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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| Format: | Article |
| Language: | English |
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BMC
2025-08-01
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| Series: | Genome Medicine |
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| Online Access: | https://doi.org/10.1186/s13073-025-01514-9 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Stefano Testa |
| collection | DOAJ |
| description | 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/ ). |
| format | Article |
| id | doaj-art-da4eedac3e3045e3b667dcd6b84e850c |
| institution | Kabale University |
| issn | 1756-994X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj-art-da4eedac3e3045e3b667dcd6b84e850c2025-08-20T03:46:28ZengBMCGenome Medicine1756-994X2025-08-0117114410.1186/s13073-025-01514-9SCAN-ACT: adoptive T cell therapy target discovery through single-cell transcriptomicsStefano Testa0Aastha Pal1Ajay Subramanian2Sushama Varma3Jack Pengfei Tang4Danielle Graham5Sara Arfan6Minggui Pan7Nam Q. Bui8Kristen N. Ganjoo9Sarah Dry10Paul Huang11Matt van de Rijn12Wei Jiang13Anusha Kalbasi14Everett J. Moding15Department of Medicine, Stanford UniversityDepartment of Radiation Oncology, Stanford UniversityDepartment of Radiation Oncology, Stanford UniversityDepartment of Pathology, Stanford UniversityDepartment of Pediatrics, Boston Children’s HospitalDepartment of Surgery, Cedars-Sinai Medical CenterDivision of Molecular Pathology, The Institute of Cancer ResearchDivision of Oncology, Department of Medicine, Stanford UniversityDivision of Oncology, Department of Medicine, Stanford UniversityDivision of Oncology, Department of Medicine, Stanford UniversityDepartment of Pathology, University of CaliforniaDivision of Molecular Pathology, The Institute of Cancer ResearchDepartment of Pathology, Stanford UniversityJWE Science Technology, IncDepartment of Radiation Oncology, Stanford UniversityDepartment of Radiation Oncology, Stanford UniversityAbstract 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/ ).https://doi.org/10.1186/s13073-025-01514-9Cellular therapyCAR-T cellsTCR-T cellsPeptide-centric CAR-TLogic-gated CAR-TSingle-cell RNA sequencing |
| spellingShingle | 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 SCAN-ACT: adoptive T cell therapy target discovery through single-cell transcriptomics Genome Medicine Cellular therapy CAR-T cells TCR-T cells Peptide-centric CAR-T Logic-gated CAR-T Single-cell RNA sequencing |
| title | SCAN-ACT: adoptive T cell therapy target discovery through single-cell transcriptomics |
| title_full | SCAN-ACT: adoptive T cell therapy target discovery through single-cell transcriptomics |
| title_fullStr | SCAN-ACT: adoptive T cell therapy target discovery through single-cell transcriptomics |
| title_full_unstemmed | SCAN-ACT: adoptive T cell therapy target discovery through single-cell transcriptomics |
| title_short | SCAN-ACT: adoptive T cell therapy target discovery through single-cell transcriptomics |
| title_sort | scan act adoptive t cell therapy target discovery through single cell transcriptomics |
| topic | Cellular therapy CAR-T cells TCR-T cells Peptide-centric CAR-T Logic-gated CAR-T Single-cell RNA sequencing |
| url | https://doi.org/10.1186/s13073-025-01514-9 |
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