High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer

Salcher, Stefan; Sturm, Gregor; Horvath, Lena; Untergasser, Gerold; Kuempers, Christiane; Fotakis, Georgios; Panizzolo, Elisa; Martowicz, Agnieszka; Trebo, Manuel; Pall, Georg; Gamerith, Gabriele; Sykora, Martina; Augustin, Florian; Schmitz, Katja; Finotello, Francesca; Rieder, Dietmar; Perner, Sven; Sopper, Sieghart; Wolf, Dominik; Pircher, Andreas; Trajanoski, Zlatko

doi:10.1016/j.ccell.2022.10.008

Cited by 149 publications

(182 citation statements)

References 128 publications

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“…The N2‐like sub‐population was characterised by immunosuppressive (e.g., TGFBI and LAGLS3) and pro‐angiogenic (e.g., MMP9) features. 42 , 43 , 44 …”

Section: Resultsmentioning

confidence: 99%

“…The N1‐like sub‐cluster displayed features of high expression levels of chemokines and cytokines (e.g., CCL3, CCL4 and C15orf48) and antigen presentation (e.g., HLA–DMB and CD74). The N2‐like sub‐population was characterised by immunosuppressive (e.g., TGFBI and LAGLS3) and pro‐angiogenic (e.g., MMP9) features 42–44 …”

Section: Resultsmentioning

confidence: 99%

“…Recently, with the advances of high‐resolution approaches, like scRNA‐seq, novel and crucial phenotypes of neutrophils were identified, contributing to better understanding their dual roles in TME. 43 , 59 …”

Section: Discussionmentioning

confidence: 99%

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Multiplex immunofluorescence and single‐cell transcriptomic profiling reveal the spatial cell interaction networks in the non‐small cell lung cancer microenvironment

Peng

Xiao-yue

Liu

et al. 2023

Clinical & Translational Med

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Background Conventional immunohistochemistry technologies were limited by the inability to simultaneously detect multiple markers and the lack of identifying spatial relationships among cells, hindering understanding of the biological processes in cancer immunology. Methods Tissue slices of primary tumours from 553 IA∼IIIB non‐small cell lung cancer (NSCLC) cases were stained by multiplex immunofluorescence (mIF) assay for 10 markers, including CD4, CD38, CD20, FOXP3, CD66b, CD8, CD68, PD‐L1, CD133 and CD163, evaluating the amounts of 26 phenotypes of cells in tumour nest and tumour stroma. StarDist depth learning model was utilised to determine the spatial location of cells based on mIF graphs. Single‐cell RNA sequencing (scRNA‐seq) on four primary NSCLC cases was conducted to investigate the putative cell interaction networks. Results Spatial proximity among CD20+ B cells, CD4+ T cells and CD38+ T cells ( r 2 = 0.41) was observed, whereas the distribution of regulatory T cells was associated with decreased infiltration levels of CD20+ B cells and CD38+ T cells ( r 2 = −0.45). Univariate Cox analyses identified closer proximity between CD8+ T cells predicted longer disease‐free survival (DFS). In contrast, closer proximity between CD133+ cancer stem cells (CSCs), longer distances between CD4+ T cells and CD20+ B cells, CD4+ T cells and neutrophils, and CD20+ B cells and neutrophils were correlated with dismal DFS. Data from scRNA‐seq further showed that spatially adjacent N1‐like neutrophils could boost the proliferation and activation of T and B lymphocytes, whereas spatially neighbouring M2‐like macrophages showed negative effects. An immune‐related risk score (IRRS) system aggregating robust quantitative and spatial prognosticators showed that high‐IRRS patients had significantly worse DFS than low‐IRRS ones (HR 2.72, 95% CI 1.87–3.94, p < .001). Conclusions We developed a framework to analyse the cell interaction networks in tumour microenvironment, revealing the spatial architecture and intricate interplays between immune and tumour cells.

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“…The N2‐like sub‐population was characterised by immunosuppressive (e.g., TGFBI and LAGLS3) and pro‐angiogenic (e.g., MMP9) features. 42 , 43 , 44 …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Multiplex immunofluorescence and single‐cell transcriptomic profiling reveal the spatial cell interaction networks in the non‐small cell lung cancer microenvironment

Peng

Xiao-yue

Liu

et al. 2023

Clinical & Translational Med

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“…Data have been downloaded from the repository of a single-cell expression study combining different datasets ( 22 ). These data were filtered to only include cells from samples with known age and smoking habit and taken from either healthy lung or tumor adjacent, pathologically normal lung samples.…”

Section: Methodsmentioning

confidence: 99%

Intratumoral Heterogeneity and Immune Modulation in Lung Adenocarcinoma in Female Smokers and Never Smokers

et al. 2022

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Lung cancer remains the leading cause of cancer death worldwide, despite declining smoking prevalence in industrialized countries. Although lung cancer is highly associated with smoking status, a significant proportion of lung cancer cases develop in patients who have never smoked, with an observable bias towards female never smokers. A better understanding of lung cancer heterogeneity and immune system involvement during tumor evolution and progression in never smokers is therefore highly needed. Here we employed single-nucleus transcriptomics of surgical lung adenocarcinoma (LUAD) and normal lung tissue samples from patients with or without a history of smoking. Immune cells as well as fibroblasts and endothelial cells responded to tobacco smoke exposure by inducing a highly inflammatory state in normal lung tissue. In LUAD, characterization of differentially expressed transcriptional programs in macrophages and cancer-associated fibroblasts provided insight into how the niche favors tumor progression. Within tumors, eight subpopulations of neoplastic cells were identified in female smokers and never smokers. Pseudotemporal ordering inferred a trajectory toward two differentiated tumor cell states implicated in cancer progression and invasiveness. A proliferating cell population sustaining tumor growth exhibited differential immune modulating signatures in both patient groups. Collectively, these results resolve cellular heterogeneity and immune interactions in LUAD, with a special emphasis on female never smokers.

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“…In addition, recent studies have used a high-resolution single-cell atlas to analyze non-small cell lung cancer infiltrating neutrophil population profiles. Four TAN subsets (TAN-1 to 4) and 2 normal adjacent tissue-associated neutrophils subsets (NAN-1 and NAN-2) have been identified, and extensive heterogeneity in phenotypes has been observed across subpopulations 63 . The TAN-1 cluster expresses high levels of CXCL1 , CXCL2 , CXCL8 , ICAM1 , and CD44 , which regulate the activation, recruitment, and cell adhesion of neutrophils, and the formation of NETs; the TAN-2 cluster, which highly expresses MHC II-associated genes such as HLA-DRA , CD74 , and HLA-DPB1 , and therefore may have immunogenic antigen presenting functions and exhibit anti-tumor immunity; and the TAN-3 cluster, which exhibits pro-tumor characteristics and high expression of the lipid metabolism-associated genes PLIN2 and PLPP3, which promote tumor proliferation.…”

Section: Neutrophil Heterogeneitymentioning

confidence: 99%

Heterogeneity of neutrophils in cancer: one size does not fit all

Chen

et al. 2022

Cancer Biol Med

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Neutrophils play an essential role in the defense against bacterial infections and orchestrate both the innate and adaptive immune responses. With their abundant numbers, diverse function and short life span, these cells are at the forefront of immune responses, and have gained attention in recent years because of their presence in tumor sites. Neutrophil involvement pertains to tumor cells’ ability to construct a suitable tumor microenvironment (TME) that accelerates their own growth and malignancy, by facilitating their interaction with surrounding cells through the circulatory and lymphatic systems, thereby influencing tumor development and progression. Studies have indicated both pro- and anti-tumor properties of infiltrating neutrophils. The TME can exploit neutrophil function, recruitment, and even production, thus resulting in pro-tumor properties of neutrophils, including promotion of genetic instability, tumor cell proliferation, angiogenesis and suppression of anti-tumor or inflammatory response. In contrast, neutrophils can mediate anti-tumor resistance by direct cytotoxicity to the tumor cells or by facilitating anti-tumor functions via crosstalk with T cells. Here, we summarize current knowledge regarding the effects of neutrophil heterogeneity under homeostatic and tumor conditions, including neutrophil phenotype and function, in cancer biology.

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High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer

Cited by 149 publications

References 128 publications

Multiplex immunofluorescence and single‐cell transcriptomic profiling reveal the spatial cell interaction networks in the non‐small cell lung cancer microenvironment

Multiplex immunofluorescence and single‐cell transcriptomic profiling reveal the spatial cell interaction networks in the non‐small cell lung cancer microenvironment

Intratumoral Heterogeneity and Immune Modulation in Lung Adenocarcinoma in Female Smokers and Never Smokers

Heterogeneity of neutrophils in cancer: one size does not fit all

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