Grant: Project Grant

Lung cancer is the highest cause of cancer death in Canada, surpassing colorectal, pancreatic and breast cancers combined. Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancer cases; although immune checkpoint inhibitors, which are new drugs developed to invigorate the immune system to fight cancer, have revolutionized survival outcomes in NSCLC, efficacy is restricted to a minority of patients. Many immune populations are diurnally regulated in these tumors and therefore, there is substantial untapped potential in exploring the temporal administration of immune-targeted therapies to optimize treatment efficacy. Amongst these cells are neutrophils, which are the most abundant white blood cell in NSCLC tumors. In preliminary experiments, we have now discovered that the CXCR2 signalling axis is central to neutrophil infiltration into lung tumors, which is tightly controlled by the circadian rhythm. We found that tumor cell-supplied CXCR2 ligands are associated with neutrophil recruitment and effector function during primary tumor growth and liver metastasis. CXCR2 coincides with the induction of neutrophil extracellular traps (NETs), which are webs of DNA released by neutrophils upon stimulation, which are elevated during periods of rest. Strikingly, lung cancer metastasis to the liver follows a diurnal pattern that coincides with circadian fluctuations in circulating NETs. Although we have established these intriguing associations, the functional connection between the circadian regulation of neutrophils and lung cancer progression, and the chronopharmacology of neutrophil-targeted immunotherapies, remain largely unexplored. Our central objective is to dissect the circadian regulation of neutrophil trafficking and effector function and its impact on lung cancer growth and metastasis.