Abstract
The role of neutrophils in cancer is still very contradictory. Several studies have demonstrated the cytotoxic capacity of neutrophils against different types of tumors, by releasing inflammatory cytokines, ROS and activating other immune cells. On the other hand, recent papers have claimed the protumorigenic action of neutrophils, mainly by changing their phenotype and producing cytokines that promote tumor growth. In this context, this study aimed to evaluate neutrophil action and function during tumor development. To do so, we used male Wistar rats inoculated with Walker 256 breast carcinoma. Tumor, circulating neutrophils and bone marrow were studied in the following time points after tumor inoculation: 12 h, 24 h, 48 h, 3 d, 5 d, 7 d, 10 d, and 14 d, in order to analyze neutrophil migration kinetics, circulating neutrophil phenotype and bone marrow response to the tumor growth. Herein, our results demonstrated that W256T was unable to trigger an intratumoral inflammatory response after 5 days of tumor development and consequently, from that point on, prevented neutrophil migration to its microenvironment. Also, the tumor changed circulating neutrophil phenotype by up-regulating inflammation-related genes. Even though circulating neutrophils were entirely able to respond to an inflammatory stimulus, they did not recognize and attack the tumor, allowing the tumor to grow without any immune interference. To promote the entry of neutrophils into the tumor microenvironment, LPS was injected intratumorally. Neutrophil migration and activation due to LPS injection resulted in complete tumor regression in all subjects. In conclusion, activating neutrophils, within the tumor, turned the carcinoma into a recognizable immune target and eliminated it.
Highlights
The role of neutrophils in cancer is still very contradictory
Neutrophils are produced in the bone marrow (BM) in a rate of 8.1 × 109 cells/kg/day in humans[2,3] and their homeostasis is finely regulated by the balance between granulopoiesis, bone marrow storage/release, margination and clearance[4]
CXCL12 is a chemokine constitutively produced by BM stromal cells and the interaction between this protein and its receptor CXCR4 in the surface of immature neutrophils prevents their release into the bloodstream
Summary
Several studies have demonstrated the cytotoxic capacity of neutrophils against different types of tumors, by releasing inflammatory cytokines, ROS and activating other immune cells. Recent papers have claimed the protumorigenic action of neutrophils, mainly by changing their phenotype and producing cytokines that promote tumor growth. Neutrophils are produced in the bone marrow (BM) in a rate of 8.1 × 109 cells/kg/day in humans[2,3] and their homeostasis is finely regulated by the balance between granulopoiesis, bone marrow storage/release, margination and clearance[4]. Margination consists in the accumulation of matured neutrophils in the capillary net of some organs, such as spleen, liver and bone marrow[12,13] The reason why these cells accumulate in these organs is still unknown. IL17 promotes neutrophil production and release from the bone marrow by up-regulating granulocyte colony-stimulating factor (G-CSF)[14]. IL1β19, TNFα20 and IL621 up-regulate granulopoiesis in response to inflammation
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