GCI Spotlight - Simon Milette

Circadian regulation of neutrophil extracellular trap formation temporally regulates metastatic lung cancer progression

When: Friday October 14th, 4pm

Where: GCI 5th floor atrium

Presenter: Simon Milette from the Quail Lab

Abstract: Neutrophils are the first responders of the innate immune system and have been implicated in lung cancer progression and metastasis to secondary organs. Homeostatic trafficking and neutrophil arming are controlled by the C-X-C chemokine receptor type 2 (CXCR2) and the circadian rhythm. These factors regulate peripheral compartmentalization and neutrophil extracellular trap (NET) formation in a time-of-day-dependent manner. However, it remains unknown whether the CXCR2 axis can be temporally targeted to prevent neutrophil induction during lung cancer progression, while avoiding neutropenia. Here, we show that neutrophil frequency, expression of CXCR2 ligands or markers of NETosis accurately predict adverse oncological outcomes in lung adenocarcinoma patients. Using pre-clinical models of primary and metastatic lung cancers, we found that tumor cell-supplied CXCR2 ligands dictate neutrophil recruitment and activation during disease progression. Interestingly, unsupervised immunophenotyping of peripheral leukocytes revealed that the host’s innate immune system is subject to robust time-dependent oscillations that modulate CXCR2 expression and NET formation. Consistently, we found that metastasis of lung cancer to the liver followed a diurnal pattern that coordinated with circadian fluctuations in circulating NETs. Finally, quantitative systems modelling of CXCR2 inhibitor pharmacodynamics identified optimal posological schedules to curb diurnal surges in neutrophil trafficking while avoiding neutropenia, which were functionally confirmed in vivo. Our findings suggest that metastatic events that are mediated by NETs may occur at specific times during the day-night cycle and provide a rationale for the temporal targeting of neutrophil functions in lung cancer.