PXD066804-1

PXD066804 is an original dataset announced via ProteomeXchange.

Title	CIRCULATING IMMUNOSUPPRESIVE MYELOID CELLS AS A MAJOR MECHANISM OF RESISTANCE TO FIRST LINE ANTI-PD1/PD-L1 IMMUNOTHERAPY IN NSCLC
Description	Immune checkpoint inhibitors (ICIs) have improved outcomes in patients with advanced non-small cell lung cancer (NSCLC), particularly when tumour PD-L1 expression is high. However, most of the patients do not respond to the treatment, and reliable predictive biomarkers are lacking. Myeloid cells have been linked to resistance to ICIs, however their role in this lack of efficacy remains unclear. Our group previously reported an association between the expansion of circulating low-density neutrophils (LDNs), an immunosuppressive myeloid subpopulation, and resistance to ICIs monotherapy. In this manuscript, we present updated results in this line of research, including a validation cohort, as well as additional data depicting the characteristics of this myeloid subpopulation from a proteomic point of view suggesting potential mechanisms associated with ICI resistance. Patients diagnosed with NSCLC and eligible to frontline treatment with anti-PD-1/PD-L1 ICI monotherapy (n=60) or in combination with chemotherapy (CT+ICI) (n=60) were prospectively recruited. Baseline (before the initiation of the treatment) blood samples and tumor tissue samples were obtained. Circulating LDNs levels were quantified by flow cytometry, and the association with clinical outcomes was analysed. Tumour-associated neutrophils (TANs) were also evaluated. Phenotypes of circulating LDNs and conventional neutrophils or high-density neutrophils (HDNs) were characterised by flow cytometry and quantitative proteomics, following purification by magnetic beads. Additionally, plasma samples were analysed using a panel quantifying 43 cytokines involved in inflammatory processes. Elevated baseline levels of LDNs are associated with primary resistance to ICI monotherapy, with an overall response rate (ORR) of 17% vs 50% (p=0.04) and median progression free survival (mPFS) of 2.3 months vs. 21.8 months (p < 0.001). No association between baseline LDNs and efficacy of CT+ICI was detected, and a progressive depletion of LDNs was observed in responding patients. LDNs exhibited a more aged phenotype compared with HDNs, and proteomic analysis revealed a distinct profile, characterized by the increased expression of proteins associated with mitochondrial metabolism and immunosuppressive functions. Additionally, plasma from patients with high LDN levels was enriched in cytokines involved in myeloid expansion (M-CSF, IL1B, IL-22) and inflammation (CXCL9, IL-25). LDNs are an immunosuppressive myeloid subpopulation with a specific proteomic profile. High baseline LDN levels are associated with resistance to ICI monotherapy in patients diagnosed with advanced NSCLC. The combination with chemotherapy might be useful to overcome resistance to ICI monotherapy in some patients. Additional therapeutic strategies targeting LDNs should be explored to improve ICI efficacy in this population.
HostingRepository	jPOST
AnnounceDate	2026-07-31
AnnouncementXML	Submission_2026-07-30_08:00:04.814.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joaquin Fernandez-Irigoyen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	S-carboxamidomethyl-L-cysteine; N6-acetyl-L-lysine; 2-pyrrolidone-5-carboxylic acid (Gln); L-methionine sulfoxide
Instrument	instrument

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-31 07:14:32	ID requested
⏵ 1	2026-07-30 08:00:05	announced

Dataset with its publication pending

submitter keyword: Immune checkpoint inhibitors (ICIs)

non-small cell lung cancer (NSCLC)

Proteomics

Hugo Arasanz
lab head
Joaquin Fernandez-Irigoyen
contact affiliation	Navarrabiomed
dataset submitter

jPOST dataset URI

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