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Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18584-18589. doi: 10.1073/pnas.1901562116. Epub 2019 Aug 28.

Neutrophils promote tumor resistance to radiation therapy.

Author information

1
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27708.
2
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110.
3
Department of Cell Biology, Duke University Medical Center, Durham, NC 27708.
4
Regeneration Next Initiative, Duke University Medical Center, Durham, NC 27708.
5
Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27708.
6
Department of Pathology, Duke University Medical Center, Durham, NC 27708.
7
Department of Pathology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
8
Department of Orthopedic Surgery, Duke University Medical Center, Durham, NC 27708.
9
Department of Cell Biology and Physiology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110.
10
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27708; david.kirsch@duke.edu.

Abstract

Nearly two-thirds of cancer patients are treated with radiation therapy (RT), often with the intent to achieve complete and permanent tumor regression (local control). RT is the primary treatment modality used to achieve local control for many malignancies, including locally advanced cervical cancer, head and neck cancer, and lung cancer. The addition of concurrent platinum-based radiosensitizing chemotherapy improves local control and patient survival. Enhanced outcomes with concurrent chemoradiotherapy may result from increased direct killing of tumor cells and effects on nontumor cell populations. Many patients treated with concurrent chemoradiotherapy exhibit a decline in neutrophil count, but the effects of neutrophils on radiation therapy are controversial. To investigate the clinical significance of neutrophils in the response to RT, we examined patient outcomes and circulating neutrophil counts in cervical cancer patients treated with definitive chemoradiation. Although pretreatment neutrophil count did not correlate with outcome, lower absolute neutrophil count after starting concurrent chemoradiotherapy was associated with higher rates of local control, metastasis-free survival, and overall survival. To define the role of neutrophils in tumor response to RT, we used genetic and pharmacological approaches to deplete neutrophils in an autochthonous mouse model of soft tissue sarcoma. Neutrophil depletion prior to image-guided focal irradiation improved tumor response to RT. Our results indicate that neutrophils promote resistance to radiation therapy. The efficacy of chemoradiotherapy may depend on the impact of treatment on peripheral neutrophil count, which has the potential to serve as an inexpensive and widely available biomarker.

KEYWORDS:

cancer biology; genetically engineered mouse model; neutrophil; radiation therapy; radiosensitivity

PMID:
31462499
PMCID:
PMC6744874
[Available on 2020-02-28]
DOI:
10.1073/pnas.1901562116

Conflict of interest statement

Conflict of interest statement: D.G.K. is a cofounder of XRAD Therapeutics, which is developing radiosensitizers.

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