Hallmarks of Neutrophil Anti Tumor Cytotoxicity

The role neutrophils play in tumor growth and metastatic progression has been a matter of debate as they were shown to possess both tumor promoting and tumor inhibitory traits. The capacity of neutrophils to limit tumor growth and metastatic progression is largely attributed to their ability to selectively kill tumor cells. Whereas the process is highly specific it is also very complex. Neutrophils are expected to migrate towards tumor cells, identify them as a target and induced tumor cell apoptosis. We have previously shown that tumor-secreted factors (G-CSF, GM-CSF) mobilize and activate (CCL2 and others) neutrophils. These neutrophils are attracted to tumor-secreted chemokines such as CXCL2 and identify surface molecules such as RAGE to target and eliminate tumor cells. Neutrophils eliminate tumor cells in an H₂O₂-dependent mechanism. Unexpectedly, we found that rather than inducing apoptosis via oxidative stress, neutrophil secreted H₂O₂ induces a transient but lethal increase in free intracellular Ca²⁺. Furthermore, we found that H₂O₂ induces an influx of Ca²⁺ from the extracellular milieu rather than from intracellular stores suggesting the involvement of an H₂O₂ dependent Ca²⁺ channel. Indeed, we found that neutrophil secreted H₂O₂ activates TRPM2, a ubiquitously expressed Ca²⁺ channel which is frequently upregulated in tumors. High levels of TRPM2 render tumor cells more susceptible to neutrophil cytotoxicity whereas low TRPM2 levels render tumor cells neutrophil resistant. Taken together these observations provide insight into key processes that mediate neutrophil anti-tumor cytotoxicity. However, neutrophils’ anti-tumor potential is rarely evident at the primary tumor due to high levels of TGFβ – a potent immunosuppressive factor. While this limits neutrophils’ contribution to tumor eradications it concomitantly highlights potential targets that may be utilized for future, neutrophil-based anti-tumor immunotherapies.