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21 pages, 3019 KiB

Open AccessEditor’s ChoiceArticle

CXCR2 Mediates Distinct Neutrophil Behavior in Brain Metastatic Breast Tumor

by Simrit Safarulla, Ankit Madan, Fei Xing and Arvind Chandrasekaran

Cancers 2022, 14(3), 515; https://doi.org/10.3390/cancers14030515 - 20 Jan 2022

Cited by 18 | Viewed by 5171

Abstract

Brain metastasis is one of the main causes of mortality among breast cancer patients, but the origins and the mechanisms that drive this process remain poorly understood. Here, we report that the upregulation of certain CXCR2-associated ligands in the brain metastatic variants of [...] Read more.

Brain metastasis is one of the main causes of mortality among breast cancer patients, but the origins and the mechanisms that drive this process remain poorly understood. Here, we report that the upregulation of certain CXCR2-associated ligands in the brain metastatic variants of the breast cancer cells (BrM) dynamically activate the corresponding CXCR2 receptors on the neutrophils, thereby resulting in the modulation of certain key functional neutrophil responses towards the BrM. Using established neutrophil-tumor biomimetic co-culture models, we show that the upregulation of CXCR2 increases the recruitment of Tumor-Associated Neutrophils (TANs) towards the BrM, to enable location-favored formation of Neutrophil Extracellular Traps (NETs). Inhibition of CXCR2 using small molecule antagonist AZD5069 reversed this behavior, limiting the neutrophil responses to the BrM and retarding the reciprocal tumor development. We further demonstrate that abrogation of NETs formation using Neutrophil Elastase Inhibitor (NEI) significantly decreases the influx of neutrophils towards BrM but not to their parental tumor, suggesting that CXCR2 activation could be used by the brain metastatic tumors as a mechanism to program the tumor-infiltrating TANs into a pro-NETotic state, so as to assume a unique spatial distribution that assists in the subsequent migration and invasion of the metastatic tumor cells. This new perspective indicates that CXCR2 is a critical target for suppressing neutrophilic inflammation in brain metastasis. Full article

(This article belongs to the Special Issue Neutrophils in Cancer: Role and Therapeutic Strategies)

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16 pages, 1741 KiB

Open AccessArticle

Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer

by Hongji Zhang, Yu Wang, Amblessed Onuma, Jiayi He, Han Wang, Yujia Xia, Rhea Lal, Xiang Cheng, Gyulnara Kasumova, Zhiwei Hu, Meihong Deng, Joal D. Beane, Alex C. Kim, Hai Huang and Allan Tsung

Cancers 2021, 13(21), 5333; https://doi.org/10.3390/cancers13215333 - 23 Oct 2021

Cited by 41 | Viewed by 4810

Abstract

Immune checkpoint inhibitors can improve the prognosis of patients with advanced malignancy; however, only a small subset of advanced colorectal cancer patients in microsatellite-instability-high or mismatch-repair-deficient colorectal cancer can benefit from immunotherapy. Unfortunately, the mechanism behind this ineffectiveness is unclear. The tumor microenvironment [...] Read more.

Immune checkpoint inhibitors can improve the prognosis of patients with advanced malignancy; however, only a small subset of advanced colorectal cancer patients in microsatellite-instability-high or mismatch-repair-deficient colorectal cancer can benefit from immunotherapy. Unfortunately, the mechanism behind this ineffectiveness is unclear. The tumor microenvironment plays a critical role in cancer immunity, and may contribute to the inhibition of immune checkpoint inhibitors and other novel immunotherapies in patients with advanced cancer. Herein, we demonstrate that the DNase I enzyme plays a pivotal role in the degradation of NETs, significantly dampening the resistance to anti-PD-1 blockade in a mouse colorectal cancer model by attenuating tumor growth. Remarkably, DNase I decreases tumor-associated neutrophils and the formation of MC38 tumor cell-induced neutrophil extracellular trap formation in vivo. Mechanistically, the inhibition of neutrophil extracellular traps with DNase I results in the reversal of anti-PD-1 blockade resistance through increasing CD8+ T cell infiltration and cytotoxicity. These findings signify a novel approach to targeting the tumor microenvironment using DNase I alone or in combination with immune checkpoint inhibitors. Full article

(This article belongs to the Special Issue Neutrophils in Cancer: Role and Therapeutic Strategies)

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20 pages, 15928 KiB

Open AccessArticle

Tumor-Derived Factors Differentially Affect the Recruitment and Plasticity of Neutrophils

by Ludovica Arpinati, Naomi Kaisar-Iluz, Merav E. Shaul, Christopher Groth, Viktor Umansky and Zvi G. Fridlender

Cancers 2021, 13(20), 5082; https://doi.org/10.3390/cancers13205082 - 11 Oct 2021

Cited by 9 | Viewed by 3123

Abstract

Neutrophils play a key role in cancer biology. In contrast to circulating normal-density neutrophils (NDN), the amount of low-density neutrophils (LDN) significantly increases with tumor progression. The correlation between these neutrophil subpopulations and intratumoral neutrophils (TANs) is still under debate. Using 4T1 (breast) [...] Read more.

Neutrophils play a key role in cancer biology. In contrast to circulating normal-density neutrophils (NDN), the amount of low-density neutrophils (LDN) significantly increases with tumor progression. The correlation between these neutrophil subpopulations and intratumoral neutrophils (TANs) is still under debate. Using 4T1 (breast) and AB12 (mesothelioma) tumor models, we aimed to elucidate the source of TANs and to assess the mechanisms driving neutrophils’ plasticity in cancer. Both NDN and LDN were found to migrate in response to CXCL1 and CXCL2 exposure, and co-infiltrate the tumor site ex vivo and in vivo, although LDN migration into the tumor was higher than NDN. Tumor-derived factors and chemokines, particularly CXCL1, were found to drive neutrophil phenotypical plasticity, inducing NDN to transition towards a low-density state (LD-NDN). LD-NDN appeared to differ from NDN by displaying a phenotypical profile similar to LDN in terms of nuclear morphology, surface receptor markers, decreased phagocytic abilities, and increased ROS production. Interestingly, all three subpopulations displayed comparable cytotoxic abilities towards tumor cells. Our data suggest that TANs originate from both LDN and NDN, and that a portion of LDN derives from NDN undergoing phenotypical changes. NDN plasticity resulted in a change in surface marker expression and functional activity, gaining characteristics of LDN. Full article

(This article belongs to the Special Issue Neutrophils in Cancer: Role and Therapeutic Strategies)

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15 pages, 2242 KiB

Open AccessArticle

CD47-SIRPα Checkpoint Inhibition Enhances Neutrophil-Mediated Killing of Dinutuximab-Opsonized Neuroblastoma Cells

by Paula Martínez-Sanz, Arjan J. Hoogendijk, Paul J. J. H. Verkuijlen, Karin Schornagel, Robin van Bruggen, Timo K. van den Berg, Godelieve A. M. Tytgat, Katka Franke, Taco W. Kuijpers and Hanke L. Matlung

Cancers 2021, 13(17), 4261; https://doi.org/10.3390/cancers13174261 - 24 Aug 2021

Cited by 17 | Viewed by 3656

Abstract

High-risk neuroblastoma, especially after recurrence, still has a very low survival rate. Immune checkpoint inhibitors targeting T cells have shown remarkable clinical efficacy in adult solid tumors, but their effects in pediatric cancers have been limited so far. On the other hand, targeting [...] Read more.

High-risk neuroblastoma, especially after recurrence, still has a very low survival rate. Immune checkpoint inhibitors targeting T cells have shown remarkable clinical efficacy in adult solid tumors, but their effects in pediatric cancers have been limited so far. On the other hand, targeting myeloid immune checkpoints, such as CD47-SIPRα, provide the opportunity to enhance antitumor effects of myeloid cells, including that of neutrophils, especially in the presence of cancer-opsonizing antibodies. Disialoganglioside (GD2)-expressing neuroblastoma cells targeted with anti-GD2 antibody dinutuximab are in part eradicated by neutrophils, as they recognize and bind the antibody targeted tumor cells through their Fc receptors. Therapeutic targeting of the innate immune checkpoint CD47-SIRPα has been shown to promote the potential of neutrophils as cytotoxic cells in different solid tumor indications using different cancer-targeting antibodies. Here, we demonstrate that the capacity of neutrophils to kill dinutuximab-opsonized neuroblastoma cells is also controlled by the CD47-SIRPα axis and can be further enhanced by antagonizing CD47-SIRPα interactions. In particular, CD47-SIRPa checkpoint inhibition enhanced neutrophil-mediated ADCC of dinutuximab-opsonized adrenergic neuroblastoma cells, whereas mesenchymal neuroblastoma cells may evade immune recognition by a reduction of GD2 expression. These findings provide a rational basis for targeting CD47-SIRPα interactions to potentiate dinutuximab responsiveness in neuroblastomas with adrenergic phenotype. Full article

(This article belongs to the Special Issue Neutrophils in Cancer: Role and Therapeutic Strategies)

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10 pages, 1560 KiB

Open AccessArticle

Risk Classification for Overall Survival by the Neutrophil–Lymphocyte Ratio and the Number of Metastatic Sites in Patients Treated with Pembrolizumab—A Multicenter Collaborative Study in Japan

by Taizo Uchimoto, Kazumasa Komura, Wataru Fukuokaya, Takahiro Kimura, Kazuhiro Takahashi, Yusuke Yano, Kazuki Nishimura, Keita Nakamori, Yuya Fujiwara, Tomohisa Matsunaga, Takeshi Tsutsumi, Takuya Tsujino, Ryoichi Maenosono, Yuki Yoshikawa, Kohei Taniguchi, Tomohito Tanaka, Hirofumi Uehara, Hajime Hirano, Hayahito Nomi, Kiyoshi Takahara, Teruo Inamoto, Shin Egawa and Haruhito Azuma Show full author list Hide full author list

Cancers 2021, 13(14), 3554; https://doi.org/10.3390/cancers13143554 - 15 Jul 2021

Cited by 16 | Viewed by 1997

Abstract

Pembrolizumab has emerged as the new standard of care in patients with platinum-refractory metastatic urothelial carcinoma (mUC), whereas the optimal risk stratification to predict survival outcomes is still controversial. We examined a risk model for overall survival (OS) in mUC treated with pembrolizumab [...] Read more.

Pembrolizumab has emerged as the new standard of care in patients with platinum-refractory metastatic urothelial carcinoma (mUC), whereas the optimal risk stratification to predict survival outcomes is still controversial. We examined a risk model for overall survival (OS) in mUC treated with pembrolizumab using our multi-institutional dataset (212 patients). The median age was 72 years old. Median OS from the initiation of pembrolizumab treatment was 11.7 months. The objective response rate (ORR) was 26.4%. On multivariate analysis, multiple metastatic sites and an NLR > 3.50 at the initiation of pembrolizumab treatment were identified as independent predictors for OS. We next developed a risk model using those two predictors. Patients without any factors were assigned to the favorable-risk group (26.5%). Patients with either factor and both factors were assigned to the intermediate-risk group (44.3%), and poor-risk group (29.2%), respectively. Kaplan–Meier curves showed clear discrimination of OS among the risk groups (p < 0.001). The ORR in each group was 35.7% in the favorable-risk group, 27.7% in the intermediate-risk group, and 17.7% in the poor-risk group. Given that the model can be concisely determined at the initiation of pembrolizumab treatment, physicians may be encouraged to consider the risk group for daily practice. Full article

(This article belongs to the Special Issue Neutrophils in Cancer: Role and Therapeutic Strategies)

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Review

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15 pages, 850 KiB

Open AccessReview

Neutrophil Extracellular Traps in Cancer Therapy Resistance

by Muhammad H. Shahzad, Lixuan Feng, Xin Su, Ariane Brassard, Iqraa Dhoparee-Doomah, Lorenzo E. Ferri, Jonathan D. Spicer and Jonathan J. Cools-Lartigue

Cancers 2022, 14(5), 1359; https://doi.org/10.3390/cancers14051359 - 7 Mar 2022

Cited by 36 | Viewed by 7323

Abstract

Neutrophils and their products are increasingly recognized to have a key influence on cancer progression and response to therapy. Their involvement has been shown in nearly every aspect of cancer pathophysiology with growing evidence now supporting their role in resistance to a variety [...] Read more.

Neutrophils and their products are increasingly recognized to have a key influence on cancer progression and response to therapy. Their involvement has been shown in nearly every aspect of cancer pathophysiology with growing evidence now supporting their role in resistance to a variety of cancer therapies. Recently, the role of neutrophils in cancer progression and therapy resistance has been further complicated with the discovery of neutrophil extracellular traps (NETs). NETs are web-like structures of chromatin decorated with a variety of microbicidal proteins. They are released by neutrophils in a process called NETosis. NET-dependent mechanisms of cancer pathology are beginning to be appreciated, particularly with respect to tumor response to chemo-, immuno-, and radiation therapy. Several studies support the functional role of NETs in cancer therapy resistance, involving T-cell exhaustion, drug detoxification, angiogenesis, the epithelial-to-mesenchymal transition, and extracellular matrix remodeling mechanisms, among others. Given this, new and promising data suggests NETs provide a microenvironment conducive to limited therapeutic response across a variety of neoplasms. As such, this paper aims to give a comprehensive overview of evidence on NETs in cancer therapy resistance with a focus on clinical applicability. Full article

(This article belongs to the Special Issue Neutrophils in Cancer: Role and Therapeutic Strategies)

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15 pages, 750 KiB

Open AccessReview

Neutrophil Extracellular Traps (NETs) in Cancer Metastasis

by Christof Kaltenmeier, Richard L. Simmons, Samer Tohme and Hamza O. Yazdani

Cancers 2021, 13(23), 6131; https://doi.org/10.3390/cancers13236131 - 6 Dec 2021

Cited by 34 | Viewed by 5463

Abstract

Metastasis is the leading cause of cancer related morbidity and mortality. The metastatic process involves several identifiable biological stages, including tumor cell dissemination, intravasation, and the extravasation of circulating cancer cells to facilitate colonization at a distant site. Immune cell infiltration and inflammation [...] Read more.

Metastasis is the leading cause of cancer related morbidity and mortality. The metastatic process involves several identifiable biological stages, including tumor cell dissemination, intravasation, and the extravasation of circulating cancer cells to facilitate colonization at a distant site. Immune cell infiltration and inflammation within the tumor microenvironment coincide with tumor progression and metastatic spread and are thought to be the key mediators of this complex process. Amongst many infiltrating cells, neutrophils have recently emerged as an important player in fueling tumor progression, both in animal models and cancer patients. The production of Neutrophil Extracellular Traps (NETs) is particularly important in the pathogenesis of the metastatic cascade. NETs are composed of web-like DNA structures with entangled proteins that are released in response to inflammatory cues in the environment. NETs play an important role in driving tumor progression both in experimental and clinical models. In this review, we aim to summarize the current advances in understanding the role of NETs in cancer, with a specific focus on their role in promoting premetastatic niche formation, interaction with circulating cancer cells, and in epithelial to mesenchymal transition during cancer metastasis. We will furthermore discuss the possible role and different treatment options for targeting NETs to prevent tumor progression. Full article

(This article belongs to the Special Issue Neutrophils in Cancer: Role and Therapeutic Strategies)

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14 pages, 868 KiB

Open AccessReview

A Multi-Modal Toolkit for Studying Neutrophils in Cancer and Beyond

by Diana Changirwa, Jared Schlechte and Braedon McDonald

Cancers 2021, 13(21), 5331; https://doi.org/10.3390/cancers13215331 - 23 Oct 2021

Cited by 4 | Viewed by 2964

Abstract

As key effector cells of the innate immune response, neutrophils are rapidly deployed to sites of inflammation where they deliver a payload of potent effector mechanisms that are essential for host defense against pathogens as well as tissue homeostasis. In addition, neutrophils are [...] Read more.

As key effector cells of the innate immune response, neutrophils are rapidly deployed to sites of inflammation where they deliver a payload of potent effector mechanisms that are essential for host defense against pathogens as well as tissue homeostasis. In addition, neutrophils are central contributors to the pathogenesis of a vast spectrum of inflammatory, degenerative, and neoplastic diseases. As our understanding of neutrophils in health and disease continually expands, so too does our appreciation of their complex and dynamic nature in vivo; from development, maturation, and trafficking to cellular heterogeneity and functional plasticity. Therefore, contemporary neutrophil research relies on multiple complementary methodologies to perform integrated analysis of neutrophil phenotypic heterogeneity, organ- and stimulus-specific trafficking mechanisms, as well as tailored effector functions in vivo. This review discusses established and emerging technologies used to study neutrophils, with a focus on in vivo imaging in animal models, as well as next-generation ex vivo model systems to study mechanisms of neutrophil function. Furthermore, we discuss how high-dimensional single-cell analysis technologies are driving a renaissance in neutrophil biology by redefining our understanding of neutrophil development, heterogeneity, and functional plasticity. Finally, we discuss innovative applications and emerging opportunities to integrate these high-dimensional, multi-modal techniques to deepen our understanding of neutrophils in cancer research and beyond. Full article

(This article belongs to the Special Issue Neutrophils in Cancer: Role and Therapeutic Strategies)

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