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

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.