Saddawi-Konefka Robert, Msari Riyam Al, Tang Shiqi, Philips Chad, Sadat Sayed, Clubb Lauren M, Luna Sarah, Fassardi Santiago, Jones Riley, Pietryga Ida Franiak, Faraji Farhoud, Schokrpur Shiruyeh, Yung Bryan S, Allevato Michael M, Decker Kelsey E, Nasamran Chanond A, Chilin-Fuentes Daisy, Rosenthal Sara Brin, Jensen Shawn M, Fox Bernard A, Bell R Bryan, Gutkind J Silvio, Sharabi Andrew, Califano Joseph A
Department of Otolaryngology-Head and Neck Surgery, UC San Diego School of Medicine, San Diego, CA, USA.
Moores Cancer Center, UC San Diego, La Jolla, CA, USA.
Nat Commun. 2025 Jul 17;16(1):6578. doi: 10.1038/s41467-025-61780-4.
Surgical ablation or broad radiation of tumor-draining lymph nodes can eliminate the primary tumor response to immunotherapy, highlighting the crucial role of these nodes in mediating the primary tumor response. Here, we show that immunoradiotherapy efficacy is dependent on treatment sequence and migration of modulated dendritic cells from tumor to sentinel lymph nodes. Using a tamoxifen-inducible reporter paired with CITE-sequencing in a murine model of oral cancer, we comprehensively characterize tumor immune cellular migration through lymphatic channels to sentinel lymph nodes at single-cell resolution, revealing a unique immunologic niche defined by distinct cellular phenotypic and transcriptional profiles. Through a structured approach of sequential immunomodulatory radiotherapy and checkpoint inhibition, we show that sequenced, lymphatic-sparing, tumor-directed radiotherapy followed by PD-1 inhibition achieves complete and durable tumor responses. Mechanistically, this treatment approach enhances migration of activated 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 tumor response to immunoradiotherapy by driving activated dendritic cells to draining sentinel lymph nodes.
对引流肿瘤的淋巴结进行手术切除或广泛放疗可消除原发性肿瘤对免疫疗法的反应，突出了这些淋巴结在介导原发性肿瘤反应中的关键作用。在此，我们表明免疫放疗疗效取决于治疗顺序以及经调节的树突状细胞从肿瘤向哨位淋巴结的迁移。在口腔癌小鼠模型中，我们使用他莫昔芬诱导型报告基因与细胞索引测序相结合，以单细胞分辨率全面表征肿瘤免疫细胞通过淋巴通道向哨位淋巴结的迁移，揭示了由不同细胞表型和转录谱定义的独特免疫生态位。通过序贯免疫调节放疗和检查点抑制的结构化方法，我们表明先进行有序的、保留淋巴的、针对肿瘤的放疗，然后进行PD-1抑制，可实现完全且持久的肿瘤反应。从机制上讲，这种治疗方法增强了活化的CCR7+树突状细胞监测在肿瘤-哨位淋巴结轴上的迁移，揭示了它们从促进耐受的典型作用向驱动抗肿瘤免疫的转变。总体而言，这项工作支持合理安排免疫致敏、保留淋巴的、针对肿瘤的放疗顺序，随后进行免疫检查点抑制，以通过驱动活化的树突状细胞向引流的哨位淋巴结迁移来优化肿瘤对免疫放疗的反应。
