Engineered T Cells Attack PD-L1-Bearing Cancer and Immune Cells

Tumours frequently evade immune attack by upregulating PD-L1, which dampens T-cell activity and sustains an immunosuppressive microenvironment. Building on their earlier identification of naturally occurring PD-L1-specific T cells, the team reconstructed a PD-L1-directed receptor (PDL101-TCR) from a patient-derived clone. Using non-viral CRISPR-Cas9 editing, they inserted it into the TRAC locus of CD8+ T cells from seven healthy donors while knocking out the endogenous TRBC loci to prevent receptor mispairing.

The edited cells produced IFN-γ and TNF-α on antigen encounter and lysed peptide-loaded targets into the low picomolar range. They preferentially killed PD-L1-positive cutaneous T-cell lymphoma cells and responded to tumour-associated macrophage- and MDSC-like myeloid subsets, both of which contribute to local immunosuppression.

Stimulation with peptide-loaded dendritic cells expanded the modest initial editing yield roughly five- to six-fold, pointing to scope for in vivo boosting through vaccination. The authors argue that a physiological, MHC-restricted receptor may carry a lower on-target, off-tumour toxicity risk than engineered PD-L1 CARs – though this remains to be confirmed. The work is framed as an early, in vitro proof-of-concept rather than a clinical candidate.

The study was led by Thomas Landkildehus Lisle and Emilie Bülow Jacobsen, with senior author Mads Hald Andersen, at the National Center for Cancer Immune Therapy (CCIT-DK), Copenhagen University Hospital Herlev, in collaboration with the Department of Biomedicine at Aarhus University. It was published as a Letter in Signal Transduction and Targeted Therapy on 24 June 2026.