Tumor-draining lymph node derived CD8⁺ T cells sustain durable systemic immunity after neoadjuvant IL-15 and PD-1 blockade

Abstract The tumor-draining lymph node (tdLN) serves as a critical reservoir of tumor-reactive T cells, yet its contribution to preventing metastatic recurrence remains poorly understood. In this study, we investigate CD8⁺ T cell clonal dynamics and memory responses induced by neoadjuvant anti–PD-1 therapy. We demonstrate that PD-1 blockade promotes the emergence of protective CD8⁺ T cell memory, enriched with tumor-relevant clones that persist in the lymph nodes of long-term survivors. Furthermore, we show that combination of a neoadjuvant IL-15 superagonist with PD-1 blockade significantly increases clonal diversity, cytotoxicity, and clonal persistence in non-draining lymph nodes. These changes result in enhanced systemic antitumor immunity and durable memory that prevents tumor relapse. Our findings establish the tdLN as a critical immunologic hub that can be therapeutically targeted by IL-15 to augment PD-1 blockade efficacy and support a rationale for a phase II neoadjuvant combination immunotherapy trial in early-stage NSCLC. One sentence summary Neoadjuvant IL-15 with PD-1 blockade expands lymph node clonal diversity and preserves stem-like CD8⁺ T cell features, yielding superior antitumor efficacy, durable memory, and reduced metastatic recurrence.