NRCAM variant defined by microexon skipping is a targetable cell surface proteoform in high-grade gliomas
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.
Authors
- Mary Higgins (ORCID: https://orcid.org/0000-0002-6469-5169)
- Jo Lynne Rokita (ORCID: https://orcid.org/0000-0003-2171-3627)
- Charles Drummer (ORCID: https://orcid.org/0000-0001-9059-1454)
- Thomas De Raedt (ORCID: https://orcid.org/0000-0002-7492-851X)
- Julien Jarroux (ORCID: https://orcid.org/0000-0002-7185-6960)
- Katharina E. Hayer
- Pamela Mishra
- Yoseph Barash (ORCID: https://orcid.org/0000-0003-3005-5048)
- Ammar S. Naqvi (ORCID: https://orcid.org/0000-0002-0625-666X)
- Priyanka Sehgal
- Justyn Fine
- Alvin Farrel (ORCID: https://orcid.org/0000-0003-1087-9840)
- Daniel J. Powell (ORCID: https://orcid.org/0000-0002-5966-8908)
- Kyra Harvey
- Grace Watterson (ORCID: https://orcid.org/0009-0008-6317-2105)
- Mathieu Quesnel-Vallières (ORCID: https://orcid.org/0000-0001-9945-8123)
- Hagen Tilgner (ORCID: https://orcid.org/0000-0002-7058-3606)
- Mateusz Koptyra (ORCID: https://orcid.org/0000-0002-3857-6633)
- Andrei Thomas‐Tikhonenko (ORCID: https://orcid.org/0000-0002-2739-2206)
- Jamie B. Spangler (ORCID: https://orcid.org/0000-0001-8187-3732)
- Adam Resnick (ORCID: https://orcid.org/0000-0003-0436-4189)
- Zhiwei Ang
- Tae Woo Kim (ORCID: https://orcid.org/0000-0001-6737-2739)
- Kai Wang (ORCID: https://orcid.org/0000-0003-3377-6289)
- Daniel Martı́nez
- Jia‐Geng Liu (ORCID: https://orcid.org/0000-0002-8170-7264)
- J DAVIS
- Annette Castro
- Adanna Mogbo
- Berk Mankaliye
Institutions
- Children's Hospital of Philadelphia (US)
- Johns Hopkins University (US)
- Cornell University (US)
- Johns Hopkins Medicine (US)
- MIND Research Institute (US)
- Weill Cornell Medicine (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-08-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116099
- Citations
- 3
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 2.09