Using orthotopic 4MOSC murine models, Saddawi-Konefka et al. showed that the preferential migration of immune cells to the tumor-draining sentinel lymph nodes (SLNs) creates a unique immunologic niche with distinct cellular composition and transcriptional profiles. Sequencing tumor-directed lymphatic-sparing immunomodulatory radiation therapy prior to anti-PD-1 therapy enhanced local immunosurveillance, antigen presentation, and the efficacy of anti-PD-1 therapy, leading to a high rate of durable cures. MMP9-dependent entry of CCR7+ dendritic cells into the SLN was critical for the efficacy of tumor-directed immunoradiotherapy.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Department of Otolaryngology-Head and Neck Surgery, UC San Diego School of Medicine, San Diego, CA, USA. rsaddawi@health.ucsd.edu. Moores Cancer Center, UC San Diego, La Jolla,
Author Info: (1) Department of Otolaryngology-Head and Neck Surgery, UC San Diego School of Medicine, San Diego, CA, USA. rsaddawi@health.ucsd.edu. Moores Cancer Center, UC San Diego, La Jolla, CA, USA. rsaddawi@health.ucsd.edu. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. rsaddawi@health.ucsd.edu. (2) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. (3) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. (4) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. (5) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. (6) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Department of Pharmacology, UC San Diego, La Jolla, CA, USA. (7) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. (8) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. (9) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Department of Radiation Medicine and Applied Sciences, UC San Diego School of Medicine, San Diego, CA, USA. (10) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Department of Radiation Medicine and Applied Sciences, UC San Diego School of Medicine, San Diego, CA, USA. (11) 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. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. (12) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Department of Medicine, Division of Hematology-Oncology, UC Davis, Sacramento, CA, USA. (13) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Department of Pharmacology, UC San Diego, La Jolla, CA, USA. (14) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Department of Pharmacology, UC San Diego, La Jolla, CA, USA. (15) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. (16) Center for Computational Biology & Bioinformatics, Department of Medicine, University of California, San Diego, La Jolla, CA, USA. (17) Center for Computational Biology & Bioinformatics, Department of Medicine, University of California, San Diego, La Jolla, CA, USA. (18) Center for Computational Biology & Bioinformatics, Department of Medicine, University of California, San Diego, La Jolla, CA, USA. (19) Earle A Chiles Research Institute, Robert W Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR, USA. Department of Molecular Microbiology and Immunology, Oregon Health Science University, Portland, OR, USA. (20) Earle A Chiles Research Institute, Robert W Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR, USA. Department of Molecular Microbiology and Immunology, Oregon Health Science University, Portland, OR, USA. (21) Earle A Chiles Research Institute, Robert W Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR, USA. Department of Molecular Microbiology and Immunology, Oregon Health Science University, Portland, OR, USA. (22) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Department of Pharmacology, UC San Diego, La Jolla, CA, USA. (23) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Department of Radiation Medicine and Applied Sciences, UC San Diego School of Medicine, San Diego, CA, USA. (24) Department of Otolaryngology-Head and Neck Surgery, UC San Diego School of Medicine, San Diego, CA, USA. jcalifano@health.ucsd.edu. Moores Cancer Center, UC San Diego, La Jolla, CA, USA. jcalifano@health.ucsd.edu. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. jcalifano@health.ucsd.edu.
