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January 22nd, 2025
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Stanford University
cancer biology
biorxiv

SCAN-ACT: Adoptive T Cell Therapy Target Discovery Through Single-Cell Transcriptomics

Testa, S.Open in Google Scholar•Pal, A.Open in Google Scholar•Subramanian, A.Open in Google Scholar•Varma, S.Open in Google Scholar•Tang, J. P.Open in Google Scholar•Graham, D.Open in Google Scholar•Arfan, S.Open in Google Scholar•Pan, M.Open in Google Scholar•Bui, N. Q.Open in Google Scholar•Ganjoo, K. N.Open in Google Scholaret al.

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-specific targets without expression in normal tissues remains a major bottleneck, especially in rare cancer subtypes. Here, we present 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 targets for both chimeric antigen receptor (CAR)- and TCR-T cells. For surface membrane targets, SCAN-ACT proposes 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. 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 5,020 peptide-MHC targets for TCR-T cells. Selected targets were validated experimentally by protein expression and for peptide-MHC binding. Proposed targets and target pairs reflected the mesenchymal, neuronal, and hematopoietic ontogeny of STS. 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.

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