Cell Rep. 2025 Aug 07. pii: S2211-1247(25)00870-8. [Epub ahead of print]44(8): 116099
Priyanka Sehgal,
Ammar S Naqvi,
Makenna Higgins,
Jiageng Liu,
Kyra Harvey,
Julien Jarroux,
Taewoo Kim,
Berk Mankaliye,
Pamela Mishra,
Grace Watterson,
Justyn Fine,
Jacinta Davis,
Katharina E Hayer,
Annette Castro,
Adanna Mogbo,
Charles Drummer,
Daniel Martinez,
Mateusz P Koptyra,
Zhiwei Ang,
Kai Wang,
Alvin Farrel,
Mathieu Quesnel-Vallieres,
Yoseph Barash,
Jamie B Spangler,
Jo Lynne Rokita,
Adam C Resnick,
Hagen U Tilgner,
Thomas De Raedt,
Daniel J Powell,
Andrei Thomas-Tikhonenko.
To overcome the paucity of known tumor-specific surface antigens in pediatric high-grade glioma (pHGG), we contrasted splicing patterns in pHGGs and normal brain samples. Among alternative splicing events affecting extracellular protein domains, the most pervasive alteration was the skipping of ≤30-nt-long exons. Several of these skipped microexons mapped to L1-immunoglobulin cell adhesion molecule (IgCAM) family members, such as neuronal CAM (NRCAM). Bulk and single-nuclei short- and long-read RNA-seq revealed uniform skipping of NRCAM microexons 5 and 19 in virtually every pHGG sample. Importantly, the Δex5Δex19 (but not the full-length) NRCAM proteoform was essential for pHGG cell migration and invasion in vitro and tumor growth in vivo. We developed a monoclonal antibody selective for Δex5Δex19 NRCAM and demonstrated that "painting" pHGG cells with this antibody enables killing by T cells armed with an FcRI-based universal immune receptor. Thus, pHGG-specific NRCAM and possibly other L1-IgCAM proteoforms are promising and highly selective targets for adoptive immunotherapies.
Keywords: CP: Cancer; CP: Immunology; alternative splicing; antibodies; cell adhesion molecules; glioblastoma; glioma; immunotherapy; mRNA processing; microexons