Ectopic NMDAR expression in cancer unmasks germline-encoded autoimmunity

Kleeman, Sam O, Michalski, Kevin, Zhao, Xiang, Steigerwald, Ruben, Ferrer, Miriam, Levett, Llewelyn, Ertel, Ethan, Schultz, Austin, Simorowski, Noriko, Moody, Pamela, Wee, Tse-Luen, Valente, Cristina, Fox, Sharon, Makuch, Mateusz, Thomsen, Selina, Harrison, Ruby, Regan, Claire, Preall, Jonathan, Gao, Qing, Thomas, Dennis, Habel, Jill, Rubino, Rachel, Irani, Sarosh, Furukawa, Hiro, Janowitz, Tobias (March 2026) Ectopic NMDAR expression in cancer unmasks germline-encoded autoimmunity. Nature. ISSN 0028-0836 (Public Dataset)

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Abstract

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.

Item Type: Paper
Subjects: diseases & disorders > cancer
diseases & disorders
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics and Genomics Program
CSHL labs > Furukawa lab
CSHL labs > Janowitz lab
CSHL labs > Preall lab
CSHL labs > Spector lab
CSHL labs > Zhang L. lab
CSHL Post Doctoral Fellows
CSHL labs > Wee Lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 25 March 2026
Date Deposited: 26 Mar 2026 12:50
Last Modified: 26 Mar 2026 12:50
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URI: https://repository.cshl.edu/id/eprint/42124

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