Expression profiling of lung neutrophils

Neutrophils are the most abundant circulating leucocytes and constitute an essential component of innate immunity. Although their role in cancer development is still poorly defined, pro- or anti-tumor properties have been attributed to tumor-associated neutrophils (TANs), suggesting major functional diversities. In this study, we focused on the mechanisms involved in neutrophil accumulation within the lung tumor mass. We first identified G-CSF as an inducer of the high-affinity glucose transporter Glut1 in neutrophils, increasing their survival ex vivo. In a genetically engineered mouse model of lung adenocarcinoma, we report that TANs have an increased Glut1 expression and glucose metabolism compared to normal neutrophils. To elucidate the impact of glucose uptake on TANs, we used an in vivo strategy based on two recombinases, Flp to initiate lung tumors, and Cre to delete Glut1 specifically in neutrophils. We demonstrate that the loss of Glut1 decreases the SiglecFhigh TAN subpopulation by accelerating neutrophil turnover in tumors through reduced survival and augmented recruitment. Accelerated TAN turnover led to a decreased tumor growth and synergized with radiotherapy. Altogether, our results demonstrate the importance of Glut1 for neutrophil turnover, which directly affects the pro- versus anti-tumor balance within the tumor. These results also suggest that metabolic vulnerabilities can be exploited to target tumor-supportive neutrophil populations. Expression profile comparisons of lung neutrophils from healthy lung or lung tumor. Lung tumor neutrophils are Control (Glut1 proficient) or Glut1 deficient (Glut1KO)