Immunotherapy has been 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 could be advantageous in high PD-L1 tumor expression. We have found that baseline circulating low-density neutrophils (LDN) identify a subset of patients intrinsically refractory to immunotherapy. Interestingly, responses can be achieved with CT+IT, detecting a progressive depletion of LDN. Besides the potential role as predictive biomarker 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 give a rationale for potential drug combinations that might improve the outcomes.

Single-agent immunotherapy has been widely accepted as frontline treatment for advanced non-small cell lung cancer (NSCLC) with high tumor PD-L1 expression, but 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. We prospectively monitored LDNs in peripheral blood from patients with NSCLC treated with anti-PD-1 immune checkpoint inhibitors (ICIs) as frontline therapy, in a cohort of patients treated with anti-PD1 immunotherapy combined with chemotherapy (CT+IT), and correlated values with outcomes. We explored the underlying mechanisms through ex vivo experiments. Elevated baseline LDNs predict primary resistance to ICI monotherapy in patients with NSCLC, and are not associated with response to CT+IT. Circulating 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 baseline LDNs might benefit from this combination. The activation of the HGF/c-MET pathway in patients with elevated LDNs revealed by quantitative proteomics supports potential drug combinations targeting this pathway.