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Discovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression
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Discovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression
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Journal Article
Discovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression
2024
Overview
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.
CAR T cell immunotherapy for paediatric solid and brain tumours is constrained by the availability of targetable antigens. Here, the authors investigate the landscape of cancer-specific exons as potential targets by analysing 1,532 RNAseq datasets from 16 types of paediatric solid and brain tumours.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/31
/ 13/44
/ 13/51
/ 38
/ 64/60
/ Animals
/ Antigens
/ Brain
/ Brain Neoplasms - immunology
/ Cancer
/ Child
/ Datasets
/ Exons
/ Gene Expression Regulation, Neoplastic
/ Humanities and Social Sciences
/ Humans
/ Immunotherapy, Adoptive - methods
/ Mice
/ Receptors, Chimeric Antigen - genetics
/ Receptors, Chimeric Antigen - immunology
/ Receptors, Chimeric Antigen - metabolism
/ RNA-Seq
/ Science
/ Tumors
/ Workflow
