Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

Neuroblastoma is a lethal childhood solid tumor of developing peripheral nerves. Two percent of children with neuroblastoma develop opsoclonus myoclonus ataxia syndrome (OMAS), a paraneoplastic disease characterized by cerebellar and brainstem-directed autoimmunity but typically with outstanding cancer-related outcomes. We compared tumor transcriptomes and tumor-infiltrating T and B cell repertoires from 38 OMAS subjects with neuroblastoma to 26 non-OMAS-associated neuroblastomas. We found greater B and T cell infiltration in OMAS-associated tumors compared to controls and showed that both were polyclonal expansions. Tertiary lymphoid structures (TLSs) were enriched in OMAS-associated tumors. We identified significant enrichment of the major histocompatibility complex (MHC) class II allele HLA-DOB∗01:01 in OMAS patients. OMAS severity scores were associated with the expression of several candidate autoimmune genes. We propose a model in which polyclonal auto-reactive B lymphocytes act as antigen-presenting cells and drive TLS formation, thereby supporting both sustained polyclonal T cell-mediated anti-tumor immunity and paraneoplastic OMAS neuropathology. [Display omitted] •OMAS-associated neuroblastomas contain more B and T cells than control neuroblastomas•OMAS-associated neuroblastoma B and T cell repertoires are diverse, with small clones•Tertiary lymphoid structures are enriched in OMAS-associated neuroblastomas•Gene expression correlated to neurological symptom severity nominates autoantigens Rosenberg et al. sought features of the systemic immune response underlying improved tumor outcomes and neurological dysfunction in patients with opsoclonus myoclonus ataxia syndrome (OMAS), an autoimmune disease caused by neuroblastoma. Diverse B and T cell lymphocytic infiltration organized in enriched tertiary lymphoid structures predominate in OMAS-associated tumors.