1479P - Association between high baseline low density neutrophils and resistance to immunotherapy in untreated non-small cell lung cancer: Molecular characterization of low-density neutrophils

Background

Circulating LDNs have been previously associated with resistance to ICI in NSCLC. We have compared the efficacy of ICI and CT + ICI in untreated patients with high LDNs. We studied the association of LDNs with clinical variables. We have compared LDNs and high-density neutrophils (HDNs) regarding activity and maturity. We have compared HDNs of NSCLC patients and healthy donors.

Methods

PBMCs from 35 patients treated with ICI and 41 treated with CT + IT were purified from fresh peripheral blood by Ficoll gradient. HDNs were purified using Mono-Poly™ buffer. Baseline LDNs were quantified by flow cytometry. Efficacy of ICI and CT + ICI was compared among those with high LDNs. Activity and maturity of LDNs and HDN were studied with PD-L1, HLA-DR, LOX1, CD119, CXCR2, CXCR4, CD10, CD95, CD62L, CD101.

Results

High levels of LDNs were found in 55.3%. Non-sq NSCLC presented higher mean levels, 22.4% vs 11.3% (p = 0.047). ORR was higher with CT + IT compared with ICI, 59.1% vs 0% (p = 0.001). mPFS and mOS were longer with CT + IT, 8.9 mo vs 1.3 mo (p < 0.001) and 24.6 mo vs 1.41 mo (p = 0.008). No differences were detected in > 70 years old. A depletion of LDNs was observed in responders to CT + IT. In patients with high LDNs, fast progressive disease (PD) was more frequent with ICI (75% vs 36.4%, p = 0.031). In patients treated with ICI, fast-PD was more frequent when LDNs were high (75% vs 16.7%, p = 0.002). LDN were more aged (CXCR4+ CXCR2-, 29.9% vs 1.95%), less immature (CXCR4+ CXCR2+, 49.2% vs 82.6%) and expressed higher LOX1 and PD-L1 (57.5% vs 41.8% and PD-L1, 2.7% vs 0.97%) than HDNs. HDNs from patients and healthy donors were equivalent.

Conclusions

LDNs are a distinct circulating myeloid subpopulation, with lower prevalence of immature neutrophils, that can be enriched in patients with NSCLC. High baseline LDNs are associated with resistance to ICI monotherapy. CT + IT can overcome this resistance.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Asociación Española Contra el Cáncer.

Disclosure

H. Arasanz: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Coordinating PI: Ferrer Farma; Non-Financial Interests, Personal, Other: Takeda, MSD, Angelini Pharma. M. Martínez Aguillo: Financial Interests, Personal, Advisory Board: Pfizer, Boehringer Ingelheim. M. Alsina Maqueda: Financial Interests, Personal, Advisory Board: MSD, BMS, Lilly, Servier, AstraZeneca; Non-Financial Interests, Principal Investigator, Investigator Initiated Trial: Merck Serono. R. Vera: Financial Interests, Personal, Advisory Board: Roche, Amgen, Sanofi; Financial Interests, Personal, Invited Speaker: Merck, Bayer, Eisai, Servier; Financial Interests, Personal, Other, Program Coordinator: Lilly. All other authors have declared no conflicts of interest.