Key role for neutrophils in radiation-induced antitumor immune responses: Potentiation with G-CSF

Abstract

Radiation therapy (RT), a major modality for treating localized tumors, can induce tumor regression outside the radiation field through an abscopal effect that is thought to involve the immune system. Our studies were designed to understand the early immunological effects of RT in the tumor microenvironment using several syngeneic mouse tumor models. We observed that RT induced sterile inflammation with a rapid and transient infiltration of CD11b + Gr-1 high+ neutrophils into the tumors. RT-recruited tumor-associated neutrophils (RT-Ns) exhibited an increased production of reactive oxygen species and induced apoptosis of tumor cells. Tumor infiltration of RT-Ns resulted in sterile inflammation and, eventually, the activation of tumor-specific cytotoxic T cells, their recruitment into the tumor site, and tumor regression. Finally, the concurrent administration of granulocyte colony-stimulating factor (G-CSF) enhanced RT-mediated antitumor activity by activating RT-Ns. Our results suggest that the combination of RT and G-CSF should be further evaluated in preclinical and clinical settings.radiation therapy | tumor-associated neutrophils | G-CSF

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

“…Neutrophil recruitment by dying tumor cells has been described recently in a mouse model where culture supernatants of tunicamycin- or mitoxanthrone-treated tumor cells were injected into the ear pinnae and in different mouse flank tumors irradiated with high single doses of 15 Gy, 48,49 thus confirming our air pouch findings. The authors of both studies also observed an essential contribution of CXCL1 together with CCL2, CXCL10, and G-CSF.…”

“…Yet, evidence is available that neutrophils can engulf dying tumor cells, exert cytotoxic activity against residual, therapy-surviving tumor cells, and thus can contribute to therapy-induced tumor control. 48,49 Additionally, neutrophils are able to create a favorable chemokine milieu for the invasion of monocytic cells and tumor-specific cytotoxic T cells. 45,49 …”

“…48,49 Additionally, neutrophils are able to create a favorable chemokine milieu for the invasion of monocytic cells and tumor-specific cytotoxic T cells. 45,49 …”

The renaissance of anti‐neoplastic immunity from tumor cell demise

“…Accordingly, depleting CD8 + T cells or interrupting the STING pathway in DC resulted in therapeutic failure . Radiotherapy can also induce sterile inflammation in the TME, indicated by a rapid and transient infiltration of neutrophils, which may be capable of eliminating tumors by releasing ROS …”

“…70 Radiotherapy can also induce sterile inflammation in the TME, indicated by a rapid and transient infiltration of neutrophils, which may be capable of eliminating tumors by releasing ROS. 71 Focal tumor ablation with HIFU, PDT, cryoablation, or radiofrequency ablation can also elicit long-term control of malignancies by boosting systemic immune reactions. These strategies rapidly shrink tumors by causing physical stresses or ROS-mediated damage.…”