Researchers at Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania developed a new screening technology, Aptamer-based T Lymphocyte Activity Screening and SEQuencing (ATLAS-seq), to better identify antigen-reactive T cells that are more likely to offer greater immune responses against cancer cells. The findings were reported this week in the journal Nature Communications.
Researchers continuously work to develop immunotherapy treatments that help the immune system recognize and attack specific protein targets on cancer cells, also known as tumor antigens, thereby training the body to fight cancer more effectively and precisely. Discovering antigen-reactive T cell receptors (TCRs) is essential to this precision medicine approach.
TCRs are protein complexes located on the surface of T cells that recognize and bind to antigen peptides presented by major histocompatibility complex (MHC) molecules, triggering a cascade of cellular responses that lead to T cell activation. However, standard methods for isolating antigen-reactive TCRs often fail to identify TCRs that effectively activate T cells.
“TCRs identified by ATLAS-seq tend to be more efficient in target cell killing than those identified by conventional technologies,” said Lan Lin, PhD, senior author of the study and Assistant Professor in Pathology and Laboratory Medicine at Children’s Hospital of Philadelphia and Penn Medicine. “Overall, ATLAS-seq improves TCR screening to more effectively identify antigen-reactive TCRs with high functional activity.”
The ATLAS-seq technology combines a single-cell approach with an aptamer-based fluorescent molecular sensor that emits a fluorescence signal when a T cell is activated. In the study, the researchers designed a microfluidic system to isolate individual T cells that react to stimulation by an antigen peptide of interest and determined their unique TCR sequences using single-cell sequencing.
“We envision that ATLAS-seq can play a pivotal role in identifying TCRs targeting tumor antigens, driving the development of novel T cell immunotherapies for a broad range of hard-to-treat cancers,” said Lin, who is also a researcher in the Raymond G. Perelman Center for Cellular and Molecular Therapeutics and the Center for Computational and Genomic Medicine at CHOP.
This work was supported by National Institutes of Health grant R01GM121827, W.W. Smith Charitable Trust grant C2004 and a CHOP Research Institute Cell & Gene Therapy Collaborative seed grant.
Luo et al. “ATLAS-seq: a microfluidic single-cell TCR screen for antigen-reactive TCRs.” Nat Commun. January 2, 2025. DOI:10.1038/s41467-024-54675-3.
