Identification of Novel Low-Density Neutrophil Markers Through Unbiased High-Dimensional Flow Cytometry Screening in Non-Small Cell Lung Cancer Patients

Valadez-Cosmes, Paulina; Maitz, Kathrin; Kindler, Oliver; Raftopoulou, Sofia; Kienzl, Melanie; Santiso, Ana; Mihalič, Zala Nikita; Brčić, Luka; Lindenmann, Jörg; Fediuk, Melanie; Pichler, Martin; Schicho, Rudolf; Houghton, A. McGarry; Heinemann, Ákos; Kargl, Julia

doi:10.3389/fimmu.2021.703846

Cited by 20 publications

(21 citation statements)

References 54 publications

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“…Pro-tumor and anti-tumor activity have been described depending on the tissue and context [ 11 , 12 ]. A population of circulating neutrophils with immunosuppressive properties known as low-density neutrophils (LDNs) has been detected in cancer patients [ 13 , 14 , 15 ], although its association with response to ICI has not yet been defined.…”

Section: Introductionmentioning

confidence: 99%

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

Arasanz

Bocanegra

Morilla

et al. 2022

Cancers

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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.

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Section: Introductionmentioning

confidence: 99%

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

Arasanz

Bocanegra

Morilla

et al. 2022

Cancers

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show abstract

“…Pro-tumor and anti-tumor activity have been described depending on the tissue and context [11][12]. A population of circulating neutrophils with immunosuppressive properties known as lowdensity neutrophils (LDNs) has been detected in cancer patients [13][14][15], although its association with response to ICI has not yet been defined.…”

Section: Introductionmentioning

confidence: 99%

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

Arasanz

Bocanegra

Morilla

et al. 2022

Preprint

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BackgroundSingle-agent immunotherapy has been widely accepted as frontline treatment for advanced non-small cell lung cancer (NSCLC) with high tumor PD-L1 expression, however 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.MethodsWe prospectively monitored LDNs in peripheral blood from patients with NSCLC treated with anti-PD-1 immune checkpoint inhibitors (ICIs) as frontline therapy, and correlated values with outcomes. We have monitored LDNs in a cohort of patients treated with anti-PD1 immunotherapy combined with chemotherapy (CT+IT). We performed ex vivo experiments, including comparative proteomics, to explore the underlying mechanisms.ResultsElevated baseline LDNs predict primary resistance to ICI monotherapy in patients with NSCLC, with a response rate of 0% when levels are higher than 7.09%. Baseline LDNs are not associated with response to CT+IT. Quantitative proteomics of the plasma revealed an enrichment of the HGF/c-MET pathway in patients with high circulating LDNs, indicating a possible regulatory mechanism of this phenomenon.ConclusionsCirculating 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 LDNs might benefit from this combination. The activation of the HGF/c-MET pathway in patients with elevated LDNs supports potential drug combinations targeting this pathway.TRANSLATIONAL RELEVANCEImmunotherapy has 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 (CT+IT) could be advantageous in some patients with high PD-L1 tumor expression.We have found that baseline circulating low-density neutrophils (LDN) identify a subset of patients that are intrinsically refractory to immunotherapy. Interestingly, responses can be achieved with CT+IT, detecting a progressive depletion of LDN in those patients. Besides the potential role as predictive biomarker, through ex vivo experiments and quantitative proteomics 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 gives a rationale for potential drug combinations that might improve the outcomes.

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“…Filters were pre-soaked in buffer (PBS with Ca2+/Mg2+ supplemented with 0.1% BSA, 10 mM HEPES, and 10 mM glucose) for 1 hr at 37°C. Polymorphonuclear leukocytes (PMNLs) were isolated from healthy, non-pregnant donors as previously described (Valadez-Cosmes et al, 2021). Bottom wells were loaded with 100 µl supernatants (1:2 dilution with media) and upper wells with 100 µl PMNL (4×106 cell/ml).…”

Section: Methodsmentioning

confidence: 99%

The human placenta shapes the phenotype of decidual macrophages

Vondra

Hoebler

Lackner

et al. 2022

Preprint

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During human pregnancy, placenta-derived extravillous trophoblasts (EVT) invade the decidua and communicate with maternal immune cells. The decidua can be distinguished into basalis (decB) and parietalis (decP), the latter being unaffected by placentation. By defining a novel gating strategy, we report accumulation of myeloid cells in decB. We identified a decidua basalis-associated macrophage (decBAM) population with a differential transcriptome and secretome when compared to decidua parietalis-associated macrophages (decPAMs). decBAMs are CD11chi and efficient inducers of Tregs, proliferate in situ and secrete high levels of CXCL1, CXCL5, M-CSF, and IL-10. In contrast, decPAMs exert a dendritic cell-like, motile phenotype characterized by induced expression of HLA class II molecules, enhanced phagocytosis, and the ability to activate T cells. Strikingly, EVT-conditioned media are able to convert decPAMs into a decBAM phenotype. Cumulatively, these findings assign distinct macrophage phenotypes to decidual areas depending on placentation and further highlight a critical role for EVTs in the induction of pregnancy-tolerant macrophage polarization.

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Identification of Novel Low-Density Neutrophil Markers Through Unbiased High-Dimensional Flow Cytometry Screening in Non-Small Cell Lung Cancer Patients

Cited by 20 publications

References 54 publications

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

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

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

The human placenta shapes the phenotype of decidual macrophages

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