Abstract
We have previously shown a novel antimetastatic role for neutrophils in the premetastatic lung of mice in models of breast cancer. Here we expand on those findings in the context of human breast cancer. We assessed the cytotoxicity of neutrophils from 90 newly diagnosed breast cancer patients, 24 ductal carcinoma in situ patients, 56 metastatic breast cancer patients, and 64 women with no history of cancer. We report that neutrophils from metastatic and newly diagnosed breast cancer patients are significantly more cytotoxic than neutrophils from cancer-free individuals. We hypothesized that tumor-secreted factors ‘prime’ neutrophils to become cytotoxic. To identify these factors we assayed for cytokines in serum from 54 breast cancer patients and 35 cancer-free controls. Tumor necrosis factor (TNFα), MCP-1 (CCL2), and IL1RA significantly correlated with cytotoxicity and directly stimulated neutrophil cytotoxicity ex vivo. RNA-seq analyses found protein kinase C iota (PRKCI) to be over expressed in patient neutrophils relative to neutrophils from cancer-free individuals. PRKCI has been implicated in NADPH oxidase assembly, required for neutrophil-mediated cell cytotoxicity. Treatment of human neutrophils with TNF-induced PRKCI expression and cytotoxicity in samples that had low basal levels of PRKCI expression. To date, this work is the first to demonstrate the cytotoxic role of neutrophils in the peripheral blood of a large cohort of breast cancer patients, and that select cytokines appear to mediate the stimulation of neutrophil cytotoxicity. Further functional studies are necessary to identify clinically relevant means of stimulating neutrophil cytotoxicity as an effective barrier against disease progression and metastasis.
Highlights
Models of cancer progression have long focused on cell-autonomous aberrations of cancer cells, such as sustained proliferation, resistance to apoptotic signals, and increased invasive characteristics
We found that MCP-1, IL1RA, IL1A, and TNF were capable of significantly stimulating neutrophil cytotoxicity relative to unstimulated neutrophils after overnight co-culture, with TNF showing the greatest induction of neutrophil cytotoxic activity (Figure 3a)
We present three key findings reflecting the potential role of neutrophils in mediating cancer progression
Summary
Models of cancer progression have long focused on cell-autonomous aberrations of cancer cells, such as sustained proliferation, resistance to apoptotic signals, and increased invasive characteristics (reviewed in ref. 1). In early stage, premetastatic disease, Granot et al.[6] demonstrated in mouse models that select neutrophils are mobilized and entrained by a primary breast tumor to become cytotoxic against cancer cells; this suggests that neutrophils may acquire the capacity to inhibit metastatic seeding in the lung. Finisguerra et al.[8] showed that MET signaling, while promoting cancer cell proliferation and survival, is required for the recruitment and cytotoxic activity of anti-tumoral neutrophils Translating these findings to human disease, we previously demonstrated that neutrophils collected from the peripheral blood of women newly diagnosed with primary breast cancer were cytotoxic to breast cancer cell lines ex vivo. We hypothesized that neutrophils from the peripheral blood of newly diagnosed breast cancer patients, as compared with healthy controls, are exposed to different cytokines and that these cytokines modulate differences in neutrophil cytotoxicity. Of which may prove helpful for the clinical management of breast cancer patients
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