PRECISE-seq links TCR potency to T cell fate in the tumor microenvironment. (A) Schematic of the PRECISE-seq workflow. T cells conjugated with an AP-HA tag are cocultured with antigen-presenting cells expressing SrtA. Upon formation of an immunological synapse, SrtA catalyzes the transfer of biotinylated probes onto adjacent T cells in a contact-dependent manner. The resulting labeling intensity reflects TCR-pMHC interaction strength. Biotin+ T cells are subsequently isolated and subjected to scRNA-seq coupled with TCR profiling, enabling simultaneous readout of antigen specificity, functional potency, and cellular phenotype. (B) Model of tumor-specific T cell fate decisions revealed by PRECISE-seq. Effector P14 T cells are adoptively transferred into C57BL/6 mice bearing MC38-gp33 tumors, with or without αPD-1 antibody treatment. PRECISE-seq analysis shows that tumor-specific TCM /TEM can differentiate into an immunosuppressive TLy49. PD-1 blockade reduces TLy49 differentiation while promoting effector TEM/TEFF expansion. AP-HA tag, acceptor peptide–HA tag; TCM, central memory T cells. Refer to the image caption for details. Panel A: A schematic illustrates biotin labeling of antigen-specific T cells followed by single-cell sequencing to identify TCR sequence, potency, and phenotype. Panel B: A workflow diagram shows transferred effector P14 T cells in mice analyzed after anti-PD-1 treatment using PRECISE-seq profiling.

PRECISE-seq links TCR potency to T cell fate in the tumor microenvironment. (A) Schematic of the PRECISE-seq workflow. T cells conjugated with an AP-HA tag are cocultured with antigen-presenting cells expressing SrtA. Upon formation of an immunological synapse, SrtA catalyzes the transfer of biotinylated probes onto adjacent T cells in a contact-dependent manner. The resulting labeling intensity reflects TCR-pMHC interaction strength. Biotin+ T cells are subsequently isolated and subjected to scRNA-seq coupled with TCR profiling, enabling simultaneous readout of antigen specificity, functional potency, and cellular phenotype. (B) Model of tumor-specific T cell fate decisions revealed by PRECISE-seq. Effector P14 T cells are adoptively transferred into C57BL/6 mice bearing MC38-gp33 tumors, with or without αPD-1 antibody treatment. PRECISE-seq analysis shows that tumor-specific TCM /TEM can differentiate into an immunosuppressive TLy49. PD-1 blockade reduces TLy49 differentiation while promoting effector TEM/TEFF expansion. AP-HA tag, acceptor peptide–HA tag; TCM, central memory T cells.

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