Functional Deorphanization of Tumor-reactive TCRs Uncovers a Landscape of Shared, Immune Dominant Antigens across Cancers
A biorxiv preprint introduces TWISTAR, a platform that deorphanizes single-cell-derived TCRs by screening them against tumor transcriptomes, validating actual TCR engagement so only functionally immunogenic antigens are recovered. Applied to melanoma, breast, and hepatocellular carcinoma patients responding to immune checkpoint blockade, it shows tumor-reactive TCRs recognize targets beyond neoantigens—including peptides from unannotated coding sequences and novel transcripts—many shared across patients and cancer types, with multiple clones converging on a few immune-dominant epitopes. Why it matters: shared, immune-dominant antigens are the prerequisite for off-the-shelf or pan-cancer vaccines, and the finding that the immunogenic landscape is broader than the neoantigen set expands the addressable target space. The work is method-stage and retrospective on ICB responders; no prospective vaccine validation is reported, so watch for independent replication and whether the platform is productized by an antigen-discovery player.