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 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.


Other Contributors

Miriam I Rosenberg 1, Erez Greenstein 2, Martin Buchkovich 3, Ayelet Peres 4, Eric Santoni-Rugiu 5, Lei Yang 6, Martin Mikl 7, Zalman Vaksman 8, David L Gibbs 9, Dan Reshef 2, Amy Salovin 10, Meredith S Irwin 11, Arlene Naranjo 12, Igor Ulitsky 13, Pedro A de Alarcon 14, Katherine K Matthay 15, Victor Weigman 3, Gur Yaari 4, Jessica A Panzer 10, Nir Friedman 2, John M Maris 16

1Hebrew University of Jerusalem, Edmond Safra Campus, Givat Ram, Jerusalem 91904, Israel.
2Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.
3Q2 Solutions, Durham, NC, USA.
4Bio-engineering, Faculty of Engineering, Bar Ilan University, Ramat Gan, Israel; Bar Ilan Institute of Nanotechnologies and Advanced Materials, Bar Ilan University, Ramat Gan, Israel.
5Department of Pathology, Rigshospitalet, Copenhagen University Hospital and Department of Clinical Medicine, University of Copenhagen, 2100 Copenhagen, Denmark.
6Pacific Northwest Research Institute, Seattle, WA 98122, USA.
7Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Mount Carmel, Haifa 31905, Israel.
8 New York Genome Center, New York, NY 10013, USA.
9Institute for Systems Biology, 401 Terry Avenue N, Seattle, WA 98109, USA.
10Division of Neurology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.
11Department of Pediatrics and Division of Hematology-Oncology, Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G1X8, Canada.
12Department of Biostatistics, University of Florida, Children’s Oncology Group Statistics & Data Center, Gainesville, FL, USA.
13Department of Immunology & Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
14Department of Pediatrics, Hematology/Oncology, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA.
15Department of Pediatrics, UCSF School of Medicine, San Francisco, CA 94143, USA.
16Department 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.