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Cancers
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Emerging Roles of Immune Cells in Cancer Development and Progression
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Emerging Roles of Immune Cells in Cancer Development and Progression

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 33374

Special Issue Editors

Dr. David Entenberg

E-Mail Website
Guest Editor
Department of Anatomy and Structural Biology, Einstein College of Medicine / Montefiore Medical Center, New York, United States
Interests: cancer metastasis; intravital imaging; surgical engineering; biophotonics; biomarker development; microscopy
Dr. Panagiota Filippou

E-Mail Website
Guest Editor
1. School of Health and Life Sciences, Teesside University, Middlesbrough TS1 3BX, UK
2. National Horizons Centre, Teesside University, Darlington DL1 1HG, UK
Interests: extracellular proteolysis; proteolytic enzymes; tumor microenvironment; cytokines; chemotherapy; clinical biomarkers
Special Issues, Collections and Topics in MDPI journals
Dr. George Karagiannis

E-Mail Website
Guest Editor
Department of Anatomy and Structural Biology, Einstein College of Medicine / Montefiore Medical Center, New York, United States
Interests: Investigation of immune cell implication in cancer cell dissemination and metastasis; Investigation of chemotherapy-induced prometastatic lesions in the primary and secondary tumor microenvironments

Special Issue Information

Dear Colleagues,

In recent years, it has become increasingly evident that the immune cell landscape is a critical constituent of the tumor microenvironment. On one hand, myeloid cells within the tumor microenvironment (e.g., macrophages, neutrophils, myeloid-derived suppressor cells), contribute significantly to the regulation of many steps of the metastatic cascade including: cancer cell invasion, migration, and intravasation; premetastatic niche formation; stem cell induction and maintenance; and growth and survival of metastatic cancer cells in secondary sites. On the other hand, cancer cells evade destruction by developing molecular and cellular strategies that alter immune responses so as to turn both innate (e.g., natural killer cells) and adaptive (CD8+ T lymphocytes) immune cells into unwitting supporters of the metastatic process. Moreover, recent data implicate complicated and reciprocal interactions among different subsets of immune cells, including the establishment of immunosuppressive milieus by myeloid cells to disrupt the infiltration and function of cytotoxic T cells in the tumor microenvironment. Altogether, these mechanisms orchestrate an immune microenvironment which may critically support a prometastatic phenotype.

Despite the vast number of studies exploring the mechanistic underpinnings of the role of immune cells in cancer metastasis, there are still challenges and unanswered questions in the field. Foremost, just how the wide variety of immune cell subsets within the local and systemic microenvironments can create a highly complex immune cell repertoire necessitates an in-depth understanding of the exact molecular pathways that regulate their phenotypes, functions, and contributions to metastasis. Further, primary and secondary tumor microenvironments each have novel immune cell subsets that are recognized to have unique properties and context-dependent functions that vary among the individual steps of the metastatic cascade. A thorough understanding of this pathobiology is paramount for the development of novel and efficient immunotherapies that are capable of specifically targeting prometastatic immune cell functions.

Thus, the conceptual theme of this Special Issue is centered around the molecular and cellular dissection of immune cell-mediated cancer invasion and metastasis. Our overarching aim also extends to highlighting novel therapeutic targets that help to overcome the devastating effects of metastatic disease.

Dr. David Entenberg
Dr. Panagiota Filippou
Dr. George Karagiannis
Guest Editors

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 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. Cancers 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 2900 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

  • cancer
  • metastasis
  • tumor microenvironment
  • immune cells
  • dissemination
  • therapeutic targets
  • premetastatic niche

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Published Papers (8 papers)

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Editorial

Jump to: Research, Review

4 pages, 198 KiB  
Editorial
Emerging Roles of Immune Cells in Cancer Development and Progression
by David Entenberg, Panagiota S. Filippou and George S. Karagiannis
Cancers 2022, 14(11), 2642; https://doi.org/10.3390/cancers14112642 - 26 May 2022
Viewed by 1479
Abstract
Immune cells are a major constituent of the tumor microenvironment, and participate in interactions with tumor cells to promote the acquisition of critical hallmarks of cancer [...] Full article
(This article belongs to the Special Issue Emerging Roles of Immune Cells in Cancer Development and Progression)

Research

Jump to: Editorial, Review

20 pages, 3677 KiB  
Article
Pivotal Role for Cxcr2 in Regulating Tumor-Associated Neutrophil in Breast Cancer
by Colin Timaxian, Christoph F. A. Vogel, Charlotte Orcel, Diana Vetter, Camille Durochat, Clarisse Chinal, Phuong NGuyen, Marie-Laure Aknin, Françoise Mercier-Nomé, Martin Davy, Isabelle Raymond-Letron, Thi-Nhu-Ngoc Van, Sarah D. Diermeier, Anastasia Godefroy, Magali Gary-Bobo, Franck Molina, Karl Balabanian and Gwendal Lazennec
Cancers 2021, 13(11), 2584; https://doi.org/10.3390/cancers13112584 - 25 May 2021
Cited by 23 | Viewed by 4728
Abstract
Chemokines present in the tumor microenvironment are essential for the control of tumor progression. We show here that several ligands of the chemokine receptor Cxcr2 were up-regulated in the PyMT (polyoma middle T oncogene) model of breast cancer. Interestingly, the knock-down of Cxcr2 [...] Read more.
Chemokines present in the tumor microenvironment are essential for the control of tumor progression. We show here that several ligands of the chemokine receptor Cxcr2 were up-regulated in the PyMT (polyoma middle T oncogene) model of breast cancer. Interestingly, the knock-down of Cxcr2 in PyMT animals led to an increased growth of the primary tumor and lung metastasis. The analysis of tumor content of PyMT-Cxcr2−/− animals highlighted an increased infiltration of tumor associated neutrophils (TANs), mirrored by a decreased recruitment of tumor associated macrophages (TAMs) compared to PyMT animals. Analysis of PyMT-Cxcr2−/− TANs revealed that they lost their killing ability compared to PyMT-Cxcr2+/+ TANs. The transcriptomic analysis of PyMT-Cxcr2−/− TANs showed that they had a more pronounced pro-tumor TAN2 profile compared to PyMT TANs. In particular, PyMT-Cxcr2−/− TANs displayed an up-regulation of the pathways involved in reactive oxygen species (ROS) production and angiogenesis and factors favoring metastasis, but reduced apoptosis. In summary, our data reveal that a lack of Cxcr2 provides TANs with pro-tumor effects. Full article
(This article belongs to the Special Issue Emerging Roles of Immune Cells in Cancer Development and Progression)
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20 pages, 2804 KiB  
Article
High M-MDSC Percentage as a Negative Prognostic Factor in Chronic Lymphocytic Leukaemia
by Michał Zarobkiewicz, Wioleta Kowalska, Sylwia Chocholska, Waldemar Tomczak, Agata Szymańska, Izabela Morawska, Agnieszka Wojciechowska and Agnieszka Bojarska-Junak
Cancers 2020, 12(9), 2614; https://doi.org/10.3390/cancers12092614 - 14 Sep 2020
Cited by 19 | Viewed by 3707
Abstract
In the current study, we analysed the role and prognostic value of myeloid-derived suppressor cells (MDSC) in chronic lymphocytic leukaemia (CLL). The frequency of circulating monocytic MDSC (M-MDSC; defined as CD14+CD11b+CD15-HLA-DR-/low cells) was assessed in correlation [...] Read more.
In the current study, we analysed the role and prognostic value of myeloid-derived suppressor cells (MDSC) in chronic lymphocytic leukaemia (CLL). The frequency of circulating monocytic MDSC (M-MDSC; defined as CD14+CD11b+CD15-HLA-DR-/low cells) was assessed in correlation with clinical and laboratory parameters characterising the disease activity and patient immune status. Samples of peripheral blood from untreated CLL patients and healthy volunteers were stained with monoclonal antibodies for flow cytometry analysis. CLL patients with M-MDSC percentages above 9.35% (according to the receiver operating characteristic (ROC) analysis) had a shorter time-to-treatment and shorter survival time than the group with a lower percentage of M-MDSC. The M-MDSC percentage was higher in patients with adverse prognostic factors (i.e., 17p and 11q deletion and CD38 and ZAP-70 expression). A high M-MDSC percentage was linked to significantly lower expression of the CD3ζ in T cells. Furthermore, an analysis of immune regulatory molecules (arginase 1 (ARG1), nitric oxide synthase (NOS2), indoleamine 2,3-dioxygenase (IDO), transforming growth factor beta (TGF-β), and interleukin (IL)-10) was performed. By the means of flow cytometry and RT-qPCR, we showed an overexpression of three of them in M-MDSC of CLL patients. M-MDSC cells seem to be an important factor in the immunosuppressive microenvironment of CLL and seem to be a good and novel prognostic factor Full article
(This article belongs to the Special Issue Emerging Roles of Immune Cells in Cancer Development and Progression)
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22 pages, 7412 KiB  
Article
Stromal CCL2 Signaling Promotes Mammary Tumor Fibrosis through Recruitment of Myeloid-Lineage Cells
by Genevra Kuziel, Victoria Thompson, Joseph V. D’Amato and Lisa M. Arendt
Cancers 2020, 12(8), 2083; https://doi.org/10.3390/cancers12082083 - 28 Jul 2020
Cited by 16 | Viewed by 3628
Abstract
Obesity is correlated with breast tumor desmoplasia, leading to diminished chemotherapy response and disease-free survival. Obesity causes chronic, macrophage-driven inflammation within breast tissue, initiated by chemokine ligand 2 (CCL2) signaling from adipose stromal cells. To understand how CCL2-induced inflammation alters breast tumor pathology, [...] Read more.
Obesity is correlated with breast tumor desmoplasia, leading to diminished chemotherapy response and disease-free survival. Obesity causes chronic, macrophage-driven inflammation within breast tissue, initiated by chemokine ligand 2 (CCL2) signaling from adipose stromal cells. To understand how CCL2-induced inflammation alters breast tumor pathology, we transplanted oncogenically transformed human breast epithelial cells with breast stromal cells expressing CCL2 or empty vector into murine mammary glands and examined tumor formation and progression with time. As tumors developed, macrophages were rapidly recruited, followed by the emergence of cancer-associated fibroblasts (CAFs) and collagen deposition. Depletion of CD11b + myeloid lineage cells early in tumor formation reduced tumor growth, CAF numbers, and collagen deposition. CCL2 expression within developing tumors also enhanced recruitment of myeloid progenitor cells from the bone marrow into the tumor site. The myeloid progenitor cell population contained elevated numbers of fibrocytes, which exhibited platelet-derived growth factor receptor-alpha (PDGFRα)-dependent colony formation and growth in vitro. Together, these results suggest that chronic inflammation induced by CCL2 significantly enhances tumor growth and promotes the formation of a desmoplastic stroma through early recruitment of macrophages and fibrocytes into the tumor microenvironment. Fibrocytes may be a novel target in the tumor microenvironment to reduce tumor fibrosis and enhance treatment responses for obese breast cancer patients. Full article
(This article belongs to the Special Issue Emerging Roles of Immune Cells in Cancer Development and Progression)
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19 pages, 1504 KiB  
Article
Prognostic Value of Immune Environment Analysis in Small Bowel Adenocarcinomas with Verified Mutational Landscape and Predisposing Conditions
by Erkki-Ville Wirta, Säde Szeto, Ulrika Hänninen, Maarit Ahtiainen, Jan Böhm, Jukka-Pekka Mecklin, Lauri A. Aaltonen and Toni T. Seppälä
Cancers 2020, 12(8), 2018; https://doi.org/10.3390/cancers12082018 - 23 Jul 2020
Cited by 6 | Viewed by 2958
Abstract
Background: Small bowel adenocarcinoma (SBA) is a rare yet insidious cancer with poor survival. The abundance of tumour-infiltrating lymphocytes is associated with improved survival, but the role of the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway in tumour escape is controversial. We evaluated immune [...] Read more.
Background: Small bowel adenocarcinoma (SBA) is a rare yet insidious cancer with poor survival. The abundance of tumour-infiltrating lymphocytes is associated with improved survival, but the role of the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway in tumour escape is controversial. We evaluated immune cell infiltration, PD1/PD-L1 expression and their prognostic value in a series of SBAs with previously verified predisposing conditions and exome-wide somatic mutation characterization. Methods: Formalin-fixed paraffin-embedded tissue sections stained for CD3, CD8, PD-L1 and PD-1 were analysed from 94 SBAs. An immune cell score (ICS) was formed from the amount of the CD3 and CD8 positive lymphocytes from the tumour centre and invasive margin. The PD-L1 and PD-1 positive immune cells (ICs) and ICS were combined into a variable called Immunoprofile. Results: High ICS, PD-L1IC and PD-1, individually and combined as Immunoprofile, were prognostic for better patient outcome. Sixty-five (69%) SBAs expressed ≥1% positive PD-L1IC. A high tumour mutation burden was common (19%) and associated with immune markers. Immunoprofile, adjusted for TNM stage, mismatch repair status, tumour location, sex and age were independent prognostic markers for disease-specific and overall survival. Conclusions: Analysing tumoral immune contexture provides prognostic information in SBA. Combining ICS, PD-1 and PD-L1IC as Immunoprofile enhanced the prognostic performance. Full article
(This article belongs to the Special Issue Emerging Roles of Immune Cells in Cancer Development and Progression)
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Review

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13 pages, 811 KiB  
Review
Targeting Tie2 in the Tumor Microenvironment: From Angiogenesis to Dissemination
by Camille L. Duran, Lucia Borriello, George S. Karagiannis, David Entenberg, Maja H. Oktay and John S. Condeelis
Cancers 2021, 13(22), 5730; https://doi.org/10.3390/cancers13225730 - 16 Nov 2021
Cited by 53 | Viewed by 5129
Abstract
The Tie2 receptor tyrosine kinase is expressed in vascular endothelial cells, tumor-associated macrophages, and tumor cells and has been a major focus of research in therapies targeting the tumor microenvironment. The most extensively studied Tie2 ligands are Angiopoietin 1 and 2 (Ang1, Ang2). [...] Read more.
The Tie2 receptor tyrosine kinase is expressed in vascular endothelial cells, tumor-associated macrophages, and tumor cells and has been a major focus of research in therapies targeting the tumor microenvironment. The most extensively studied Tie2 ligands are Angiopoietin 1 and 2 (Ang1, Ang2). Ang1 plays a critical role in vessel maturation, endothelial cell migration, and survival. Ang2, depending on the context, may function to disrupt connections between the endothelial cells and perivascular cells, promoting vascular regression. However, in the presence of VEGF-A, Ang2 instead promotes angiogenesis. Tie2-expressing macrophages play a critical role in both tumor angiogenesis and the dissemination of tumor cells from the primary tumor to secondary sites. Therefore, Ang-Tie2 signaling functions as an angiogenic switch during tumor progression and metastasis. Here we review the recent advances and complexities of targeting Tie2 signaling in the tumor microenvironment as a possible anti-angiogenic, and anti-metastatic, therapy and describe its use in combination with chemotherapy. Full article
(This article belongs to the Special Issue Emerging Roles of Immune Cells in Cancer Development and Progression)
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18 pages, 1471 KiB  
Review
Natural Killer Cells and Dendritic Cells: Expanding Clinical Relevance in the Non-Small Cell Lung Cancer (NSCLC) Tumor Microenvironment
by Pankaj Ahluwalia, Meenakshi Ahluwalia, Ashis K. Mondal, Nikhil S. Sahajpal, Vamsi Kota, Mumtaz V. Rojiani and Ravindra Kolhe
Cancers 2021, 13(16), 4037; https://doi.org/10.3390/cancers13164037 - 11 Aug 2021
Cited by 20 | Viewed by 4235
Abstract
Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer that accounts for almost 85% of lung cancer cases worldwide. Although recent advances in chemotherapy, radiotherapy, and immunotherapy have helped in the clinical management of these patients, the survival rate in [...] Read more.
Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer that accounts for almost 85% of lung cancer cases worldwide. Although recent advances in chemotherapy, radiotherapy, and immunotherapy have helped in the clinical management of these patients, the survival rate in advanced stages remains dismal. Furthermore, there is a critical lack of accurate prognostic and stratification markers for emerging immunotherapies. To harness immune response modalities for therapeutic benefits, a detailed understanding of the immune cells in the complex tumor microenvironment (TME) is required. Among the diverse immune cells, natural killer (NK cells) and dendritic cells (DCs) have generated tremendous interest in the scientific community. NK cells play a critical role in tumor immunosurveillance by directly killing malignant cells. DCs link innate and adaptive immune systems by cross-presenting the antigens to T cells. The presence of an immunosuppressive milieu in tumors can lead to inactivation and poor functioning of NK cells and DCs, which results in an adverse outcome for many cancer patients, including those with NSCLC. Recently, clinical intervention using modified NK cells and DCs have shown encouraging response in advanced NSCLC patients. Herein, we will discuss prognostic and predictive aspects of NK cells and DC cells with an emphasis on NSCLC. Additionally, the discussion will extend to potential strategies that seek to enhance the anti-tumor functionality of NK cells and DCs. Full article
(This article belongs to the Special Issue Emerging Roles of Immune Cells in Cancer Development and Progression)
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19 pages, 1331 KiB  
Review
Neutrophil Extracellular Traps in Tumor Metastasis: Pathological Functions and Clinical Applications
by Qian Chen, Lu Zhang, Xiang Li and Wei Zhuo
Cancers 2021, 13(11), 2832; https://doi.org/10.3390/cancers13112832 - 6 Jun 2021
Cited by 36 | Viewed by 6058
Abstract
Neutrophil extracellular trap (NET) formation is an ability of neutrophils to capture and kill pathogens by releasing chromatin scaffolds, along with associated cytotoxic enzymes and proteases, into the extracellular space. NETs are usually stimulated by pathogenic microorganisms and their products, surgical pressure or [...] Read more.
Neutrophil extracellular trap (NET) formation is an ability of neutrophils to capture and kill pathogens by releasing chromatin scaffolds, along with associated cytotoxic enzymes and proteases, into the extracellular space. NETs are usually stimulated by pathogenic microorganisms and their products, surgical pressure or hypoxia. Interestingly, a number of recent studies suggest that tumor cells can induce NET formation, which in turn confers tumor cell malignancy. Notably, emerging studies indicate that NETs are involved in enhancing local invasion, increasing vascular permeability and facilitating immune escape and colonization, thus promoting tumor metastasis. In this article, we review the pivotal roles of NETs in the tumor metastasis cascade. We also recapitulate the potential of NETs as a cancer prognostic biomarker and therapeutic target. Full article
(This article belongs to the Special Issue Emerging Roles of Immune Cells in Cancer Development and Progression)
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