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CIRCULATING IMMUNOSUPPRESIVE MYELOID CELLS AS A MAJOR MECHANISM OF RESISTANCE TO FIRST LINE ANTI-PD1/PD-L1 IMMUNOTHERAPY IN NSCLC

ABSTRACT: 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.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Hugo Arasanz

PROVIDER: PXD066804 | JPOST Repository | Fri Jul 31 00:00:00 GMT+01:00 2026

REPOSITORIES: jPOST

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Project description:Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Although immune checkpoint inhibitors (ICIs) have demonstrated outstanding clinical efficacy in the treatment of NSCLC patients, ICIs-based therapy has also been associated with a paradoxical acceleration of tumor growth defined as hyperprogressive disease (HPD). In this paper we evaluated distinct plasticity traits in a model of HPD-NSCLC, with the aim of clarifying the mechanisms contributing to ICI resistance that involve IFN-γ and PD-L1. For this purpose, primary cell cultures were established from two stage IV NSCLC samples obtained from a single patient: one, prior to ICI initiation (NSCLC-B, baseline) and the other at the time of radiological evidence of hyperprogression under ICI treatment (NSCLC-H, hyperprogression). Compared to NSCLC-B cells, NSCLC-H cells exhibited a more aggressive in vivo and in vitro behavior, higher MAPK activation and owned the ability to develop tumoroids. The 3500 differentially expressed transcripts, according to whole transcriptome analysis, well described the profound plastic evolution of cells from NSCLC-B to NSCLC-H culture, as well as the increase of CD44 in the NSCLC-H cell line model, in which transcripts of CD44 isoforms lacking the variant domain were abundant. Transcripts of genes involved in the cellular response to IFN-γ were down-modulated in NSCLC-H compared to NSCLC-B, together with CD274. Conversely, an up-regulation of genes related to inflammatory response, including IL1- and IFNGR1, was found. In vitro response to IFN- γ was compromised in both NSCLC-B and NSCLC-H cells, since IFN- γ failed to exert its antiproliferative effect on these cells and to effectively induce PD-L1 expression in 2D-growth assays. Nevertheless, the cytokine induced the activation of both type I and type II IFN-pathway mediators. In addition, treatment with IFN-γ induced NSCLC-H traits in NSCLC-B cells, promoting a striking increase in the number of NSCLC-B 3D-soft agar colonies. Low IFN-γ doses or modulation of PD-L1 contributed to the evolution of NSCLC-B towards NSCLC-H phenotype through the augment of CD44 on cell membrane, cell morphological changes and increased cell growth or sphere formation ability. In conclusion, we report a modulation of plasticity by PD-L1 modulation and IFN-γ in a NSCLC cell culture established from a treatment-naïve patient, who developed HPD under ICI therapy, suggesting an association between NSCLC plasticity and these main actors involved in ICI activity.

Project description:Background: The tumor cell-intrinsic function of programmed cell death-ligand 1 (PD-L1) is poorly understood. The roles of the intrinsic function of PD-L1 in interleukin (IL)-6-mediated immunosuppression and the response to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) were investigated. Methods: Cohorts of NSCLC patients treated with ICI and public datasets were analyzed. PD-L1-overexpressing and PD-L1-knockdown NSCLC cells were submitted to RNA-seq, in vitro analyses, ChIP-qPCR, CUT&Tag, and biochemical assays. Human myeloid-derived suppressor cells (MDSCs) sorted from peripheral blood mononuclear cells were co-cultured with NSCLC cells, and then assessed for their immunosuppressive activity on T-cells. Mouse Lewis lung carcinoma (LLC) cells with PD-L1 overexpression/or knockdown were subcutaneously injected into wild-type or PD-1-knockout C57BL/6 mice in the presence of IL-6 and/or PD-1 blockade. Results: In the ICI cohort with RNA-seq data, the IL-6/Jak/Stat3 pathway was enriched and IL-6 expression was higher in patients with no response to ICI in PD-L1-high NSCLCs. IL-6 expression in PD-L1-high NSCLCs correlated positively with MDSCs and Tregs, but negatively with cytotoxic lymphocytes. In another ICI cohort, a higher baseline serum IL-6 level was associated with poor clinical outcome after ICI therapy. PD-L1 activated Jak2/Stat3 signaling by binding to and inhibiting tyrosine phosphatase PTP1B. PD-L1 also bound to p-Stat3 in the nucleus, thus promoting the activity of p-Stat3 on the transcription of several cytokines (IL-6, TGFβ, TNFα, IL-1β) and chemokines (CXCL1, CXCL3, CXCL8). PD-L1-overexpressing NSCLC cells enhanced the migration and immunosuppressive activity of human MDSC in vitro, mediated by IL-6 and CXCL1. In both wild-type and PD-1-knockout mice, PD-L1-overexpressing mouse lung tumors were heavily infiltrated by MDSCs with high immunosuppressive function. Treg numbers were increased while the numbers of granzyme B+ or IFNγ+ CD8 T-cells decreased. These responses were shown to be mediated by IL-6 secreted from PD-L1-overexpressing tumor cells. Combined blockade of PD-1 and IL-6 was effective in tumor control and decreased MDSCs while increasing granzyme B+ or IFNγ+ CD8 T-cells. Conclusions: The tumor-cell-intrinsic function of PD-L1 contributes to immunosuppression and tumor progression by MDSCs through the IL-6/Jak/Stat3 pathway, which may serve as therapeutic target to improve ICI efficacy in patients with PD-L1-high NSCLC.

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Dataset Information

CIRCULATING IMMUNOSUPPRESIVE MYELOID CELLS AS A MAJOR MECHANISM OF RESISTANCE TO FIRST LINE ANTI-PD1/PD-L1 IMMUNOTHERAPY IN NSCLC

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