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 Friedman,
John M. Maris
Affiliations
Miriam I. Rosenberg
Hebrew University of Jerusalem, Edmond Safra Campus, Givat Ram, Jerusalem 91904, Israel; Corresponding author
Erez Greenstein
Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
Martin Buchkovich
Q2 Solutions, Durham, NC, USA
Ayelet Peres
Bio-engineering, Faculty of Engineering, Bar Ilan University, Ramat Gan, Israel; Bar Ilan Institute of Nanotechnologies and Advanced Materials, Bar Ilan University, Ramat Gan, Israel
Eric Santoni-Rugiu
Department of Pathology, Rigshospitalet, Copenhagen University Hospital and Department of Clinical Medicine, University of Copenhagen, 2100 Copenhagen, Denmark
Lei Yang
Pacific Northwest Research Institute, Seattle, WA 98122, USA
Martin Mikl
Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Mount Carmel, Haifa 31905, Israel
Zalman Vaksman
New York Genome Center, New York, NY 10013, USA
David L. Gibbs
Institute for Systems Biology, 401 Terry Avenue N, Seattle, WA 98109, USA
Dan Reshef
Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
Amy Salovin
Division of Neurology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Meredith S. Irwin
Department of Pediatrics and Division of Hematology-Oncology, Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G1X8, Canada
Arlene Naranjo
Department of Biostatistics, University of Florida, Children’s Oncology Group Statistics & Data Center, Gainesville, FL, USA
Igor Ulitsky
Department of Immunology & Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
Pedro A. de Alarcon
Department of Pediatrics, Hematology/Oncology, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
Katherine K. Matthay
Department of Pediatrics, UCSF School of Medicine, San Francisco, CA 94143, USA
Victor Weigman
Q2 Solutions, Durham, NC, USA
Gur Yaari
Bio-engineering, Faculty of Engineering, Bar Ilan University, Ramat Gan, Israel; Bar Ilan Institute of Nanotechnologies and Advanced Materials, Bar Ilan University, Ramat Gan, Israel
Jessica A. Panzer
Division of Neurology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Nir Friedman
Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
John M. Maris
Department of Pediatrics and Division of Oncology, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
Summary: 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.
