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Cells
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The Role of Neutrophils in Cancer
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The Role of Neutrophils in Cancer

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 17246

Special Issue Editor

Dr. Jadwiga Jabłońska

E-Mail Website
Guest Editor
Translational Oncology, Department of Otorhinolaryngology, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany
Interests: neutrophils; tumor-associated neutrophils; exosomes; type I IFNs; cancer immunology; angiogenesis

Special Issue Information

Dear Colleagues,

Over the past years it has become apparent that tumor progression is not only determined by tumor cell-autonomous features, but also by variety of immune cells that infiltrate tumor site. Neutrophils make a significant proportion of such cells and once recruited to the tumor microenvironment, these cells regulate its angiogenesis, growth and spread. The plasticity and versatility of neutrophils due to different microenvironmental cues make them highly heterogeneous as they can change their phenotype, depending on the activating stimulus, and can either support or inhibit tumor development and spread.

Authors are invited to submit manuscripts that cover specific aspects of neutrophil biology in cancer with a focus on cell-cell crosstalk with cancer cells or other immune cells, NETosis and angiogenesis. The data may provide useful information on how to better and more selectively target pro-tumoral activity of neutrophil in order to provide functional therapeutic approach.

In this Special Issue, we aim to shed light on the state-of-the-art, as well as novel data that contribute to the increase of our knowledge on the role of neutrophil activity in supporting cancerogenesis and modulation of anti-cancer immune responses. We welcome experts in the field to contribute research papers and critical reviews on the various facets of neutrophil biology that either impair or promote disease development, as well as on how neutrophil activity modulators may be exploited as therapeutic tools.

Dr. Jadwiga Jabłońska
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Neutrophil heterogeneity
  • Cancer
  • Inflammation
  • innate immunity
  • Myeloid-derived suppressor cells
  • Angiogenesis
  • Cytotoxicity
  • NETosis

Published Papers (5 papers)

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Research

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15 pages, 3193 KiB  
Article
Extracellular Vesicles Derived from MDA-MB-231 Cells Trigger Neutrophils to a Pro-Tumor Profile
by Carolinne Amorim, Clara Luisa Docasar, Daniel Guimarães-Bastos, Ana Clara Frony, Christina Barja-Fidalgo, Mariana Renovato-Martins and João Alfredo Moraes
Cells 2022, 11(12), 1875; https://doi.org/10.3390/cells11121875 - 09 Jun 2022
Cited by 7 | Viewed by 2304
Abstract
Immune system cells, including neutrophils, are recruited by the tumor microenvironment as a site of chronic inflammation and begin to favor tumor growth. Neutrophils present in the tumor site are called tumor-associated neutrophils (TAN) and can present two phenotypes: N1 (antitumor) or N2 [...] Read more.
Immune system cells, including neutrophils, are recruited by the tumor microenvironment as a site of chronic inflammation and begin to favor tumor growth. Neutrophils present in the tumor site are called tumor-associated neutrophils (TAN) and can present two phenotypes: N1 (antitumor) or N2 (pro-tumor). Evidence shows the high capacity of immune system cells to interact with extracellular vesicles (Evs) released by tumor cells. Evs can modulate the phenotype of cells within the immune system, contributing to tumor development. Here, we investigated the role of MDA-MB-231-derived Evs upon the polarization of neutrophils towards an N2 phenotype and the underlying mechanisms. We observed that neutrophils treated with Evs released by MDA cells (MDA-Evs) had their half-life increased, increased their chemotactic capacity, and released higher levels of NETs and ROS than neutrophils treated with non-tumoral Evs. We also observed that neutrophils treated with MDA-Evs released increased IL-8, VEGF, MMP9, and increased expression of CD184, an N2-neutrophil marker. Finally, neutrophils treated with MDA-Evs increased tumor cell viability. Our results show that MDA-Evs induce an N2-like phenotype, and the blockage of phosphatidylserine by annexin-V may be an essential agent counter-regulating this effect. Full article
(This article belongs to the Special Issue The Role of Neutrophils in Cancer)
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18 pages, 1933 KiB  
Article
The Bilateral Interplay between Cancer Immunotherapies and Neutrophils’ Phenotypes and Sub-Populations
by Naomi Kaisar-Iluz, Ludovica Arpinati, Merav E. Shaul, Sojod Mahroum, Mohamad Qaisi, Einat Tidhar and Zvi G. Fridlender
Cells 2022, 11(5), 783; https://doi.org/10.3390/cells11050783 - 23 Feb 2022
Cited by 7 | Viewed by 2458
Abstract
Immunotherapy has become a leading modality for the treatment of cancer, but despite its increasing success, a substantial number of patients do not benefit from it. Cancer-related neutrophils have become, in recent years, a subject of growing interest. Distinct sub-populations of neutrophils have [...] Read more.
Immunotherapy has become a leading modality for the treatment of cancer, but despite its increasing success, a substantial number of patients do not benefit from it. Cancer-related neutrophils have become, in recent years, a subject of growing interest. Distinct sub-populations of neutrophils have been identified at advanced stages of cancer. In this study, we aimed to evaluate the role of neutrophils in mediating the efficacy of immune checkpoint inhibitors (ICI) treatments (α-PD-1/PD-L1), by assessing lung tumor models in mice. We found that G-CSF overexpression by the tumor significantly potentiates the efficacy of ICI, whereas neutrophils’ depletion abrogated their responses. Adoptive transfer of circulating normal-density neutrophils (NDN) resulted in significantly reduced tumor growth, whereas low-density neutrophils (LDN) had no effect. We next investigated the effect of ICI on neutrophils’ functions. Following α-PD-L1 treatment, NDN displayed increased ROS production and increased cytotoxicity toward tumor cells but decreased degranulation. Together, our results suggest that neutrophils are important mediators of the ICI treatments and that mainly NDN are modulated following α-PD-L1 treatment. This research provides a better understanding of the function of neutrophils following immunotherapies and their impact on the efficacy of immunotherapy, supporting better understanding and future improvement of currently available treatments. Full article
(This article belongs to the Special Issue The Role of Neutrophils in Cancer)
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16 pages, 1454 KiB  
Article
Prognostic Relevance of Neutrophil to Lymphocyte Ratio (NLR) in Luminal Breast Cancer: A Retrospective Analysis in the Neoadjuvant Setting
by Antonino Grassadonia, Vincenzo Graziano, Laura Iezzi, Patrizia Vici, Maddalena Barba, Laura Pizzuti, Giuseppe Cicero, Eriseld Krasniqi, Marco Mazzotta, Daniele Marinelli, Antonella Amodio, Clara Natoli and Nicola Tinari
Cells 2021, 10(7), 1685; https://doi.org/10.3390/cells10071685 - 03 Jul 2021
Cited by 12 | Viewed by 2784
Abstract
The neutrophil to lymphocyte ratio (NLR) is a promising predictive and prognostic factor in breast cancer. We investigated its ability to predict disease-free survival (DFS) and overall survival (OS) in patients with luminal A- or luminal B-HER2-negative breast cancer who received neoadjuvant chemotherapy [...] Read more.
The neutrophil to lymphocyte ratio (NLR) is a promising predictive and prognostic factor in breast cancer. We investigated its ability to predict disease-free survival (DFS) and overall survival (OS) in patients with luminal A- or luminal B-HER2-negative breast cancer who received neoadjuvant chemotherapy (NACT). Pre-treatment complete blood cell counts from 168 consecutive patients with luminal breast cancer were evaluated to assess NLR. The study population was stratified into NLRlow or NLRhigh according to a cut-off value established by receiving operator curve (ROC) analysis. Data on additional pre- and post-treatment clinical-pathological characteristics were also collected. Kaplan–Meier curves, log-rank tests, and Cox proportional hazards models were used for statistical analyses. Patients with pre-treatment NLRlow showed a significantly shorter DFS (HR: 6.97, 95% CI: 1.65–10.55, p = 0.002) and OS (HR: 7.79, 95% CI: 1.25–15.07, p = 0.021) compared to those with NLRhigh. Non-ductal histology, luminal B subtype, and post-treatment Ki67 ≥ 14% were also associated with worse DFS (p = 0.016, p = 0.002, and p = 0.001, respectively). In a multivariate analysis, luminal B subtype, post-treatment Ki67 ≥ 14%, and NLRlow remained independent prognostic factors for DFS, while only post-treatment Ki67 ≥ 14% and NLRlow affected OS. The present study provides evidence that pre-treatment NLRlow helps identify women at higher risk of recurrence and death among patients affected by luminal breast cancer treated with NACT. Full article
(This article belongs to the Special Issue The Role of Neutrophils in Cancer)
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13 pages, 4231 KiB  
Article
The PD-L1/PD-1 Axis Blocks Neutrophil Cytotoxicity in Cancer
by Olga Yajuk, Maya Baron, Sapir Toker, Tamir Zelter, Tanya Fainsod-Levi and Zvi Granot
Cells 2021, 10(6), 1510; https://doi.org/10.3390/cells10061510 - 15 Jun 2021
Cited by 32 | Viewed by 3715
Abstract
The PD-L1/PD-1 axis mediates immune tolerance and promotes tumor growth and progression via the inhibition of anti-tumor immunity. Blocking the interaction between PD-L1 and PD-1 was clinically shown to be beneficial in maintaining the anti-tumor functions of the adaptive immune system. Still, the [...] Read more.
The PD-L1/PD-1 axis mediates immune tolerance and promotes tumor growth and progression via the inhibition of anti-tumor immunity. Blocking the interaction between PD-L1 and PD-1 was clinically shown to be beneficial in maintaining the anti-tumor functions of the adaptive immune system. Still, the consequences of blocking the PD-L1/PD-1 axis on innate immune responses remain largely unexplored. In this context, neutrophils were shown to consist of distinct subpopulations, which possess either pro- or anti-tumor properties. PD-L1-expressing neutrophils are considered pro-tumor as they are able to suppress cytotoxic T cells and are propagated with disease progression. That said, we found that PD-L1 expression is not limited to tumor promoting neutrophils, but is also evident in anti-tumor neutrophils. We show that neutrophil cytotoxicity is effectively and efficiently blocked by tumor cell-expressed PD-1. Furthermore, the blocking of either neutrophil PD-L1 or tumor cell PD-1 maintains neutrophil cytotoxicity. Importantly, we show that tumor cell PD-1 blocks neutrophil cytotoxicity and promotes tumor growth via a mechanism independent of adaptive immunity. Taken together, these findings highlight the therapeutic potential of enhancing anti-tumor innate immune responses via blocking of the PD-L1/PD-1 axis. Full article
(This article belongs to the Special Issue The Role of Neutrophils in Cancer)
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Review

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48 pages, 4830 KiB  
Review
Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled
by Ronit Vogt Sionov
Cells 2021, 10(9), 2486; https://doi.org/10.3390/cells10092486 - 20 Sep 2021
Cited by 17 | Viewed by 5151
Abstract
Neutrophils are the most abundant immune cell in the circulation of human and act as gatekeepers to discard foreign elements that have entered the body. They are essential in initiating immune responses for eliminating invaders, such as microorganisms and alien particles, as well [...] Read more.
Neutrophils are the most abundant immune cell in the circulation of human and act as gatekeepers to discard foreign elements that have entered the body. They are essential in initiating immune responses for eliminating invaders, such as microorganisms and alien particles, as well as to act as immune surveyors of cancer cells, especially during the initial stages of carcinogenesis and for eliminating single metastatic cells in the circulation and in the premetastatic organs. Since neutrophils can secrete a whole range of factors stored in their many granules as well as produce reactive oxygen and nitrogen species upon stimulation, neutrophils may directly or indirectly affect carcinogenesis in both the positive and negative directions. An intricate crosstalk between tumor cells, neutrophils, other immune cells and stromal cells in the microenvironment modulates neutrophil function resulting in both anti- and pro-tumor activities. Both the anti-tumor and pro-tumor activities require chemoattraction towards the tumor cells, neutrophil activation and ROS production. Divergence is seen in other neutrophil properties, including differential secretory repertoire and membrane receptor display. Many of the direct effects of neutrophils on tumor growth and metastases are dependent on tight neutrophil–tumor cell interactions. Among them, the neutrophil Mac-1 interaction with tumor ICAM-1 and the neutrophil L-selectin interaction with tumor-cell sialomucins were found to be involved in the neutrophil-mediated capturing of circulating tumor cells resulting in increased metastatic seeding. On the other hand, the anti-tumor function of neutrophils was found to rely on the interaction between tumor-surface-expressed receptor for advanced glycation end products (RAGE) and Cathepsin G expressed on the neutrophil surface. Intriguingly, these two molecules are also involved in the promotion of tumor growth and metastases. RAGE is upregulated during early inflammation-induced carcinogenesis and was found to be important for sustaining tumor growth and homing at metastatic sites. Cathepsin G was found to be essential for neutrophil-supported lung colonization of cancer cells. These data level up the complexity of the dual role of neutrophils in cancer. Full article
(This article belongs to the Special Issue The Role of Neutrophils in Cancer)
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