International Journal of Molecular Sciences

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Dear Colleagues,

Neutrophils are the most abundant population of immune cells and perform a variety of functions, including neutrophil extracellular trap formation, phagocytosis, and the release of proteolytic enzymes, cytokines, chemokines, and immunosuppressive molecules. These functions not only serve as a defense mechanism against inflammation and infection but also regulate adaptive immunity in cancers. Recent research has highlighted the growing relevance of neutrophils in the tumor microenvironment, where they can have both pro- and anti-tumor effects, but their precise role remains unclear. Due to their rapid turnover from bone marrow and easy recruitment to metastatic sites, neutrophils can express a unique transcription signature that can render them either pro- or anti-tumorogenic. Tumor-infiltrating neutrophils induce the expression of chemokine receptors and molecules such as arginase 1 (ARG1), PDL-1, and reactive oxygen/nitrogen species (RONS). To fully understand the molecular aspects of neutrophil function in tumors, further research is necessary, with a focus on signaling pathways, gene expression profiles, and molecular interactions within the tumor microenvironment. Investigating the impact of factors such as hypoxia and inflammation on neutrophil function in tumors may also yield valuable insights. This Special Issue invites researchers to contribute their work on the intriguing molecular aspects of neutrophil plasticity as pro- and anti-metastatic immune cells in various cancers, with the potential to develop new strategies for targeting neutrophils in cancer therapy and improving patient outcomes.

Dr. Deepika Awasthi
Guest Editor

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Keywords

neutrophils
cancer
tumor microenvironment
tumor-associated neutrophils
innate immunity

Published Papers (2 papers)

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Research

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15 pages, 1978 KiB

Open AccessArticle

SIGLEC-5/14 Inhibits CD11b/CD18 Integrin Activation and Neutrophil-Mediated Tumor Cell Cytotoxicity

by Panagiota Bouti, Colin Blans, Bart J. A. M. Klein, Debarati Shome, Reza Nadafi, Michel Van Houdt, Karin Schornagel, Paul J. J. H. Verkuijlen, Virginie Roos, Rogier M. Reijmers, Robin Van Bruggen, Taco W. Kuijpers and Hanke L. Matlung

Int. J. Mol. Sci. 2023, 24(24), 17141; https://doi.org/10.3390/ijms242417141 - 5 Dec 2023

Viewed by 1547

Abstract

Since the successful introduction of checkpoint inhibitors targeting the adaptive immune system, monoclonal antibodies inhibiting CD47-SIRPα interaction have shown promise in enhancing anti-tumor treatment efficacy. Apart from SIRPα, neutrophils express a broad repertoire of inhibitory receptors, including several members of the sialic acid-binding receptor (SIGLEC) family. Here, we demonstrate that interaction between tumor cell-expressed sialic acids and SIGLEC-5/14 on neutrophils inhibits antibody-dependent cellular cytotoxicity (ADCC). We observed that conjugate formation and trogocytosis, both essential processes for neutrophil ADCC, were limited by the sialic acid-SIGLEC-5/14 interaction. During neutrophil-tumor cell conjugate formation, we found that inhibition of the interaction between tumor-expressed sialic acids and SIGLEC-5/14 on neutrophils increased the CD11b/CD18 high affinity conformation. By dynamic acoustic force measurement, the binding between tumor cells and neutrophils was assessed. The interaction between SIGLEC-5/14 and the sialic acids was shown to inhibit the CD11b/CD18-regulated binding between neutrophils and antibody-opsonized tumor cells. Moreover, the interaction between sialic acids and SIGLEC-5/14-consequently hindered trogocytosis and tumor cell killing. In summary, our results provide evidence that the sialic acid-SIGLEC-5/14 interaction is an additional target for innate checkpoint blockade in the tumor microenvironment. Full article

(This article belongs to the Special Issue The Emerging Role of Neutrophils in Cancer: Molecular Aspects of Plasticity and Potential Therapeutic Targets)

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Review

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22 pages, 977 KiB

Open AccessReview

Neutrophils at the Crossroads: Unraveling the Multifaceted Role in the Tumor Microenvironment

by Deepika Awasthi and Aditya Sarode

Int. J. Mol. Sci. 2024, 25(5), 2929; https://doi.org/10.3390/ijms25052929 - 2 Mar 2024

Viewed by 959

Abstract

Over the past decade, research has prominently established neutrophils as key contributors to the intricate landscape of tumor immune biology. As polymorphonuclear granulocytes within the innate immune system, neutrophils play a pivotal and abundant role, constituting approximately ∼70% of all peripheral leukocytes in humans and ∼10–20% in mice. This substantial presence positions them as the frontline defense against potential threats. Equipped with a diverse array of mechanisms, including reactive oxygen species (ROS) generation, degranulation, phagocytosis, and the formation of neutrophil extracellular traps (NETs), neutrophils undeniably serve as indispensable components of the innate immune system. While these innate functions enable neutrophils to interact with adaptive immune cells such as T, B, and NK cells, influencing their functions, they also engage in dynamic interactions with rapidly dividing tumor cells. Consequently, neutrophils are emerging as crucial regulators in both pro- and anti-tumor immunity. This comprehensive review delves into recent research to illuminate the multifaceted roles of neutrophils. It explores their diverse functions within the tumor microenvironment, shedding light on their heterogeneity and their impact on tumor recruitment, progression, and modulation. Additionally, the review underscores their potential anti-tumoral capabilities. Finally, it provides valuable insights into clinical therapies targeting neutrophils, presenting a promising approach to leveraging innate immunity for enhanced cancer treatment. Full article

(This article belongs to the Special Issue The Emerging Role of Neutrophils in Cancer: Molecular Aspects of Plasticity and Potential Therapeutic Targets)

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