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

Introduction: Opsoclonus myoclonus ataxia syndrome (OMAS) is a devastating neuroimmune disease that occurs in 2-3% of children with neuroblastoma (NB), characterized by ataxia, myoclonic jerks, chaotic eye movements, and mood and behavioral disturbances in a previously well child. While high risk (HR) NB has poor survival- approximately 60% of HR patients succumb to the disease- tumor related outcomes in patients with both OMAS and NB are excellent. We hypothesize that defining the OMAS immune response in NB patients may help illuminate mechanisms of effective anti-NB tumor immunity.

Materials and Methods: A large cohort of OMAS NB samples were collected for a COG clinical trial of IVIg as part of OMAS therapy. We used the Illumina RNA Access platform for RNAseq of OMAS NB, alongside low- and high-risk NB without OMAS, to identify differentially expressed or novel antigens that may drive anti-neuronal or anti-tumor immunity. We also inferred HLA types from RNAseq to carry out the first OMAS association study. Finally, we used genomic DNA from tumors to profile T cell receptor beta chain (TCRB) and Ig heavy chain (IgH) repertoires in OMAS and control NBs.

Results and Discussion: While we predicted a clonal, antigen driven TCR response in OMAS patient tumors, instead, we observe extremely diverse T cell (and B cell) receptor repertoires in patients with OMAS, with very little clonality. While all NBs in our cohort exhibited considerable lymphocytic infiltration, OMAS associated NBs are significantly more infiltrated by T cells and B cells than high risk NB, a finding supported both by immune repertoire sequencing and RNAseq data. Immune features dominated differentially expressed gene sets in RNAseq. In spite of their diversity, we identify TCRB and IGH sequences and features shared across OMAS patients. Finally, we identify several MHC Class II alleles whose expression is skewed in OMAS patients compared to non-OMAS NB patients, suggesting a basis for OMAS predisposition.

Conclusion: We conclude that effective anti-tumor activity in OMAS patients is likely shaped by their autoimmunity, which results in tremendous diversity of both TCRs and BCRs that also respond to tumor. Identification of antigens and receptors involved in OMAS etiology will be of interest in development of novel immune therapies for NB.