Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

Miriam I Rosenberg, Erez Greenstein, Martin Buchkovich, Martin Mikl, Ayelet Peres, Eric Santoni-Rugiu, Dan Reshef, Amy J Salovin, David L Gibbs, Meredith S Irwin, Arlene Naranjo, Igor Ulitsky, Pedro A de Alarcon, Victor Weigman, Gur Yaari, Jessica A Panzer, Nir Friedman, John M Maris

Research output: Working paperPreprint


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, but unexpectedly showed that both were polyclonal expansions. Tertiary lymphoid structures (TLS) were enriched in OMAS-associated tumors. We identified significant enrichment of the 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 autoreactive B lymphocytes act as antigen presenting cells and drive TLS formation, thereby crucially supporting both sustained polyclonal T-cell-mediated anti-tumor immunity and paraneoplastic OMAS neuropathology.
Original languageEnglish
StatePublished - 14 Dec 2021

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  • cancer-biology


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