Expression- and immune-profiling of neuroblastoma-associated Opsoclonus Myoclonus Syndrome (OMS) identifies features of auto- and tumor-immunity

author.DisplayName ¹ author.DisplayName ² author.DisplayName ³ author.DisplayName ⁴ author.DisplayName ³ author.DisplayName ⁵ author.DisplayName ⁶ author.DisplayName ² author.DisplayName ⁷ author.DisplayName ⁶ author.DisplayName ⁸ author.DisplayName ² author.DisplayName ⁴ author.DisplayName ³ author.DisplayName ⁹

¹Hebrew University of Jerusalem, Jerusalem, Israel
²Department of Neurology, Children’s Hospital of Philadelphia, USA
³Department of Immunology, Weizmann Institute of Science, Israel
⁴Faculty of Engineering, Bar Ilan University, Israel
⁵Department of Computer Science and Applied Mathematics, Department of Molecular Cell Biology, Weizmann Institute of Science, Israel
⁶Morrisville, Q2 Solutions, USA
⁷Department of Pediatrics, University of Illinois College of Medicine,, USA
⁸Department of Biological Regulation, Weizmann Institute of Science, Israel
⁹Department of Oncology, Children’s Hospital of Philadelphia, USA

Opsoclonus myoclonus syndrome (OMS) is a devastating neuroimmune disease occuring in 2-3% of children with neuroblastoma (NB), and characterized by ataxia, myoclonic jerks, chaotic eye movements, and behavioral disturbances. While high risk (HR) NB has poor survival, tumor related outcomes in patients with both OMS and NB are significantly better. We hypothesize that defining the OMS immune response in NB patients may help illuminate mechanisms of effective anti-NB tumor immunity.

We investigated a large cohort of OMS NB samples collected during a COG clinical trial of IVIg as part of OMS therapy, alongside low- and high-risk NB without OMS, using RNAseq to identify candidate antigens that may drive anti-neuronal or anti-tumor immunity, and to carry out the first comprehensive OMS association study. We also used tumor genomic DNA to profile T cell receptor beta chain (TCRB) and Ig heavy chain (IgH) repertoires in OMS and control NBs.

We observe significantly greater lymphocytic infiltration in OMS associated tumors, and extremely diverse TCRB and IgH repertoires in those patients, with little clonality. Immune features also dominate differentially expressed gene sets in RNAseq. In spite of their diversity, we identify TCRB and IGH sequences and features shared across OMS patients. Finally, we identify several MHC Class II alleles whose skewed expression in OMS patients compared to controls suggests a basis for OMS predisposition.

We conclude that effective anti-tumor activity in OMS patients is likely shaped by their autoimmunity, which results in tremendous diversity of both TCRs and BCRs responding to tumor.