Neutrophils promote tumor resistance to radiation therapy.

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.

• Authors: Amy J Wisdom, Cierra S Hong, Alexander J Lin, Yu Xiang, Daniel E Cooper, Jin Zhang, Eric S Xu, Hsuan-Cheng Kuo, Yvonne M Mowery, David J Carpenter, Kushal T Kadakia, Jonathon E Himes, Lixia Luo, Yan Ma, Nerissa Williams, Diana M Cardona, Malay Haldar, Yarui Diao, Stephanie Markovina, Julie K Schwarz, David G Kirsch
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 116 Issue 37 Pg. 18584-18589 (09 10 2019) ISSN: 1091-6490 [Electronic] United States
• PMID: 31462499 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Animals
• Chemoradiotherapy
• Disease Models, Animal
• Disease-Free Survival
• Female
• Humans
• Kaplan-Meier Estimate
• Leukocyte Count
• Mice
• Mice, Transgenic
• Middle Aged
• Neutrophils (immunology)
• Radiation Tolerance (genetics, immunology)
• Retrospective Studies
• Sarcoma (blood, immunology, therapy)
• Uterine Cervical Neoplasms (blood, immunology, mortality, therapy)
• Whole-Body Irradiation
• Young Adult