Abstract Adoptive T-cell therapy (ACT), particularly tumor-infiltrating lymphocyte (TIL) therapy, demonstrates that durable regression of solid tumors can occur when polyclonal T cells target authentic tumor antigens, including private neoantigens. Yet scalable identification of tumor-reactive clonotypes remains limited because the relevant cells are rare, patient-specific, and poorly captured by indirect markers, expansion behavior, or predictive algorithms. We examined whether productive engagement between T cells and tumor cells or antigen-presenting cells provides a more direct organizing principle for tumor-reactive T-cell discovery. Across published tumor and blood datasets reanalyzed here, T cells recovered through physical clustering, target-cell extraction, or antigen-dependent activation are enriched for clonotypes occupying antigen-experienced, progenitor-like states with restrained cytotoxic differentiation. Productive engagement can therefore serve as a practical enrichment variable, enabling recovery of rare neoantigen-reactive T cells from circulation while preserving developmental states associated with persistence and therapeutic responsiveness. These analyses support a shift in tumor-specific T-cell discovery from prediction-first nomination to interaction-first recovery: enrich for T cells bearing evidence of prior tumor-antigen encounter in vivo, recover clonotypes preserved in a restrained progenitor-like state, expand them before culture competition erases them, and reinforce them therapeutically with matched antigenic information.
Restifo, N. P., Vodnala, S. K., Thompson, D. B., Klemen, N. D., Mellman, I., Millanova, D.
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