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Updated: Jun 27, 2025
Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Discovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression
Timothy I Shaw1,2, Jessica Wagner3, Liqing Tian1,3
1Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
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.
Insights
Researchers identified novel cancer-specific exon targets for chimeric antigen receptor T cell immunotherapy in pediatric solid and brain tumors. This discovery expands the potential for effective cancer treatments by uncovering new targets with high specificity.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
- Bioinformatics
Background:
- Chimeric antigen receptor T cell (CAR-T) immunotherapy for pediatric solid and brain tumors is limited by the scarcity of suitable targetable antigens.
- Cancer-specific exons represent an underexplored source of highly specific tumor targets.
- Systematic, pan-cancer validation of these exon targets is lacking.
Purpose of the Study:
- To systematically identify and validate cancer-specific exon targets for pediatric solid and brain tumors.
- To develop novel CAR-T cell therapies targeting these identified antigens.
Main Methods:
- Analysis of 1532 RNA-sequencing datasets from 16 pediatric tumor types compared to normal tissues using a novel bioinformatics workflow.
- Identification of genes encoding surfaceome or matrisome proteins with cancer-specific exons.
- Validation of selected targets (e.g., fibronectin 1 EDB domain, COL11A1) in patient-derived xenograft models.
- Generation and testing of CAR-T cells targeting validated antigens.
Main Results:
- Discovery of 2933 cancer-specific exons in 157 genes, with high specificity at the gene (148 genes) or alternatively spliced isoform (9 genes) level.
- Validation of expression for selected alternatively spliced and gene targets in pediatric xenograft tumors.
- Demonstration of antitumor activity by CAR-T cells engineered to target the fibronectin 1 EDB domain or COL11A1.
Conclusions:
- A comprehensive list of cancer-specific exon targets has been identified, offering a promising resource for pediatric solid and brain tumor immunotherapy.
- The developed interactive web portal provides an accessible platform for exploring these novel targets.
- Targeting cancer-specific exons represents a viable strategy to enhance the efficacy and specificity of CAR-T cell therapies in pediatric cancers.
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