The successful combination of immunotherapy and radiation therapy (RT) depends on better understanding how RT modulates the tumor microenvironment, especially tumor-infiltrating leukocytes (TILs). Using multiple syngeneic mouse tumor models, we recently reported (Takeshima et al, PNAS, 2016) that RT induces a rapid infiltration of CD11b+Gr-1high neutrophils into tumors within 24 to 48 hours (Fig 1). These RT-recruited tumor-associated neutrophils (RT-Ns) exhibit an increased production of reactive oxygen species and induce apoptosis of tumor cells. Notably, RT-Ns do not express F4/80 and are not part of myeloid-derived suppressor cells (MDSCs). Importantly, RT-Ns are at least in part responsible for the tumor inhibition effects of RT (Fig 2). Furthermore, concurrent administration of granulocyte colony stimulating factor (G-CSF), a well-known stimulator of neutrophils, enhances anti-tumor effects of RT (Fig 3). In addition, G-CSF enhances RT-mediated production of tumor-specific cytotoxic T lymphocytes (CTLs) in the tumor, and this effect depends on RT-Ns (Fig 4).
All these findings suggest that RT-Ns play an important role in RT-induced anti-tumor immunity. These newly discovered early events of RT-Ns indicate a tumor-specific response that reveals anti-tumor properties. Such innate and inflammatory responses often pave the way for more specific adaptive immune responses although their underlying mechanisms are largely unknown. Therefore, neutrophils may be the missing link to how DNA-sensing pathway activation leads to anti-tumor immunity. Exploiting this mechanism can optimize RT-induced DNA-sensing activation, leading to a more robust anti-tumor immune response and eventually overcoming tumors’ resistance to immunotherapy. Currently, we are investigating the mechanisms underlying the accumulation of RT-Ns in the tumor after RT. Specifically, we are identifying which DNA-sensing pathways and which adhesion molecules, cytokines, and chemokines as a downstream effect of DNA-sensing are responsible for recruiting RT-Ns. In addition, we hypothesize that RT-Ns are the key to enhancing DNA sensing by RT. Therefore, we are also identifying the mechanism of enhanced DNA sensing by RT-Ns. Furthermore, we are evaluating anti-tumor effects of potentiating DNA sensing effect of RT-Ns with other drugs (e.g. G-CSF + beta-lapachone).