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The Tumor-Sentinel Lymph Node Immune Migratome Reveals a Key Role for Migratory CCR7+ Dendritic Cells in Response to Immunoradiotherapy [TCR-seq]

ABSTRACT: Surgical ablation or radiation of tumor-draining lymph nodes can eliminate the primary tumor response to immunotherapy, indicating that local tumor response to immunotherapy is mediated by tumor-draining lymph nodes. Here, we show that immunoradiotherapy efficacy is dependent on immune cell migration from tumor to sentinel lymph nodes. Using a tamoxifen-inducible reporter paired with CITE-sequencing in a murine model of oral cancer, we characterized tumor immune cellular migration through lymphatic channels to sentinel lymph nodes at single-cell resolution. Within a structured approach of sequential immunomodulatory radiotherapy and checkpoint inhibition, we demonstrate that lymphatic-sparing, tumor-directed radiotherapy followed by PD-1 inhibition achieves complete and durable tumor responses. Mechanistically, this treatment approach enhances activated, migratory CCR7+ dendritic cell surveillance across the tumor-sentinel lymph node axis, revealing a shift from their canonical role in promoting tolerance to driving antitumor immunity. Overall, this work supports rationally sequencing immune-sensitizing, lymphatic-preserving, tumor-directed radiotherapy followed by immune checkpoint inhibition to optimize the tumor response. By characterizing the tumor-sentinel lymph node immunomigratome that drives durable antitumor response, we reveal a therapeutic opportunity to enhance the response to immunotherapy by optimizing activated dendritic cell migration to tumor-draining sentinel nodes.

ORGANISM(S): Mus musculus

PROVIDER: GSE276437 | GEO | 2025/06/07

REPOSITORIES: GEO

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The Tumor-Sentinel Lymph Node Immune Migratome Reveals a Key Role for Migratory CCR7+ Dendritic Cells in Response to Immunoradiotherapy [TCR-seq]

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