Dual roles of neutrophils in metastatic colonization are governed by the host NK cell status

Li, Peishan; Lu, Ming; Shi, Jiayuan; Li, Hua; Gong, Zheng; Li, Qing; Shultz, Leonard D.; Ren, Guosheng

doi:10.1038/s41467-020-18125-0

Cited by 90 publications

(92 citation statements)

References 68 publications

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“…With the help of neutrophil extracellular trap formation (NETosis), tumor cells can even escape immune surveillance. [15][16][17][18] Previous researches suggested that neutrophils may have heterogenous immunophenotypes with dynamic functional plasticity. For instance, once stimulated by transforming growth factor-β (TGF-β), resident tumor-associated neutrophils could polarize into N2 phenotype.…”

Section: Introductionmentioning

confidence: 99%

Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma

Deng

Kan

Lyu

et al. 2021

J Immunother Cancer

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BackgroundNeutrophils play a controversial role in tumor development. The function of programmed cell death-1 ligand (PD-L1+) neutrophils, however, may inhibit the cytotoxicity of anti-tumor immunity. In this study, we elucidate the stimulators of PD-L1+ neutrophils in tumor microenvironment (TME) and explore the optimal combination to enhance the effect of lenvatinib by inhibiting PD-L1+ neutrophils in hepatocellular carcinoma.MethodsNeutrophil infiltration after lenvatinib treatment was examined with RNA sequencing and multicolor flow cytometry analysis in patient samples, subcutaneous and orthotopic mouse models. Neutrophils and T cells were isolated from peripheral blood and tumor tissues and purified with magnetic beads for cytotoxicity assay. Metabolites and cytokines were detected by a biochemical analyzer manufactured by Yellow Springs Instrument (YSI) and proteome profiler cytokines array. In vitro screening of pathway inhibitors was used to identify possible candidates that could reduce PD-L1+ neutrophil infiltration. Further in vivo assays were used for verification.ResultsLenvatinib increased neutrophil recruitment by inducing CXCL2 and CXCL5 secretion in TME. After entering TME, neutrophils polarized toward N2 phenotype. PD-L1 expression was simultaneously upregulated. Thus, lenvatinib efficacy on tumor cells hindered. The increasing PD-L1+ neutrophils positively corelated with a suppressive T cell phenotype. Further investigation indicated that JAK/STAT1 pathway activated by immune-cell-derived interferon γ and MCT1/NF-kB/COX-2 pathway activated by high concentrations of tumor-derived lactate could induce PD-L1+ neutrophils. The latter could be significantly inhibited by COX-2 inhibitor celecoxib. Further in vivo assays verified that Celecoxib decreased the survival of lactate-stimulated PD-L1+ neutrophil and promoted the antitumor effect of lenvatinib.ConclusionsPD-L1+ neutrophils decrease T cell cytotoxicity. Tumor-derived lactate induces PD-L1 expression on neutrophils via MCT1/NF-κB/COX-2 pathway. Thus, COX-2 inhibitor could reduce PD-L1+ neutrophil and restore T cell cytotoxicity. This may provide a potent addition to lenvatinib.

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Section: Introductionmentioning

confidence: 99%

Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma

Deng

Kan

Lyu

et al. 2021

J Immunother Cancer

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“…S2b, c ). Mature NK cells can have a major role in controlling B16F10 lung colonization 25 , and then we studied the effect of NK cells by injecting NK1.1 antibody 26 – 28 . As expected, depletion of NK cells leads to an increase of the lung colonization of B16F10 tumor cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Neutrophil-derived reactive oxygen species promote tumor colonization

Zhong

Luo

et al. 2021

Commun Biol

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A single-nucleotide polymorphism of neutrophil cytosolic factor 1 (Ncf1), leading to an impaired generation of reactive oxygen species (ROS), is a causative genetic factor for autoimmune disease. To study a possible tumor protection effect by the Ncf1 mutation in a manner dependent on cell types, we used experimental mouse models of lung colonization assay by B16F10 melanoma cells. We observed fewer tumor foci in Ncf1 mutant mice, irrespective of αβT, γδT, B-cell deficiencies, or of a functional Ncf1 expression in CD68-positive monocytes/macrophages. The susceptibility to tumor colonization was restored by the human S100A8 (MRP8) promoter directing a functional Ncf1 expression to granulocytes. This effect was associated with an increase of both ROS and interleukin 1 beta (IL-1β) production from lung neutrophils. Moreover, neutrophil depletion by anti-Ly6G antibodies increased tumor colonization in wild type but failed in the Ncf1 mutant mice. In conclusion, tumor colonization is counteracted by ROS-activated and IL-1β-secreting tissue neutrophils.

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“…For example, neutrophils exert immunosuppressive effects on T cells by producing H 2 O 2 , thereby decreasing CD3ζ chain and cytokine expression [ 57 , 58 ]. Additionally, neutrophil derived H 2 O 2 is capable of inhibiting natural killer (NK) cell function which decreases tumor clearance as well as promotes lung colonization in a mouse model of breast cancer metastasis [ 28 , 59 , 60 ]. However, neutrophil-produced ROS can also impair the proliferation of γδ-T cells, thereby decreasing the production of the pro-tumorigenic cytokine IL-17 [ 61 ].…”

Section: Impact Of Tic-produced Ros On Local Tumor Growth and Metastasismentioning

confidence: 99%

Immune cell - produced ROS and their impact on tumor growth and metastasis

Kennel

Greten

2021

Redox Biology

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Reactive oxygen species (ROS) are derivatives of molecular oxygen (O 2 ) involved in various physiological and pathological processes. In immune cells, ROS are mediators of pivotal functions such as phagocytosis, antigen presentation and recognition, cytolysis as well as phenotypical differentiation. Furthermore, ROS exert immunosuppressive effects on T and natural killer (NK) cells which is of particular importance in the so-called “tumor microenvironment” (TME) of solid tumors. This term describes the heterogenous group of non-malignant cells including tumor-associated fibroblasts and immune cells, vascular cells, bacteria etc. by which cancer cells are surrounded and with whom they engage in functional crosstalk. Importantly, pharmacological targeting of the TME and, specifically, tumor-associated immune cells utilizing immune checkpoint inhibitors - monoclonal antibodies that mitigate immunosuppression - turned out to be a major breakthrough in the treatment of malignant tumors. In this review, we aim to give an overview of the role that ROS produced in tumor-associated immune cells play during initiation, progression and metastatic outgrowth of solid cancers. Finally, we summarize findings on how ROS in the TME could be targeted therapeutically to increase the efficacy of cancer immunotherapy and discuss factors determining therapeutic success of redox modulation in tumors.

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Dual roles of neutrophils in metastatic colonization are governed by the host NK cell status

Cited by 90 publications

References 68 publications

Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma

Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma

Neutrophil-derived reactive oxygen species promote tumor colonization

Immune cell - produced ROS and their impact on tumor growth and metastasis

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