Radiation Exposure Primes Neutrophil-Mediated Metastasis to the Lung

Patients with cancer commonly receive radiotherapy to achieve local tumor control, but the clinical impact of exposing neighboring healthy tissues to radiation-induced damage is not completely understood. To address how radiation-induced injury may contribute to disease progression, Nolan and colleagues used multiple murine models to investigate the effect of lung irradiation on breast cancer metastasis to the lung, observing that pre-exposure of lung tissue to radiation enhanced metastatic burden following transplantation of cancer cells with high or low metastatic frequencies. Analysis of lung tissue 1 week after radiation revealed substantial neutrophil infiltration as well as morphologic and proteomic phenotypes indicative of proinflammatory neutrophil activation. Administration of anti-LY6G antibodies to drive neutrophil depletion or knockout of Csf3, which encodes G-CSF to prevent neutrophil mobilization, reversed the phenotype of enhanced metastasis following radiation, whereas adoptive transfer of radiation-primed neutrophils was sufficient to increase metastatic burden, suggesting that neutrophils play a central role in regulating metastatic colonization. Notably, when lung epithelial cells were isolated from mice irradiated in the presence or absence of neutrophils, only lung cells primed by neutrophils were able to form organoids, implying that neutrophils promote fitness and progenitor function following injury. Analysis of the neutrophil-driven transcriptional response in lung epithelial cells upon radiation identified an enrichment in Notch signaling, a pathway known to regulate many processes including tissue repair, with Notch activation in lung alveoli being sufficient to foster lung metastasis. In agreement with these observations, pharmacologic inhibition of Notch signaling significantly reduced the growth of tumor metastases in irradiated lungs. Together, this work describes a tissue damage response that inadvertently preconditions sites for metastatic colonization and elucidates a role for neutrophils in supporting tumor progression in the context of injury. Current technologies for radiotherapy administration are effective at strongly limiting off-target effects; therefore, these findings encourage attention to neutrophil response and demonstrate mechanisms of exploitation to improve radiation treatment.

Nolan E, Bridgeman VL, Ombrato L, Karoutas A, Rabas N, Sewneth CAN, et al. Radiation exposure elicits a neutrophil-driven response in healthy lung tissue that enhances metastatic colonization. Nat Cancer 2022;3:173–87.

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