Hebrew University of Jerusalem, Edmond Safra Campus, Givat Ram, Jerusalem 91904, Israel.
Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.
Cell Rep. 2023 Aug 29;42(8):112879. doi: 10.1016/j.celrep.2023.112879. Epub 2023 Aug 2.
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.
神经母细胞瘤是一种致命的儿童期实体肿瘤，起源于发育中的周围神经。2%的神经母细胞瘤患儿会发展为眼阵挛-肌阵挛共济失调综合征（OMAS），这是一种副肿瘤性疾病，其特征为小脑和脑干定向自身免疫，但通常与出色的癌症相关结果相关。我们比较了 38 例 OMAS 相关神经母细胞瘤患者和 26 例非 OMAS 相关神经母细胞瘤患者的肿瘤转录组和肿瘤浸润性 T 和 B 细胞库。与对照组相比，我们发现 OMAS 相关肿瘤中有更多的 B 和 T 细胞浸润，并且表明它们都是多克隆扩增。三级淋巴结构（TLS）在 OMAS 相关肿瘤中丰富。我们发现 OMAS 患者 HLA-DOB01:01 主要组织相容性复合体（MHC）II 等位基因显著富集。OMAS 严重程度评分与几个候选自身免疫基因的表达相关。我们提出了一个模型，其中多克隆自身反应性 B 淋巴细胞作为抗原呈递细胞，驱动 TLS 形成，从而支持持续的多克隆 T 细胞介导的抗肿瘤免疫和副肿瘤性 OMAS 神经病理学。
