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| Home > Publications database > Low-dose radiotherapy synergizes with PD-1 blockade to achieve durable survival in advanced NSCLC through antitumor neutrophil programming. |
| Home > Publications database > Low-dose radiotherapy synergizes with PD-1 blockade to achieve durable survival in advanced NSCLC through antitumor neutrophil programming. |
| Journal Article | DKFZ-2026-01084 |
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2026
Macmillan Publishers, part of Springer Nature
London
Abstract: The optimal strategy for combining radiotherapy (RT) and immunotherapy remains under intensive investigation. Here we developed TRIDENT (Triple Radio-Immunotherapy-Driven ENhanced Therapy), a novel triple-modality regimen combining immunomodulatory low-dose RT (LDRT) to large tumor(s), immunogenic high-dose RT (HDRT) to small tumor(s), and PD-1 blockade. In our phase I trial of 29 patients with treatment-naïve, PD-L1-positive advanced non-small cell lung cancer (NSCLC), TRIDENT achieved a median overall survival (mOS) of 51.3 months (95% CI, 20.7-not reached), higher than outcomes typically reported with contemporary standard (chemo)immunotherapy. This durable survival signal was corroborated in an independent real-world cohort of 97 patients with advanced lung cancer (mOS: 41.5 months; 95% CI, 26.3-63.7). Mechanistically, TRIDENT elicited neutrophil-dependent, systemic antitumor immunity and induced a distinct population of antitumor TNF-α⁺ neutrophils marked by increased MHC and costimulatory molecule expression. Neutrophil recruitment was driven by the CXCL-CXCR2 axis, and polarization toward an antitumor state was programmed by treatment-induced IFN-γ and GM-CSF. TNF-α⁺ neutrophils enhanced CD8⁺ T-cell function via ICAM-1-LFA-1 interactions, and adoptive transfer confirmed their intrinsic antitumor activity in vivo. Spatial transcriptomics of patient tumor tissues further identified a TNF-α+ neutrophil-effector CD8+ T-cell niche after TRIDENT, providing a stimulatory signal to effector CD8⁺ T cells. In line with these mechanistic findings, clinical biomarker analyses linked neutrophil number with prolonged survival. TRIDENT activates an RT-driven neutrophil-CD8⁺ T-cell axis and promotes survival-associated neutrophil activation. These mechanistic insights, coupled with durable survival in our phase I trial, position TRIDENT as a promising strategy for metastatic NSCLC currently undergoing randomized phase II evaluation. Our study also highlights TNF-α+ neutrophils as a promising therapeutic strategy to enhance antitumor efficacy.
Keyword(s): Humans (MeSH) ; Carcinoma, Non-Small-Cell Lung: immunology (MeSH) ; Carcinoma, Non-Small-Cell Lung: radiotherapy (MeSH) ; Carcinoma, Non-Small-Cell Lung: therapy (MeSH) ; Carcinoma, Non-Small-Cell Lung: pathology (MeSH) ; Carcinoma, Non-Small-Cell Lung: genetics (MeSH) ; Lung Neoplasms: immunology (MeSH) ; Lung Neoplasms: radiotherapy (MeSH) ; Lung Neoplasms: pathology (MeSH) ; Lung Neoplasms: therapy (MeSH) ; Lung Neoplasms: genetics (MeSH) ; Lung Neoplasms: mortality (MeSH) ; Female (MeSH) ; Male (MeSH) ; Neutrophils: immunology (MeSH) ; Middle Aged (MeSH) ; Aged (MeSH) ; Programmed Cell Death 1 Receptor: antagonists & inhibitors (MeSH) ; Programmed Cell Death 1 Receptor: immunology (MeSH) ; Programmed Cell Death 1 Receptor: genetics (MeSH) ; Immune Checkpoint Inhibitors: administration & dosage (MeSH) ; Programmed Cell Death 1 Receptor ; PDCD1 protein, human ; Immune Checkpoint Inhibitors
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