Circulating Low Density Neutrophils Are Associated with Resistance to First-Line Anti-PD1/PDL1 Immunotherapy in Non-Small Cell Lung Cancer
Authors: Arasanz H , Bocanegra A , Morilla I , Fernández-Irigoyen J , Martínez-Aguillo M , Teijeira L , Garnica M , Blanco E , Chocarro L , Ausin K , Zuazo M , Fernández-Hinojal G , Echaide M , Fernández-Rubio L , Piñeiro-Hermida S , Ramos P , Mezquita L , Escors D , Vera R , Kochan G 
Published: April 2022

ABSTRACTBackgroundSingle-agent immunotherapy has been widely accepted as frontline treatment for advanced non-small cell lung cancer (NSCLC) with high tumor PD-L1 expression, however most patients do not respond and the mechanisms of resistance are not well known. Several works have highlighted the immunosuppressive activities of myeloid subpopulations, including low-density neutrophils (LDNs), although the context in which these cells play their role is not well defined.MethodsWe prospectively monitored LDNs in peripheral blood from patients with NSCLC treated with anti-PD-1 immune checkpoint inhibitors (ICIs) as frontline therapy, and correlated values with outcomes. We have monitored LDNs in a cohort of patients treated with anti-PD1 immunotherapy combined with chemotherapy (CT+IT). We performed ex vivo experiments, including comparative proteomics, to explore the underlying mechanisms.ResultsElevated baseline LDNs predict primary resistance to ICI monotherapy in patients with NSCLC, with a response rate of 0% when levels are higher than 7.09%. Baseline LDNs are not associated with response to CT+IT. Quantitative proteomics of the plasma revealed an enrichment of the HGF/c-MET pathway in patients with high circulating LDNs, indicating a possible regulatory mechanism of this phenomenon.ConclusionsCirculating LDNs mediate resistance in NSCLC receiving ICI as frontline therapy through humoral immunosuppression. A depletion of this population with CT+IT might overcome resistance, suggesting that patients with high PD-L1 tumor expression and high LDNs might benefit from this combination. The activation of the HGF/c-MET pathway in patients with elevated LDNs supports potential drug combinations targeting this pathway.TRANSLATIONAL RELEVANCEImmunotherapy has positioned as frontline therapy for advanced non-small cell lung cancer (NSCLC), alone when PD-L1 tumor expression is high, or combined with chemotherapy otherwise. However, 50% of the patients do not respond to the treatment and the mechanisms of resistance are not well defined. Moreover, it is not clear whether chemo-immunotherapy (CT+IT) could be advantageous in some patients with high PD-L1 tumor expression.We have found that baseline circulating low-density neutrophils (LDN) identify a subset of patients that are intrinsically refractory to immunotherapy. Interestingly, responses can be achieved with CT+IT, detecting a progressive depletion of LDN in those patients. Besides the potential role as predictive biomarker, through ex vivo experiments and quantitative proteomics we observed that resistance was mediated by soluble molecules related with the HGF/c-MET pathway. Our findings establish circulating myeloid cells as one of the main mediators of resistance to immunotherapy in NSCLC, and gives a rationale for potential drug combinations that might improve the outcomes.