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 poly clonal 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.

Automated summary

Neuroblastoma is a lethal childhood solid tumor. Opsoclonus myoclonus ataxia syndrome (OMAS) is found in 2% of neuroblastoma patients and is characterized by cerebellar and brainstem-directed autoimmunity. In this study, OMAS-associated tumors showed greater B and T cell infiltration, poly clonal expansions, and enrichment of tertiary lymphoid structures (TLSs). The major histocompatibility complex (MHC) class II allele HLA-DOB*01:01 was significantly enriched in OMAS patients. OMAS severity scores were associated with the expression of candidate autoimmune genes. A proposed model suggests that polyclonal auto-reactive B lymphocytes act as antigen-presenting cells and drive TLS formation, supporting both anti-tumor immunity and OMAS neuropathology.