Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

Miriam I. Rosenberg, Erez Greenstein, Martin Buchkovich, Ayelet Peres, Eric Santoni-Rugiu, Lei Yang, Martin Mikl, Zalman Vaksman, David L. Gibbs, Dan Reshef, Amy Salovin, Meredith S. Irwin, Arlene Naranjo, Igor Ulitsky, Pedro A. de Alarcon, Katherine K. Matthay, Victor Weigman, Gur Yaari, Jessica A. Panzer, Nir FriedmanJohn M. Maris

Research output: Contribution to journalArticlepeer-review


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-DOB01:01 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.

Original languageEnglish
Article number112879
JournalCell Reports
Issue number8
StatePublished - 29 Aug 2023

Bibliographical note

Funding Information:
This work was funded by grants to M.I.R. and J.A.P. from the Pablove Foundation , the Rally Foundation , Open Hands/Overflowing Hearts Foundation , and The Truth 365 Foundation . This work was also funded by NIH grant R35 CA220500 (J.M.M.), the Giulio D’Angio Endowed Chair (J.M.M.) and RC1MD004418 to the NCI-TARGET consortium ( COG SDC grant U10 CA180899 ), NCTN Operations Center grant U10CA180886 and NCTN Statistics & Data Center grant U10CA180899 , and support from St. Baldrick's Foundation to Children’s Oncology Group .

Publisher Copyright:
© 2023 The Authors


  • ataxia
  • autoimmunity
  • CP: Cancer
  • CP: Immunology
  • IgH
  • immune profiling
  • myoclonus
  • neuroblastoma
  • opsoclonus
  • paraneoplastic
  • repertoires
  • TCRB

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)


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