SCAN-ACT: adoptive T cell therapy target discovery through single-cell transcriptomics

SCAN-ACT: adoptive T cell therapy target discovery through single-cell transcriptomics

Abstract Background The FDA approval of T cell receptor-engineered T cells (TCR-T) for synovial sarcoma demonstrates the potential for adoptive T cell therapies (ACTs) in solid tumors. However, the paucity of tumor-associated targets without expression in normal tissues remains a major bottleneck, e...

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Main Authors: Stefano Testa, Aastha Pal, Ajay Subramanian, Sushama Varma, Jack Pengfei Tang, Danielle Graham, Sara Arfan, Minggui Pan, Nam Q. Bui, Kristen N. Ganjoo, Sarah Dry, Paul Huang, Matt van de Rijn, Wei Jiang, Anusha Kalbasi, Everett J. Moding
Format: Article
Language:English
Published: BMC 2025-08-01
Series:Genome Medicine
Subjects:
Cellular therapy
CAR-T cells
TCR-T cells
Peptide-centric CAR-T
Logic-gated CAR-T
Single-cell RNA sequencing
Online Access:https://doi.org/10.1186/s13073-025-01514-9
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Summary:Abstract Background The FDA approval of T cell receptor-engineered T cells (TCR-T) for synovial sarcoma demonstrates the potential for adoptive T cell therapies (ACTs) in solid tumors. However, the paucity of tumor-associated targets without expression in normal tissues remains a major bottleneck, especially in rare cancer subtypes. Methods We developed a comprehensive computational pipeline called SCAN-ACT that leverages single-cell RNA sequencing and multi-omics data from tumor and normal tissues to nominate and prioritize putative targets for both chimeric antigen receptor (CAR)- and TCR-T cells. For surface membrane targets, SCAN-ACT proposes monospecific targets and potential target pairs for bispecific Boolean logic-gated CAR T cells. For peptide-MHC targets, SCAN-ACT proposes intracellular peptides bound to a diverse set of human leukocyte antigens. Selected targets were validated experimentally by protein expression and for peptide-MHC binding. Results We applied the SCAN-ACT pipeline to soft tissue sarcoma (STS), analyzing 986,749 single cells to identify and prioritize 395 monospecific CAR-T targets, 14,192 bispecific CAR-T targets, and 5020 peptide-MHC targets for TCR-T cells. Proposed targets and target pairs reflected the mesenchymal, neuronal, and hematopoietic ontogeny of STS. We further validated SCAN-ACT in glioblastoma revealing its versatility. Conclusions This work provides a robust data repository along with a web-based and user-friendly set of analysis tools to accelerate ACT development for solid tumors ( https://scanact.stanford.edu/ ).
ISSN:1756-994X

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