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SCAN-ACT: adoptive T cell therapy target discovery through single-cell transcriptomics
Stefano Testa1,2, Aastha Pal3, Ajay Subramanian3
1Department of Medicine, Stanford University, Stanford, CA, USA.
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/ ).
Insights
SCAN-ACT is a computational pipeline that identifies tumor-specific targets for adoptive T cell therapies (ACTs). It analyzes single-cell data to accelerate the development of novel cancer treatments for solid tumors.
Area of Science:
- Immunology
- Genomics
- Computational Biology
Background:
- Adoptive T cell therapies (ACTs) show promise for solid tumors, but identifying suitable tumor-specific targets is challenging.
- Rare cancer subtypes particularly suffer from a lack of well-defined targets for T cell receptor-engineered T cells (TCR-T) and chimeric antigen receptor (CAR)-T cells.
Purpose of the Study:
- To develop a computational pipeline (SCAN-ACT) for nominating and prioritizing targets for ACTs in solid tumors.
- To enable the identification of both surface membrane and peptide-MHC targets for CAR-T and TCR-T cell therapies, respectively.
Main Methods:
- SCAN-ACT utilizes single-cell RNA sequencing and multi-omics data from tumor and normal tissues.
- It nominates monospecific and bispecific targets for CAR-T cells and peptide-MHC targets for TCR-T cells.
- Experimental validation of protein expression and peptide-MHC binding was performed for selected targets.
Main Results:
- Applied to soft tissue sarcoma (STS), SCAN-ACT identified 395 monospecific CAR-T targets, 14,192 bispecific CAR-T targets, and 5020 peptide-MHC targets.
- The identified targets reflected the diverse cellular origins within STS.
- The pipeline's versatility was further demonstrated through its application to glioblastoma.
Conclusions:
- SCAN-ACT provides a robust data repository and user-friendly web tools to advance ACT development for solid tumors.
- This resource aims to accelerate the discovery of novel therapeutic targets for challenging cancer types.
