Document Type
Article
Publication Date
5-3-2024
Original Citation
Shaw T,
Wagner J,
Tian L,
Wickman E,
Poudel S,
Wang J,
Paul R,
Koo S,
Lu M,
Sheppard H,
Fan Y,
O'Neill F,
Lau C,
Zhou X,
Zhang J,
Gottschalk S.
Discovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression. Nat Commun. 2024;15(1):3732.
Keywords
JGM, Humans, Brain Neoplasms, Animals, Exons, Child, Receptors, Chimeric Antigen, Mice, Immunotherapy, Alternative Splicing, Fibronectins, Xenograft Model Antitumor Assays, Gene Expression Regulation, Neoplastic, RNA-Seq, T-Lymphocytes, Cell Line, Tumor, Immunotherapy, Adoptive
JAX Source
Nat Commun. 2024;15(1):3732.
ISSN
2041-1723
PMID
38702309
DOI
https://doi.org/10.1038/s41467-024-47649-y
Abstract
Immunotherapy with chimeric antigen receptor T cells for pediatric solid and brain tumors is constrained by available targetable antigens. Cancer-specific exons present a promising reservoir of targets; however, these have not been explored and validated systematically in a pan-cancer fashion. To identify cancer specific exon targets, here we analyze 1532 RNA-seq datasets from 16 types of pediatric solid and brain tumors for comparison with normal tissues using a newly developed workflow. We find 2933 exons in 157 genes encoding proteins of the surfaceome or matrisome with high cancer specificity either at the gene (n = 148) or the alternatively spliced isoform (n = 9) level. Expression of selected alternatively spliced targets, including the EDB domain of fibronectin 1, and gene targets, such as COL11A1, are validated in pediatric patient derived xenograft tumors. We generate T cells expressing chimeric antigen receptors specific for the EDB domain or COL11A1 and demonstrate that these have antitumor activity. The full target list, explorable via an interactive web portal ( https://cseminer.stjude.org/ ), provides a rich resource for developing immunotherapy of pediatric solid and brain tumors using gene or AS targets with high expression specificity in cancer.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.