Circulating Low Density Neutrophils Are Associated with Resistance to First Line Anti-PD1/PDL1 Immunotherapy in Non-Small Cell Lung Cancer

Abstract

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.

Immune Profiling Uncovers Memory T-Cell Responses with a Th17 Signature in Cancer Patients with Previous SARS-CoV-2 Infection Followed by mRNA Vaccination

“…Finally, we confirmed that the cancer patients in our cohort showed elevated percentages of circulating neutrophils, which is a signature of dysfunctionality and elevated baseline inflammation as previously shown by us [ 43 , 46 , 47 ]. This could explain the exacerbated Th17 responses after vaccination and/or SARS-CoV-2 infection in cancer patients.…”

“…We previously showed in lung cancer patients that myeloid profiles enriched in granulocytes contribute to dysfunctional immunity and treatment failure [ 43 , 44 , 45 , 46 ]. Therefore, we evaluated whether cancer patients in our cohort showed dysfunctional myeloid profiles that could explain accentuated inflammatory responses to COVID-19 and mRNA vaccination.…”

Systemic CD4 Immunity and PD-L1/PD-1 Blockade Immunotherapy

“…Indeed, PD-L1/PD-1 blockade is carried out systemically and will have a broad impact in the immune system. These global effects will probably contribute to clinical responses, and systemic immune biomarkers could be an inexpensive way forward for their clinical use [ 19 , 29 , 45 , 48 , 50 , 57 , 144 , 174 , 175 ]. Therefore, immune profiling of immune cells in peripheral blood samples could be a promising non-invasive procedure to evaluate biomarkers of response in immunotherapies.…”

“…To achieve this, high-dimensional techniques, such as multiparametric flow cytometry, can provide more accurate quantification of different cell types, leading to better correlations with clinical outcomes. Using these techniques, the prognostic value of cell populations such as monocytes, neutrophils and other granulocytes have been confirmed in NSCLC patients undergoing PD-L1/PD-1 blockade immunotherapies [ 45 , 174 ].…”

Diverse Neutrophil Functions in Cancer and Promising Neutrophil-Based Cancer Therapies

“…Furthermore, compared with NDNs, LDNs express higher levels of PD-L1 and can inhibit cytotoxic T cells and natural killer (NK) cells [ 49 , 82 ]. In a recent study, Arasanz et al showed a possible role of circulating LDNs in the development of resistance to PD-1/PDL1 immunotherapy in non-small-cell lung cancer (NSCLC) patients [ 83 ]. In breast cancer patients, LDN levels were associated with a worse prognosis and were significantly higher in the case of metastatic cancer than in non-metastatic cases [ 77 ].…”