Discovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression

Timothy I. Shaw, Jessica Wagner, Liqing Tian, Elizabeth Wickman, Suresh Poudel, Jian Wang, Robin Paul, Selene C. Koo, Meifen Lu, Heather Sheppard, Yiping Fan, Francis H. O’Neill, Ching C. Lau, Xin Zhou, Jinghui Zhang () and Stephen Gottschalk ()
Additional contact information
Timothy I. Shaw: St. Jude Children’s Research Hospital
Jessica Wagner: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital
Liqing Tian: St. Jude Children’s Research Hospital
Elizabeth Wickman: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital
Suresh Poudel: Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital
Jian Wang: St. Jude Children’s Research Hospital
Robin Paul: St. Jude Children’s Research Hospital
Selene C. Koo: Department of Pathology, St. Jude Children’s Research Hospital
Meifen Lu: Department of Pathology, St. Jude Children’s Research Hospital
Heather Sheppard: Department of Pathology, St. Jude Children’s Research Hospital
Yiping Fan: St. Jude Children’s Research Hospital
Francis H. O’Neill: The Jackson Laboratory for Genomic Medicine
Ching C. Lau: The Jackson Laboratory for Genomic Medicine
Xin Zhou: St. Jude Children’s Research Hospital
Jinghui Zhang: St. Jude Children’s Research Hospital
Stephen Gottschalk: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47649-y

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