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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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 (<a href="https://scanact.stanford.edu/">https://scanact.stanford.edu/</a>).</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月14日

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  • 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

摘要

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/).