Autoimmunity and anti-cancer immunity lie on the same biological continuum1,2, but their link remains obscure. The paraneoplastic neurological syndrome ANRE (anti-NMDA receptor (NMDAR) encephalitis) is a paradigm for their connectivity3, given that intratumoural NMDAR expression is correlated with the generation of anti-NMDAR antibodies4,5. Here we verify ectopic expression of GluN1 and GluN2B NMDAR subunits in triple-negative breast cancer (TNBC)6 and model this using orthotopic TNBC tumours with inducible expression of GluN1–GluN2B NMDARs. We show that NMDAR expression is sufficient to induce the recruitment of B cells and their affinity maturation, consistent with an integrated adaptive immune response. Reconstruction of extended intratumoural B cell phylogenies and cryogenic electron microscopy structural analyses demonstrate that affinity-matured hypermutated and class-switched antibodies emerged from pre-existing germline-configuration lower-affinity anti-NMDAR antibodies. Distinct matured antibodies targeted specific epitopes and induced conformational rearrangements within the NMDAR amino-terminal domain, predictive of their functional effects, ranging from inhibition to potentiation. Passive transfer of an NMDAR-potentiating antibody caused autonomic dysregulation and lowered the seizure threshold in healthy female mice, recapitulating key diagnostic criteria of ANRE4,5. We further identify a correlation between intratumoural NMDAR expression and anti-NMDAR antibody titres in patients with TNBC. Taken together, our data establish a direct connection between intratumoural NMDAR expression, antibody maturation and the onset of autoimmunity. These findings suggest that germline-encoded anti-NMDAR antibodies contribute to immune surveillance but can also trigger autoimmune disease after maturation, revealing a mechanistic trade-off between cancer immunity and neurotoxicity.
自身免疫和抗肿瘤免疫处于同一生物学连续统一体中，但二者之间的联系仍不清楚。副肿瘤性神经综合征 ANRE（抗 N-甲基-D-天冬氨酸受体脑炎）是阐明这种关联性的典型范例，因为肿瘤内 NMDAR 的表达与抗 NMDAR 抗体的产生相关。本研究验证了三阴性乳腺癌中 GluN1 和 GluN2B NMDAR 亚基的异位表达，并通过构建可诱导表达 GluN1-GluN2B NMDAR 的原位三阴性乳腺癌肿瘤模型进行模拟。结果表明，NMDAR 表达足以诱导 B 细胞的募集及其亲和力成熟，这与整合性适应性免疫应答一致。通过重建肿瘤内 B 细胞的扩展系统发育树及低温电子显微镜结构分析，发现亲和力成熟的超突变和类别转换抗体源自预先存在的种系构型低亲和力抗 NMDAR 抗体。不同的成熟抗体靶向特定表位，并诱导 NMDAR 氨基末端结构域的构象重排，从而预测其功能效应（从抑制到增强）。被动转移增强型 NMDAR 抗体可导致健康雌性小鼠出现自主神经调节障碍并降低癫痫发作阈值，重现了 ANRE 的关键诊断标准。本研究进一步证实三阴性乳腺癌患者肿瘤内 NMDAR 表达与抗 NMDAR 抗体滴度之间存在相关性。综上所述，我们的数据确立了肿瘤内 NMDAR 表达、抗体成熟与自身免疫发病之间的直接联系。这些发现提示，种系编码的抗 NMDAR 抗体有助于免疫监视，但在成熟后也可能触发自身免疫疾病，揭示了抗癌免疫与神经毒性之间的机制性权衡。
Ectopic NMDAR expression in cancer unmasks germline-encoded autoimmunity
肿瘤(癌症)患者之家