T-cell Priming by High-Avidity Neoantigens in Lymph Nodes Augments Adoptive Immunotherapy

Adoptive transfer of T lymphocytes specific for neoantigens can elicit immunity against solid tumors in patients. However, how these antigens affect T-cell function, effector differentiation, and persistence remains unclear. We examined how an identical CD8+ T-cell product was shaped by melanoma expressing either a low-avidity self/tumor-associated antigen or high-avidity neoantigen and kinetically profiled T-cell differentiation in these two contexts across host tissues. High-avidity neoantigen expression was sufficient to activate naïve CD8+ T cells-leading to robust tumor regression and long-term protective immunity upon tumor rechallenge. Mechanistically, transferred naïve CD8+ T cells reacting to high-avidity neoantigen exhibited enhanced cytokine production, heightened effector function, and sustained persistence compared with the low-avidity wild-type tumors. Antitumor activity to these high-avidity tumors was preserved even in the absence of functional host T and B lymphocytes, and early lymph node (LN) trafficking was found to be essential for adoptive T-cell therapy efficacy. Expanded effector or stem memory T cells were compared with the naïve pmel-1 T-cell product. Stem memory (but not effector memory) cells exhibited similar antitumor efficacy and LN trafficking patterns to the naïve cells in mice with high-avidity neoantigen-expressing tumors. These findings highlight how differential tumor antigens shape divergent cellular fate and uncover a critical role of T-cell trafficking in LNs in shaping high-avidity neoantigen-specific responses.