Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

Rosenberg, M. I.; Greenstein, E.; Buchkovich, M.; Mikl, M.; Peres, A.; Santoni-Rugiu, E.; Reshef, D.; Salovin, A. J.; Gibbs, D. L.; Irwin, M. S.; Naranjo, A.; Ulitsky, I.; de Alarcon, P. A.; Weigman, V.; Yaari, G.; Panzer, J. A.; Friedman, N.; Maris, J. M.

doi:10.1101/2021.12.14.471886

bioRxiv · 10.1101/2021.12.14.471886

Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

Rosenberg, M. I.·Greenstein, E.·Buchkovich, M.·Mikl, M.·Peres, A.·Santoni-Rugiu, E.·Reshef, D.·Salovin, A. J.·Gibbs, D. L.·Irwin, M. S.·Naranjo, A.·Ulitsky, I.·de Alarcon, P. A.·Weigman, V.·Yaari, G.·Panzer, J. A.·Friedman, N.·Maris, J. M.

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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, 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.

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Rosenberg, M. I., Greenstein, E., Buchkovich, M., Mikl, M., Peres, A., Santoni-Rugiu, E., Reshef, D., Salovin, A. J., Gibbs, D. L., Irwin, M. S., Naranjo, A., Ulitsky, I., de Alarcon, P. A., Weigman, V., Yaari, G., Panzer, J. A., Friedman, N., Maris, J. M.. 2021-12-14. Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma. https://doi.org/10.1101/2021.12.14.471886

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