Functional Deorphanization of Tumor-reactive TCRs Uncovers a Landscape of Shared, Immune Dominant Antigens across Cancers
Single-cell sequencing has charted the clonal landscape of tumor-infiltrating T cells, but the antigens that drive these responses remain largely undefined, limiting rational immunotherapy design. Here, we introduce TWISTAR, a platform that systematically deorphanizes single-cell-derived TCRs against tumor transcriptomes. By directly validating TCR engagement, TWISTAR exclusively recovers…
A novel platform, TWISTAR, has been developed to deorphanize single-cell-derived T cells targeting tumor transcriptomes. This breakthrough allows for the direct validation of TCR engagement, ensuring the recovery of functionally immunogenic antigens. When applied to melanoma, breast, and hepatocellular carcinoma patients who responded to immune checkpoint blockade, TWISTAR revealed that tumor-reactive TCRs have the ability to recognize a diverse array of immunogenic targets.
These targets extend beyond neoantigens to encompass peptides from unannotated coding sequences and novel transcripts. Interestingly, many of these antigens are shared across various patients and cancer types, suggesting the existence of communal targets. Moreover, the study observed immune dominance, where multiple clones converge on a few immune dominant epitopes.
These findings collectively paint a broader landscape of tumor immunogenicity, thereby opening up new avenues for the creation of pan-cancer vaccines.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
