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

Abstract

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
Volume42
Issue number8
DOIs
StatePublished - 29 Aug 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Keywords

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

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