Targeting the aging of tumor-associated neutrophils in lung cancer

Neutrophils are leukocytes that play a key role in innate immunity. Their mode of action in case of infection is well described, but their impact in different chronic diseases, such as cancer, remains unclear. Nevertheless, recent publications describe neutrophils as a heterogeneous population, with different subgroups that can support tumor growth while others may prevent it. In this project, we focus on lung cancer neutrophils, in the preclinical KrasLox-STOP-Lox-G12D/WT; p53Flox/Flox (KP) mouse model. In vivo, we show that tumor-associated neutrophils (TANs) abnormally survive within the tumor, up to 6 days. Moreover, they express SiglecF, a marker of tumor-supportive cells, distinguishing them from young neutrophils. In vitro, we were able to induce neutrophil survival by incubating them with tumor-derived supernatant (SN) and KP-derived SV2 cells SN. I found that neutrophil survival correlated with increased Bcl2l1 expression, coding for the anti-apoptotic BCL-XL protein. Prolonged and not basal neutrophil survival was blocked when I used BCL-XL-specific inhibitors. During the next years, I will investigate the mechanisms involved in TANs survival. I will also exploit their abnormal aging by using anti apoptotic BCL-XL -specific drugs and monitor their impact on tumor growth in vivo. These approaches could be crucial to develop clinically-safe strategies blocking pro-tumor TANs without affecting normal and essential neutrophils.