The lack of type I interferon induces neutrophil-mediated pre-metastatic niche formation in the mouse lung

Wu, Ching-Yang; Andzinski, Lisa; Kasnitz, Nadine; Kröger, Andrea; Klawonn, Frank; Lienenklaus, Stefan; Jabłońska, Jadwiga

doi:10.1002/ijc.29444

Cited by 121 publications

(135 citation statements)

References 40 publications

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“…TGFβ and G-CSF activate a tumor-and metastasispromoting program 25,27,65,[85][86][87][88] , by regulating the transcription factors inhibitor of DNA 1 (ID1), retinoblastoma 1 (RB1) and interferon regulatory factor 8 (IRF8) that control the immunosuppressive functions of neutrophils 25,87,89,90 . IFNβ acts as a negative regulator of the pro-tumorigenic phenotype of neutrophils 91,92 . Cytokine concentration and tumor physiology (such as hypoxia) may also be important for neutrophil polarization, because cytotoxic neutrophils are shaped into cancer-promoting cells as tumors expand and evolve 93 .…”

Section: Tumor-induced Neutrophil Polarization and Activationmentioning

confidence: 99%

Neutrophils in cancer: neutral no more

2016

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SummaryNeutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view.The traditionally held belief that neutrophils are inert bystanders is being challenged by recent literature. Emerging evidence indicates that tumors manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumor behavior. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets. 2The name neutrophil -given to polymorphonuclear, granulocytic cells by Paul Ehrlich in the late 19th century -is based on the inability of these cells to retain acidic or basic dyes and for their preferential uptake of pH neutral dyes 1 . Although their neutral staining led to the identification of these cells, neutrophils in the cancer setting are anything but neutral.Neutrophils in tumor-bearing hosts can oppose or potentiate cancer progression. These two types of behavior are controlled by signals emanating from cancer cells or stromal cells within the tumor microenvironment, which educate neutrophils to execute the demise of the tumor or facilitate support networks that lead to its expansive spread. These functions can occur locally in or around the tumor microenvironment, as well as systemically in distant organs.Until the past few years, other immune cells such as macrophages have overshadowed the role of neutrophils in cancer. But recent studies and the development of new genetic tools have provided the cancer community with new insights into the profound influence of these dynamic cells by uncovering distinct capabilities for neutrophils throughout each step of carcinogenesis: from tumor initiation to primary tumor growth to metastasis.During these processes, neutrophils take on different phenotypes and sometimes opposing functions. Emerging evidence also indicates that these cells are highly influential, and are able to change the behavior of other tumor-associated cell types -primarily other immune cells. In this Review, we focus on how tumors manipulate the generation and release of neutrophils from the bone marrow. We discuss the mechanisms identified in animal models by which neutrophils participate in tumor initiation, growth and metastasis. Finally, we highlight the potential of these cells as clinical biomarkers and therapeutic targets. In humans, neutrophils are the most abundant immune cell population, representing 50-70% of all leukocytes. Over 10 11 neutrophils may be produced per day 2 , and tumors can increase this number by even more. Indeed, patients with various cancer types, including but not limited to breast, lung and colorectal cancer, often exhibit increased numbers of circulating neutrophils 3,4 . Recent studies have identified key pathways that tumors exploit to disrupt normal neutrophil homeostasis and these are discuss...

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Section: Tumor-induced Neutrophil Polarization and Activationmentioning

confidence: 99%

Neutrophils in cancer: neutral no more

2016

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“…Interestingly, it has been proposed that there can be phenotypic or functional plasticity, where neutrophils infiltrating a tumor are modulated by cues present in the tumor environment. 23 This has been well exemplified by recent works showing that TANs can be modulated and polarized toward an N1 phenotype by type-1 interferons [24][25][26] or a pro-tumorigenic (N2) phenotype by the presence of TGFb 7 as demonstrated by the observation that systemic inhibition of TGFb using a specific Alk5 kinase inhibitor called SM16 in mice caused a shift toward a pro-inflammatory and antitumor phenotype (N1).…”

Section: Introductionmentioning

confidence: 94%

Tumor-associated neutrophils display a distinct N1 profile following TGFβ modulation: A transcriptomics analysis of pro- vs. antitumor TANs

et al. 2016

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It is becoming increasingly clear that tumor-associated neutrophils (TANs) play an important role in cancer biology, through direct impact on tumor growth and by recruitment of other cells types into the tumor. The function of neutrophils in cancer has been the subject of seemingly contradicting reports, pointing toward a dual role played by TANs in tumor progression. The existence of multiple neutrophil subsets, as well as phenotypic modulation of the neutrophils by various factors in the tumor microenvironment, has been shown. TGFb plays a significant role in the determination of neutrophils' phenotype, by shifting the balance from an antitumor (N1) toward a more permissive (N2) phenotype. The full range of mechanisms responsible for the pro-vs. antitumor effects of TANs has not yet been elucidated. Therefore, the ability to identify the different neutrophil subpopulations in the tumor is critical in order to understand TANs evolution and contribution throughout tumor progression. Using a transcriptomic approach, we identified alternations in gene expression profile following TGFb inhibition. We show that N1 and N2 TANs represent distinct subpopulations with different transcriptional signatures and both differ from naive bone marrow neutrophils. The analysis highlights a clear difference in pathways involved in neutrophil function such as cytoskeletal organization and antigen presentation, as well as alterations in chemokine profile, eventually affecting their effect on tumor cells and tumor growth. These data highlights several potential new pathways and mechanisms by which neutrophils can influence both the tumor cells and the adaptive immune system.

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“…Endogenously produced type I IFN by innate immune cells is a key event for inducing the priming of tumor Ag-specific CD8 T lymphocytes (3,4). Similarly, genes involved in the type I IFN pathway, including the transcription factor IFN regulatory factor (IRF)7, its predicted target genes, as well as the upstream regulators such as STAT1, are severely downregulated in bone metastases compared with the murine primary mammary tumor, and a novel mechanism of metastasis suppression reliant on intact host IFNAR signaling and a competent immune response is currently suggested (5,6).…”

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In Vivo Visualizing the IFN-β Response Required for Tumor Growth Control in a Therapeutic Model of Polyadenylic-Polyuridylic Acid Administration

Nocera

Roselli

Araya

et al. 2016

The Journal of Immunology

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The crucial role that endogenously produced IFN-β plays in eliciting an immune response against cancer has recently started to be elucidated. Endogenous IFN-β has an important role in immune surveillance and control of tumor development. Accordingly, the role of TLR agonists as cancer therapeutic agents is being revisited via the strategy of intra/peritumoral injection with the idea of stimulating the production of endogenous type I IFN inside the tumor. Polyadenylic-polyuridylic acid (poly A:U) is a dsRNA mimetic explored empirically in cancer immunotherapy a long time ago with little knowledge regarding its mechanisms of action. In this work, we have in vivo visualized the IFN-β required for the antitumor immune response elicited in a therapeutic model of poly A:U administration. In this study, we have identified the role of host type I IFNs, cell populations that are sources of IFN-β in the tumor microenvironment, and other host requirements for tumor control in this model. One single peritumoral dose of poly A:U was sufficient to induce IFN-β, readily visualized in vivo. IFN-β production relied mainly on the activation of the transcription factor IFN regulatory factor 3 and the molecule UNC93B1, indicating that TLR3 is required for recognizing poly A:U. CD11c+ cells were an important, but not the only source of IFN-β. Host type I IFN signaling was absolutely required for the reduced tumor growth, prolonged mice survival, and the strong antitumor-specific immune response elicited upon poly A:U administration. These findings add new perspectives to the use of IFN-β–inducing compounds in tumor therapy.

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The lack of type I interferon induces neutrophil-mediated pre-metastatic niche formation in the mouse lung

Cited by 121 publications

References 40 publications

Neutrophils in cancer: neutral no more

Neutrophils in cancer: neutral no more

Tumor-associated neutrophils display a distinct N1 profile following TGFβ modulation: A transcriptomics analysis of pro- vs. antitumor TANs

In Vivo Visualizing the IFN-β Response Required for Tumor Growth Control in a Therapeutic Model of Polyadenylic-Polyuridylic Acid Administration

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