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Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application
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Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (15 November 2019) | Viewed by 101057

Special Issue Editor

Prof. Dr. Paola Cappello

E-Mail Website
Guest Editor
Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy
Interests: pancreatic tumor; identification of antigens as diagnostic markers and potential immunotherapeutic targets; DNA vaccination; inflammation and fibrosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Myeloid cells, both macrophages and dendritic cells, play an active role in shaping the tumor micro-environment and anti-tumor immune response. As antigen-presenting cells, they can phagocyte tumor debris and dying cells and present tumor antigens to T cells by eliciting an anti-tumor response. However, some of them differentiate in suppressive or “alternative-differentiated” cells under stimuli secreted by tumor and stroma cells. Hypoxia, metabolites, growth factors, and cytokines represent only a part of those stimuli. The general features of myeloid cell populations, as well as of other immune cells, are high heterogenicity and plasticity.

In recent years, the deep characterization of myeloid cell populations in terms of surface markers, functions, transcriptional activity, and epigenetic profile has led to the idea of targeting them in the attempt to fight tumor progression or make more efficient antigen-specific strategies against tumors.

This issue would like to be a collection of different types of contributions from methodological to translational papers and reviews widely discussing myeloid cell contribution in shaping tumor behavior and anti-tumor immune response. It would be important for the scientific community to have methodological and translational contributions to know how correctly treat myeloid cells in vitro and in vivo, how to perform experiments with them to better compare results obtained around the world, as well have comprehensive reviews to learn how to analyze them in depth within the tumors.

Dr. Paola Cappello
Guest Editor

Manuscript Submission Information

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Keywords

  • macrophage
  • myeloid-derived suppressor cells
  • dendritic cells
  • human and mouse models of cancer

Published Papers (17 papers)

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Research

Jump to: Review

12 pages, 1350 KiB  
Communication
Unique Pro-Inflammatory Response of Macrophages during Apoptotic Cancer Cell Clearance
by Veronica Mendoza-Reinoso, Dah Youn Baek, Adrianne Kurutz, John R. Rubin, Amy J. Koh, Laurie K. McCauley and Hernan Roca
Cells 2020, 9(2), 429; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020429 - 12 Feb 2020
Cited by 13 | Viewed by 4347
Abstract
The clearance of apoptotic cells by macrophages (efferocytosis) is crucial to maintain normal tissue homeostasis; however, efferocytosis of cancer cells frequently results in inflammation and immunosuppression. Recently, we demonstrated that efferocytosis of apoptotic prostate cancer cells by bone marrow-derived macrophages induced a pro-inflammatory [...] Read more.
The clearance of apoptotic cells by macrophages (efferocytosis) is crucial to maintain normal tissue homeostasis; however, efferocytosis of cancer cells frequently results in inflammation and immunosuppression. Recently, we demonstrated that efferocytosis of apoptotic prostate cancer cells by bone marrow-derived macrophages induced a pro-inflammatory response that accelerated metastatic tumor growth in bone. To evaluate the microenvironmental impact of macrophages and their efferocytic function, we compared peritoneal macrophages (P-MΦ) versus bone marrow-derived macrophages (BM-MΦs) using an efferocytosis in vitro model. The capability to engulf apoptotic prostate cells was similar in BM-MΦs and P-MΦs. Ex vivo analysis of BM-MΦs showed an M2-like phenotype compared with a predominantly M1-like phenotype in P-MΦs. A distinct gene and protein expression profile of pro-inflammatory cytokines was found in BM-MΦs as compared with P-MΦs engulfing apoptotic prostate cancer cells. Importantly, the reprogramming of BM-MΦs toward an M1-like phenotype mitigated their inflammatory cytokine expression profile. In conclusion, BM-MΦs and P-MΦs are both capable of efferocytosing apoptotic prostate cancer cells; however, BM-MΦs exert increased inflammatory cytokine expression that is dependent upon the M2 polarization stage of macrophages. These findings suggest that bone marrow macrophage efferocytosis of apoptotic cancer cells maintains a unique pro-inflammatory microenvironment that may support a fertile niche for cancer growth. Finally, bone marrow macrophage reprogramming towards M1-type by interferon-γ (IFN-γ) induced a significant reduction in the efferocytosis-mediated pro-inflammatory signature. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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14 pages, 2916 KiB  
Article
Paracrine Signaling from Breast Cancer Cells Causes Activation of ID4 Expression in Tumor-Associated Macrophages
by Sara Donzelli, Andrea Sacconi, Chiara Turco, Enzo Gallo, Elisa Milano, Ilaria Iosue, Giovanni Blandino, Francesco Fazi and Giulia Fontemaggi
Cells 2020, 9(2), 418; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020418 - 11 Feb 2020
Cited by 10 | Viewed by 3597
Abstract
Background: Tumor-associated macrophages (TAMs) constitute a major portion of the leukocyte infiltrate found in breast cancer (BC). BC cells may reprogram TAMs in a pro-angiogenic and immunosuppressive sense. We previously showed that high expression of the ID4 protein in triple-negative BC cells leads [...] Read more.
Background: Tumor-associated macrophages (TAMs) constitute a major portion of the leukocyte infiltrate found in breast cancer (BC). BC cells may reprogram TAMs in a pro-angiogenic and immunosuppressive sense. We previously showed that high expression of the ID4 protein in triple-negative BC cells leads to the induction of a proangiogenic program in TAMs also through the downregulation of miR-107. Here, we investigated the expression and function of the ID4 protein in TAMs. Methods: Human macrophages obtained from peripheral blood-derived monocytes (PBDM) and mouse RAW264.7 cells were used as macrophage experimental systems. ID4-correlated mRNAs of the TCGA and E-GEOD-18295 datasets were analyzed. Results: We observed that BC cells determine a paracrine induction of ID4 expression and activation of the ID4 promoter in neighboring macrophages. Interestingly, ID4 expression is higher in macrophages associated with invasive tumor cells compared to general TAMs, and ID4-correlated mRNAs are involved in various pathways that were previously reported as relevant for TAM functions. Selective depletion of ID4 expression in macrophages enabled validation of the ability of ID4 to control the expression of YAP1 and of its downstream targets CTGF and CYR61. Conclusion: Collectively, our results show that activation of ID4 expression in TAMs is observed as a consequence of BC cell paracrine activity and could participate in macrophage reprogramming in BC. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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13 pages, 3908 KiB  
Article
Opposite Macrophage Polarization in Different Subsets of Ovarian Cancer: Observation from a Pilot Study
by Ann Vankerckhoven, Roxanne Wouters, Thomas Mathivet, Jolien Ceusters, Thaïs Baert, Anaïs Van Hoylandt, Holger Gerhardt, Ignace Vergote and An Coosemans
Cells 2020, 9(2), 305; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020305 - 27 Jan 2020
Cited by 22 | Viewed by 3427
Abstract
The role of the innate immune system in ovarian cancer is gaining importance. The relevance of tumor-associated macrophages (TAM) is insufficiently understood. In this pilot project, comprising the immunofluorescent staining of 30 biopsies taken from 24 patients with ovarian cancer, we evaluated the [...] Read more.
The role of the innate immune system in ovarian cancer is gaining importance. The relevance of tumor-associated macrophages (TAM) is insufficiently understood. In this pilot project, comprising the immunofluorescent staining of 30 biopsies taken from 24 patients with ovarian cancer, we evaluated the presence of total TAM (cluster of differentiation (CD) 68 expression), M1 (major histocompatibility complex (MHC) II expression), and M2 (anti-mannose receptor C type 1 (MRC1) expression), and the blood vessel diameter. We observed a high M1/M2 ratio in low-grade ovarian cancer compared to high-grade tumors, more total TAM and M2 in metastatic biopsies, and a further increase in total TAM and M2 at interval debulking, without beneficial effects of bevacizumab. The blood vessel diameter was indicative for M2 tumor infiltration (Spearman correlation coefficient of 0.65). These data mainly reveal an immune beneficial environment in low-grade ovarian cancer in contrast to high-grade serous ovarian cancer, where immune suppression is not altered by neoadjuvant therapy. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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24 pages, 7390 KiB  
Article
Tumor Infiltrating Neutrophils Are Enriched in Basal-Type Urothelial Bladder Cancer
by Giulio Eugenio Mandelli, Francesco Missale, Debora Bresciani, Luisa Benerini Gatta, Patrizia Scapini, Elena Caveggion, Elisa Roca, Mattia Bugatti, Matilde Monti, Luca Cristinelli, Sandra Belotti, Claudio Simeone, Stefano Calza, Laura Melocchi and William Vermi
Cells 2020, 9(2), 291; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020291 - 25 Jan 2020
Cited by 18 | Viewed by 3662
Abstract
Background: Urothelial bladder cancers (UBCs) are distinct in two main molecular subtypes, namely basal and luminal type. Subtypes are also diverse in term of immune contexture, providing a rationale for patient selection to immunotherapy. Methods: By digital microscopy analysis of a muscle-invasive BC [...] Read more.
Background: Urothelial bladder cancers (UBCs) are distinct in two main molecular subtypes, namely basal and luminal type. Subtypes are also diverse in term of immune contexture, providing a rationale for patient selection to immunotherapy. Methods: By digital microscopy analysis of a muscle-invasive BC (MIBC) cohort, we explored the density and clinical significance of CD66b+ tumor-associated-neutrophils (TAN) and CD3+ T cells. Bioinformatics analysis of UBC datasets and gene expression analysis of UBC cell lines were additionally performed. Results: Basal type BC contained a significantly higher density of CD66b+ TAN compared to the luminal type. This finding was validated on TCGA, GSE32894 and GSE124305 datasets by computing a neutrophil signature. Of note, basal-type MIBC display a significantly higher level of chemokines (CKs) attracting neutrophils. Moreover, pro-inflammatory stimuli significantly up-regulate CXCL1, CXCL2 and CXCL8 in 5637 and RT4 UBC cell lines and induce neutrophil chemotaxis. In term of survival, a high density of T cells and TAN was significantly associated to a better outcome, with TAN density showing a more limited statistical power and following a non-linear predicting model. Conclusions: TAN are recruited in basal type MIBC by pro-inflammatory CKs. This finding establishes a groundwork for a better understanding of the UBC immunity and its relevance. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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17 pages, 4478 KiB  
Article
Interleukin-22 Mediates the Chemotactic Migration of Breast Cancer Cells and Macrophage Infiltration of the Bone Microenvironment by Potentiating S1P/SIPR Signaling
by Eun-Young Kim, Bongkun Choi, Ji-Eun Kim, Si-On Park, Sang-Min Kim and Eun-Ju Chang
Cells 2020, 9(1), 131; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010131 - 06 Jan 2020
Cited by 17 | Viewed by 3204
Abstract
The interleukin-22 (IL-22) signaling pathway is well known to be involved in the progression of various cancer types but its role in bone metastatic breast cancer remains unclear. We demonstrate using human GEO profiling that bone metastatic breast cancer displays elevated interleukin-22 receptor [...] Read more.
The interleukin-22 (IL-22) signaling pathway is well known to be involved in the progression of various cancer types but its role in bone metastatic breast cancer remains unclear. We demonstrate using human GEO profiling that bone metastatic breast cancer displays elevated interleukin-22 receptor 1 (IL-22R1) and sphingosine-1-phosphate receptor 1 (S1PR1) expression. Importantly, IL-22 stimuli promoted the expression of IL-22R1 and S1PR1 in aggressive MDA-MB-231 breast cancer cells. IL-22 treatment also increased sphingosine-1-phosphate production in mesenchymal stem cells (MSCs) and induced the sphingosine-1-phosphate (S1P)-mediated chemotactic migration of MDA-MB-231 cells. This effect was inhibited by an S1P antagonist. In addition to the S1PR1 axis, IL-22 stimulated the expression of matrix metalloproteinase-9 (MMP-9), thereby promoting breast cancer cell invasion. Moreover, IL-22 induced IL22R1 and S1PR1 expression in macrophages, myeloid cell, and MCP1 expression in MSCs to facilitate macrophage infiltration. Immunohistochemistry indicated that IL-22R1 and S1PR1 are overexpressed in invasive malignant breast cancers and that this correlates with the MMP-9 levels. Collectively, our present results indicate a potential role of IL-22 in driving the metastasis of breast cancers into the bone microenvironment through the IL22R1-S1PR1 axis. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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16 pages, 6082 KiB  
Article
Octyl Gallate Induces Pancreatic Ductal Adenocarcinoma Cell Apoptosis and Suppresses Endothelial-Mesenchymal Transition-Promoted M2-Macrophages, HSP90α Secretion, and Tumor Growth
by Kee Voon Chua, Chi-Shuan Fan, Chia-Chi Chen, Li-Li Chen, Shu-Chen Hsieh and Tze-Sing Huang
Cells 2020, 9(1), 91; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010091 - 30 Dec 2019
Cited by 10 | Viewed by 3786
Abstract
Octyl gallate (OG) is a common antioxidant and preservative safely used in food additive and cosmetics. In this study, OG exhibited an activity to induce apoptosis in pancreatic ductal adenocarcinoma (PDAC) cells. It induced BNIP3L level and facilitated physical associations of BNIP3L with [...] Read more.
Octyl gallate (OG) is a common antioxidant and preservative safely used in food additive and cosmetics. In this study, OG exhibited an activity to induce apoptosis in pancreatic ductal adenocarcinoma (PDAC) cells. It induced BNIP3L level and facilitated physical associations of BNIP3L with Bcl-2 as well as Bcl-XL to set the mitochondrial Bax/Bak channels free for cytochrome c release. In addition, in vivo evaluation also showed that daily oral administration of OG was efficacious to prevent the tumor growth of PDAC cell grafts. Considering PDAC is a desmoplastic tumor consisting of many cancer-associated fibroblasts (CAFs), we further evaluated the efficacy of OG in a CAFs-involved PDAC mouse model. Endothelial-to-mesenchymal transition (EndoMT) is an important source of CAFs. The mix of EndoMT-derived CAFs with PDAC cell grafts significantly recruited myeloid-derived macrophages but prevented immune T cells. HSP90α secreted by EndoMT-derived CAFs further induced macrophage M2-polarization and more HSP90α secretion to expedite PDAC tumor growth. OG exhibited its potent efficacy against the tumor growth, M2-macrophages, and serum HSP90α level in the EndoMT-involved PDAC mouse model. CD91 and TLR4 are cell-surface receptors for extracellular HSP90α (eHSP90α). OG blocked eHSP90α–TLR4 ligation and, thus, prevented eHSP90α-induced M2-macrophages and more HSP90α secretion from macrophages and PDAC cells. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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17 pages, 6314 KiB  
Article
Distinct Role of CD11b+Ly6G−Ly6C− Myeloid-Derived Cells on the Progression of the Primary Tumor and Therapy-Associated Recurrent Brain Tumor
by Sheng-Yan Wu and Chi-Shiun Chiang
Cells 2020, 9(1), 51; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010051 - 24 Dec 2019
Cited by 7 | Viewed by 4973
Abstract
Myeloid-derived cells have been implicated as playing essential roles in cancer therapy, particularly in cancer immunotherapy. Most studies have focused on either CD11b+Ly6G+Ly6C+ granulocytic or polymorphonuclear myeloid-derived suppressor cells (G-MDSCs or PMN-MDSCs) or CD11b+Ly6G−Ly6C [...] Read more.
Myeloid-derived cells have been implicated as playing essential roles in cancer therapy, particularly in cancer immunotherapy. Most studies have focused on either CD11b+Ly6G+Ly6C+ granulocytic or polymorphonuclear myeloid-derived suppressor cells (G-MDSCs or PMN-MDSCs) or CD11b+Ly6G−Ly6C+ monocytic MDSCs (M-MDSCs), for which clear roles have been established. On the other hand, CD11b+Ly6G−Ly6C− myeloid-derived cells (MDCs) have been less well studied. Here, the CD11b-diphtheria toxin receptor (CD11b-DTR) transgenic mouse model was used to evaluate the role of CD11b+ myeloid-derived cells in chemotherapy for an orthotopic murine astrocytoma, ALTS1C1. Using this transgenic mouse model, two injections of diphtheria toxin (DT) could effectively deplete CD11b+Ly6G−Ly6C− MDCs while leaving CD11b+Ly6G+Ly6C+ PMN-MDSCs and CD11b+Ly6G−Ly6C+ M-MDSCs intact. Depletion of CD11b+Ly6G−Ly6C− MDCs in mice bearing ALTS1C1-tk tumors and receiving ganciclovir (GCV) prolonged the mean survival time for mice from 30.7 to 37.8 days, but not the controls, while the effectiveness of temozolomide was enhanced. Mechanistically, depletion of CD11b+Ly6G−Ly6C− MDCs blunted therapy-induced increases in tumor-associated macrophages (TAMs) and compromised therapy-elicited angiogenesis. Collectively, our findings suggest that CD11b+Ly6G−Ly6C− MDCs could be manipulated to enhance the efficacy of chemotherapy for brain tumors. However, our study also cautions that the timing of any MDC manipulation may be critical to achieve the best therapeutic result. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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Review

Jump to: Research

27 pages, 1566 KiB  
Review
Role of Tumor-Associated Myeloid Cells in Breast Cancer
by Yoon Jin Cha and Ja Seung Koo
Cells 2020, 9(8), 1785; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9081785 - 27 Jul 2020
Cited by 48 | Viewed by 7699
Abstract
Stromal immune cells constitute the tumor microenvironment. These immune cell subsets include myeloid cells, the so-called tumor-associated myeloid cells (TAMCs), which are of two types: tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Breast tumors, particularly those in human epidermal growth factor receptor [...] Read more.
Stromal immune cells constitute the tumor microenvironment. These immune cell subsets include myeloid cells, the so-called tumor-associated myeloid cells (TAMCs), which are of two types: tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Breast tumors, particularly those in human epidermal growth factor receptor 2 (HER-2)-positive breast cancer and triple-negative breast cancer, are solid tumors containing immune cell stroma. TAMCs drive breast cancer progression via immune mediated, nonimmune-mediated, and metabolic interactions, thus serving as a potential therapeutic target for breast cancer. TAMC-associated breast cancer treatment approaches potentially involve the inhibition of TAM recruitment, modulation of TAM polarization/differentiation, reduction of TAM products, elimination of MDSCs, and reduction of MDSC products. Furthermore, TAMCs can enhance or restore immune responses during cancer immunotherapy. This review describes the role of TAMs and MDSCs in breast cancer and elucidates the clinical implications of TAMs and MDSCs as potential targets for breast cancer treatment. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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14 pages, 1899 KiB  
Review
Decoding the Role of Interleukin-30 in the Crosstalk between Cancer and Myeloid Cells
by Emma Di Carlo
Cells 2020, 9(3), 615; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9030615 - 04 Mar 2020
Cited by 9 | Viewed by 2841
Abstract
In the last few years, a new actor hit the scene of the tumor microenvironment, the p28 subunit of interleukin (IL)-27, known as IL-30. Its molecular structure allows it to function as an autonomous cytokine and, alternatively, to pair with other subunits to [...] Read more.
In the last few years, a new actor hit the scene of the tumor microenvironment, the p28 subunit of interleukin (IL)-27, known as IL-30. Its molecular structure allows it to function as an autonomous cytokine and, alternatively, to pair with other subunits to form heterodimeric complexes and enables it to play different, and not fully elucidated, roles in immunity. However, data from the experimental models and clinical samples, suggest IL-30′s engagement in the relationship between cancer and myeloid cells, which fosters the tumor microenvironment and the cancer stem cell niche, boosting the disease progression. Activated myeloid cells are the primary cellular source and one of the targets of IL-30, which can also be produced by cancer cells, especially, in aggressive tumors, as observed in the breast and prostate. This review briefly reports on the immunobiology of IL-30 and related cytokines, by comparing mouse and human counterparts, and then focuses on the mechanisms whereby IL-30 amplifies intratumoral myeloid cell infiltrate and triggers a vicious cycle that worsens immunosuppression in the tumor microenvironment (TME) and constitutes a real threat for a successful immunotherapeutic strategy. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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29 pages, 3774 KiB  
Review
Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer
by Andrew M. K. Law, Fatima Valdes-Mora and David Gallego-Ortega
Cells 2020, 9(3), 561; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9030561 - 27 Feb 2020
Cited by 276 | Viewed by 17032
Abstract
The emergence of immunotherapy has been an astounding breakthrough in cancer treatments. In particular, immune checkpoint inhibitors, targeting PD-1 and CTLA-4, have shown remarkable therapeutic outcomes. However, response rates from immunotherapy have been reported to be varied, with some having pronounced success and [...] Read more.
The emergence of immunotherapy has been an astounding breakthrough in cancer treatments. In particular, immune checkpoint inhibitors, targeting PD-1 and CTLA-4, have shown remarkable therapeutic outcomes. However, response rates from immunotherapy have been reported to be varied, with some having pronounced success and others with minimal to no clinical benefit. An important aspect associated with this discrepancy in patient response is the immune-suppressive effects elicited by the tumour microenvironment (TME). Immune suppression plays a pivotal role in regulating cancer progression, metastasis, and reducing immunotherapy success. Most notably, myeloid-derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells, have potent mechanisms to inhibit T-cell and NK-cell activity to promote tumour growth, development of the pre-metastatic niche, and contribute to resistance to immunotherapy. Accumulating research indicates that MDSC can be a therapeutic target to alleviate their pro-tumourigenic functions and immunosuppressive activities to bolster the efficacy of checkpoint inhibitors. In this review, we provide an overview of the general immunotherapeutic approaches and discuss the characterisation, expansion, and activities of MDSCs with the current treatments used to target them either as a single therapeutic target or synergistically in combination with immunotherapy. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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24 pages, 1781 KiB  
Review
Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses
by Clément Anfray, Aldo Ummarino, Fernando Torres Andón and Paola Allavena
Cells 2020, 9(1), 46; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010046 - 23 Dec 2019
Cited by 185 | Viewed by 12929
Abstract
: Established evidence demonstrates that tumor-infiltrating myeloid cells promote rather than stop-cancer progression. Tumor-associated macrophages (TAMs) are abundantly present at tumor sites, and here they support cancer proliferation and distant spreading, as well as contribute to an immune-suppressive milieu. Their pro-tumor activities hamper [...] Read more.
: Established evidence demonstrates that tumor-infiltrating myeloid cells promote rather than stop-cancer progression. Tumor-associated macrophages (TAMs) are abundantly present at tumor sites, and here they support cancer proliferation and distant spreading, as well as contribute to an immune-suppressive milieu. Their pro-tumor activities hamper the response of cancer patients to conventional therapies, such as chemotherapy or radiotherapy, and also to immunotherapies based on checkpoint inhibition. Active research frontlines of the last years have investigated novel therapeutic strategies aimed at depleting TAMs and/or at reprogramming their tumor-promoting effects, with the goal of re-establishing a favorable immunological anti-tumor response within the tumor tissue. In recent years, numerous clinical trials have included pharmacological strategies to target TAMs alone or in combination with other therapies. This review summarizes the past and current knowledge available on experimental tumor models and human clinical studies targeting TAMs for cancer treatment. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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12 pages, 507 KiB  
Review
Small Particles, Big Effects: The Interplay Between Exosomes and Dendritic Cells in Antitumor Immunity and Immunotherapy
by Bruno Deltreggia Benites, Marisa Claudia Alvarez and Sara Teresinha Olalla Saad
Cells 2019, 8(12), 1648; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8121648 - 16 Dec 2019
Cited by 18 | Viewed by 3713
Abstract
Dendritic cells play a fundamental role in the antitumor immunity cycle, and the loss of their antigen-presenting function is a recognized mechanism of tumor evasion. We have recently demonstrated the effect of exosomes extracted from serum of patients with acute myeloid leukemia as [...] Read more.
Dendritic cells play a fundamental role in the antitumor immunity cycle, and the loss of their antigen-presenting function is a recognized mechanism of tumor evasion. We have recently demonstrated the effect of exosomes extracted from serum of patients with acute myeloid leukemia as important inducers of dendritic cell immunotolerance, and several other works have recently demonstrated the effects of these nanoparticles on immunity to other tumor types as well. The aim of this review was to highlight the recent findings on the effects of tumor exosomes on dendritic cell functions, the mechanisms by which they can lead to tumor evasion, and their manipulation as a possible strategy in cancer treatment. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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16 pages, 480 KiB  
Review
Myeloid-Derived Suppressor Cells: Major Figures that Shape the Immunosuppressive and Angiogenic Network in Cancer
by Eleni-Kyriaki Vetsika, Aristeidis Koukos and Athanasios Kotsakis
Cells 2019, 8(12), 1647; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8121647 - 15 Dec 2019
Cited by 80 | Viewed by 5382
Abstract
Myeloid-derived suppressor cells (MDSCs) constitute a vast population of immature myeloid cells implicated in various conditions. Most notably, their role in cancer is of great complexity. They exert immunosuppressive functions like hampering cancer immunity mediated by T lymphocytes and natural killer cells, while [...] Read more.
Myeloid-derived suppressor cells (MDSCs) constitute a vast population of immature myeloid cells implicated in various conditions. Most notably, their role in cancer is of great complexity. They exert immunosuppressive functions like hampering cancer immunity mediated by T lymphocytes and natural killer cells, while simultaneously they can recruit T regulatory cells to further promote immunosuppression, thus shielding tumor cells against the immune defenses. In addition, they were shown to support tumor invasion and metastasis by inducing vascularization. Yet again, in order to exert their angiogenic activities, they do have at their disposal a variety of occasionally overlapping mechanisms, mainly driven by VEGF/JAK/STAT signaling. In this concept, they have risen to be a rather attractive target for therapies, including depletion or maturation, so as to overcome cancer immunity and suppress angiogenic activity. Even though, many studies have been conducted to better understand these cells, there is much to be done yet. This article hopes to shed some light on the paradoxal complexity of these cells, while elucidating some of the key features of MDSCs in relation to immunosuppression and, most importantly, to the vascularization processes, along with current therapeutic options in cancer, in relation to MDSC depletion. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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15 pages, 655 KiB  
Review
Tumor-Associated Macrophages in Hematologic Malignancies: New Insights and Targeted Therapies
by Amy J. Petty and Yiping Yang
Cells 2019, 8(12), 1526; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8121526 - 27 Nov 2019
Cited by 45 | Viewed by 5131
Abstract
The growth of hematologic malignant cells can be facilitated by other non-tumor cells within the same microenvironment, including stromal, vascular, immune and mesenchymal stem cells. Macrophages are an integral part of the human innate immune system and the tumor microenvironment. Complex interplays between [...] Read more.
The growth of hematologic malignant cells can be facilitated by other non-tumor cells within the same microenvironment, including stromal, vascular, immune and mesenchymal stem cells. Macrophages are an integral part of the human innate immune system and the tumor microenvironment. Complex interplays between the malignant hematologic cells and the infiltrating macrophages promote the formation of leukemia, lymphoma or myeloma-associated macrophages. These pro-tumorigenic macrophages in turn play an important part in facilitating tumor growth, metastasis and chemotherapeutic resistance. Previous reports have highlighted the association between tumor-associated macrophages (TAMs) and disease progression in hematologic malignancies. This review summarizes the role of TAMs in different subtypes of leukemia, lymphoma and myeloma, focusing on new insights and targeted therapies. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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25 pages, 1551 KiB  
Review
MicroRNA—A Tumor Trojan Horse for Tumor-Associated Macrophages
by Shahzad Nawaz Syed, Ann-Christin Frank, Rebecca Raue and Bernhard Brüne
Cells 2019, 8(12), 1482; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8121482 - 21 Nov 2019
Cited by 31 | Viewed by 5131
Abstract
MicroRNAs (miRs) significantly contribute to the regulation of gene expression, by virtue of their ability to interact with a broad, yet specific set of target genes. MiRs are produced and released by almost every cell type and play an important role in horizontal [...] Read more.
MicroRNAs (miRs) significantly contribute to the regulation of gene expression, by virtue of their ability to interact with a broad, yet specific set of target genes. MiRs are produced and released by almost every cell type and play an important role in horizontal gene regulation in the tumor microenvironment (TME). In the TME, both tumor and stroma cells cross-communicate via diverse factors including miRs, which are taking central stage as a therapeutic target of anti-tumor therapy. One of the immune escape strategies adopted by tumor cells is to release miRs as a Trojan horse to hijack circulating or tumor-localized monocytes/macrophages to tune them for pro-tumoral functions. On the other hand, macrophage-derived miRs exert anti-tumor functions. The transfer of miRs from host to recipient cells depends on the supramolecular structure and composition of miR carriers, which determine the distinct uptake mechanism by recipient cells. In this review, we provide a recent update on the miR-mediated crosstalk between tumor cells and macrophages and their mode of uptake in the TME. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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30 pages, 543 KiB  
Review
Impact of HPV Infection on the Immune System in Oropharyngeal and Non-Oropharyngeal Squamous Cell Carcinoma: A Systematic Review
by Jerome R. Lechien, Imelda Seminerio, Géraldine Descamps, Quentin Mat, Francois Mouawad, Stéphane Hans, Morbize Julieron, Didier Dequanter, Thibault Vanderhaegen, Fabrice Journe and Sven Saussez
Cells 2019, 8(9), 1061; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8091061 - 10 Sep 2019
Cited by 38 | Viewed by 4036
Abstract
Objectives: To review the current knowledge regarding the involvement of human papilloma virus (HPV) infection and the immune system in the development of head and neck squamous cell carcinoma (HNSCC). Methods: An electronic literature search was conducted to identify articles published between 1990 [...] Read more.
Objectives: To review the current knowledge regarding the involvement of human papilloma virus (HPV) infection and the immune system in the development of head and neck squamous cell carcinoma (HNSCC). Methods: An electronic literature search was conducted to identify articles published between 1990 and 2019 pertaining to tumor-infiltrating immune cells (TICs) in HNSCC using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Issues of clinical relevance, including tumor location, the number of tumor samples, the inclusion of additional specimens (dysplastic or normal mucosa), tumor size, methods used for HPV detection, relationship between antigen expression and patient characteristics (age, gender, smoking, alcohol consumption, etc.), and prognostic data (overall survival (OS) and recurrence-free survival (RFS)) were assessed by four blinded investigators. Results: The search identified 335 relevant studies, of which 41 met the inclusion criteria. Of these, 7 studies focused on the peripheral blood immune cell concentration in patients with HNSCC according to HPV status, and 36 studies investigated TICs in the intraepithelial and/or stromal compartment(s) according to HPV status. The immune cells studied were CD8+ T cells (N = 19), CD4+ T cells (N = 7), regulatory T cells (Tregs, N = 15), macrophages (N = 13), myeloid-derived suppressor cells (MDSCs, N = 4), and Langerhans cells (LCs, N = 2). Conclusions: Irrespective of tumor location, CD8+ and CD4+ T cells appear to play a key role in the development of HPV−related HNSCC, and their infiltration is likely associated with a significant impact on OS and RFS. To date, the roles and prognostic value of Tregs, macrophages, DCs and MDSCs remain unclear. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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17 pages, 1383 KiB  
Review
Macrophage-Mediated Subversion of Anti-Tumour Immunity
by Valeria Quaranta and Michael C. Schmid
Cells 2019, 8(7), 747; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8070747 - 19 Jul 2019
Cited by 66 | Viewed by 9043
Abstract
Despite the incredible clinical benefits obtained by the use of immune checkpoint blockers (ICBs), resistance is still common for many types of cancer. Central for ICBs to work is activation and infiltration of cytotoxic CD8+ T cells following tumour-antigen recognition. However, it [...] Read more.
Despite the incredible clinical benefits obtained by the use of immune checkpoint blockers (ICBs), resistance is still common for many types of cancer. Central for ICBs to work is activation and infiltration of cytotoxic CD8+ T cells following tumour-antigen recognition. However, it is now accepted that even in the case of immunogenic tumours, the effector functions of CD8+ T cells are highly compromised by the presence of an immunosuppressive tumour microenvironment (TME) at the tumour site. Tumour-associated macrophages (TAMs) are among the most abundant non-malignant stromal cell types within the TME and they are crucial drivers of tumour progression, metastasis and resistance to therapy. TAMs are able to regulate either directly or indirectly various aspects of tumour immunity, including T cell recruitment and functions. In this review we discuss the mechanisms by which TAMs subvert CD8+ T cell immune surveillance and how their targeting in combination with ICBs represents a very powerful therapeutic strategy. Full article
(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)
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