCs) in those diseases. Ongoing experiments, including BCRseq and MHC typing from OMAS associated NBs, will help address questions about critical B cell functions in OMAS. Citation Format: Miriam I. Rosenberg, Jessica A. Panzer, Tal Sagiv, Pedro A. de Alarcon, Nir Friedman, Igor Ulitsky, John M. Maris. Expression- and immune-profiling of neuroblastoma associated with Opsoclonus-myoclonus-ataxia syndrome (OMAS) to identify features of auto- and tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-225. doi:10.1158/1538-7445.AM2017-LB-225