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.

The Na+/K+ATPase Regulates Glycolysis and Modifies Immune Metabolism in Tumors

“…Myeloid cells (i.e. type I and type II macrophages, M1 and M2 respectively) were the most abundant immune cell population ( Figure 4E), consistent with previous reports of autochthonous KP sarcomas 44 .…”

“…It will be interesting in future studies to determine the functional consequences of these variations in metabolic reprogramming between immune cell populations, especially upon consideration of previous studies reporting consequences of digoxin on immune cell activity in various noncancerous settings 70,71 . Additional studies of these interactions could illuminate possible synergistic mechanisms that may elicit enhanced clinical efficacy of digoxin when combined with targeted immune therapies as has been found with other compounds 44,72,73 .…”

“…Cells were cultured at 37°C, with 5% atmospheric CO 2 in RPMI-1640 (Gibco), 10% heatinactivated fetal bovine serum (FBS; F2442, Sigma), 100 U/mL penicillin (Gibco), and 100 mg/mL streptomycin (Gibco). HCT-116 cells were obtained from the American Tissue Culture Collection (ATCC), and cultured murine sarcoma cells were generated from primary murine sarcomas described previously 44 and below in "Allograft Mouse Studies".…”

“…Fresh tumor samples were harvested after euthanasia, fixed in 4% PFA overnight, and preserved in 70% ethanol until paraffin embedding. Immunohistochemistry was performed in order to stain for CD31 as previously described 44 . Representative images of each H&E section were captured using a Leica DM IL LED microscope equipped with a Leica MC170HD camera with a 20× objective using LAS EZ software (Leica).…”

Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

“…In addition, a study communicated very recently by Wisdom et al has indicated that TANs may also attenuate the efficacy of traditional anti-cancer therapies such as radiation therapy [42]. In this retrospective, single-centre study conducted during the period 2006-2017, the authors investigated associations between pre-treatment circulating neutrophil counts and responsiveness to definitive chemo-radiation in patients (n = 278) with cervical cancer [42], a malignancy in which the TAN count had previously been reported to be an independent prognostic factor for short recurrence-free survival [43]. Wisdom et al observed that lower pre-treatment circulating neutrophil counts were correlated with enhanced efficacy of chemo-radiation therapy (higher rates of local control, metastasis-free survival and overall survival) [42].…”