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Cancers
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Macrophages in Cancer Progression, Diagnosis and Treatment
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Macrophages in Cancer Progression, Diagnosis and Treatment

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 10326

Special Issue Editor

Dr. Panagiotis F. Christopoulos

E-Mail Website
Guest Editor
Department of Pathology, Section of Research, Rikshospitalet, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway
Interests: immuno-oncology; tumor microenvironment; macrophages; inflammation; immunotherapy; autoimmunity

Special Issue Information

Dear Colleagues,

Despite the devastating times we are currently living in due to the SARS-CoV-2 outbreak, cancer has been and remains a leading cause of death worldwide. In recent years we have witnessed the rediscovery of the immune system’s role in the pathophysiology of the disease and the introduction of different immunotherapies into clinical practice.

Research in the field increasingly points to the direct interactions of tumor-associated macrophages (TAMs) with tumor cells, other key cellular components of the tumor microenvironment (TME) and immune cells, towards tumor progression and metastasis. However, macrophages may also possess potent anti-tumor properties depending on their activation status. Microenvironmental cues, epigenetic modifications and metabolic events can drive macrophages’ plasticity fate.

Several key questions still remain: What is the contribution of the many different, and usually contradictory factors present in the TME, in the TAMs phenotype and consequently in the disease’s outcome? How many macrophage intermediate phenotypes exist in tumors and are all essential for tumor progression? Do we have specific markers for the different phenotypes and what’s the prognostic value of each? How can the identification of novel phenotypes help us to design personalized treatment schemes?

Since most of the research so far in macrophage activation has been performed in mouse models, can the current knowledge fully reflect the human scenario? How can the results in different fields like in autoimmunity and inflammation research, be applied into the cancer setting?

Moreover, are all the macrophage phenotypic populations interchangeable? How can we efficiently and persistently activate macrophages for cancer immunotherapy? Which part of the progress made in the cellular engineering field can be applied to overcome the natural plasticity of macrophages? In addition to the direct cytotoxic properties of macrophages, which other mechanisms of action hold promising potentials in the design of future therapeutic strategies?

Finally, with lessons learned from the current pandemia, to what extent can the gained knowledge and emerged technologies propel cancer research and the development of novel macrophage-based immunotherapies? For the first time in this century we have witnessed the vast involvement of the scientific community and the fruits of immunology research in the management and treatment of global health threats.

Dr. Panagiotis F. Christopoulos
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. 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 progression and diagnosis
  • tumor-associated macrophages (TAMs)
  • inflammation
  • tumor microenvironment (TME)
  • M1/M2 macrophage activation
  • immunotherapies
  • innate immunity
  • tumor immunogenicity
  • cytokines/chemokines
  • reactive oxygen/nitrogen species (ROS/RNS)
  • phagocytosis
  • cellular and targeted therapeutics
  • immunogenic cell death

Published Papers (5 papers)

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Research

13 pages, 2392 KiB  
Article
High Numbers of CD163+ Tumor-Associated Macrophages Predict Poor Prognosis in HER2+ Breast Cancer
by Minna M. Jääskeläinen, Ritva Tumelius, Kirsi Hämäläinen, Kirsi Rilla, Sanna Oikari, Aino Rönkä, Tuomas Selander, Arto Mannermaa, Satu Tiainen and Päivi Auvinen
Cancers 2024, 16(3), 634; https://doi.org/10.3390/cancers16030634 - 1 Feb 2024
Viewed by 854
Abstract
Tumor-associated macrophages (TAMs) are associated with a poor outcome in breast cancer (BC), but their prognostic value in different BC subtypes has remained somewhat unclear. Here, we investigated the prognostic value of M2-like TAMs (CD163+) and all TAMs (CD68+) in a patient cohort [...] Read more.
Tumor-associated macrophages (TAMs) are associated with a poor outcome in breast cancer (BC), but their prognostic value in different BC subtypes has remained somewhat unclear. Here, we investigated the prognostic value of M2-like TAMs (CD163+) and all TAMs (CD68+) in a patient cohort of 278 non-metastatic BC patients, half of whom were HER2+ (n = 139). The survival endpoints investigated were overall survival (OS), breast cancer-specific survival (BCSS) and disease-free survival (DFS). In the whole patient cohort (n = 278), a high CD163+ TAM count and a high CD68+ TAM count were associated with a worse outcome (p ≤ 0.023). In HER2+ BC, a high CD163+ TAM count was an independent factor for a poor prognosis across all the investigated survival endpoints (p < 0.001). The prognostic effect was evident in both the HER2+/hormone receptor-positive (p < 0.001) and HER2+/hormone receptor-negative (p ≤ 0.012) subgroups and regardless of the provision of adjuvant trastuzumab (p ≤ 0.002). In HER2-negative BC, the CD163+ TAM count was not significantly associated with survival. These results suggest that a high CD163+ TAM count predicts an inferior outcome, especially in HER2+ BC patients, and as adjuvant trastuzumab did not overcome the poor prognostic effect, combination treatments including therapies targeting the macrophage function could represent an effective therapeutic approach in HER2+ BC. Full article
(This article belongs to the Special Issue Macrophages in Cancer Progression, Diagnosis and Treatment)
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18 pages, 14522 KiB  
Article
MICA+ Tumor Cell Upregulated Macrophage-Secreted MMP9 via PROS1-AXL Axis to Induce Tumor Immune Escape in Advanced Hepatocellular Carcinoma (HCC)
by Qiulin Wu, Xicai Li, Yan Yang, Jingquan Huang, Ming Yao, Jianjun Li, Yubin Huang, Xiaoyong Cai, David A. Geller and Yihe Yan
Cancers 2024, 16(2), 269; https://doi.org/10.3390/cancers16020269 - 8 Jan 2024
Cited by 1 | Viewed by 1249
Abstract
Background: tumor-associated macrophages (TAMs) constitute a significant proportion of non-cancerous cells within the intricate tumor microenvironment (TME) of hepatocellular carcinoma (HCC). Understanding the communication between macrophages and tumor cells, as well as investigating potential signaling pathways, holds promise for enhancing therapeutic responses in [...] Read more.
Background: tumor-associated macrophages (TAMs) constitute a significant proportion of non-cancerous cells within the intricate tumor microenvironment (TME) of hepatocellular carcinoma (HCC). Understanding the communication between macrophages and tumor cells, as well as investigating potential signaling pathways, holds promise for enhancing therapeutic responses in HCC. Methods: single-cell RNA-sequencing data and bulk RNA-sequencing data were derived from open source databases Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Through this analysis, we elucidated the interactions between MICA+ tumor cells and MMP9+ macrophages, primarily mediated via the PROS1-AXL axis in advanced HCC. Subsequently, we employed a range of experimental techniques including lentivirus infection, recombinant protein stimulation, and AXL inhibition experiments to validate these interactions and unravel the underlying mechanisms. Results: we presented a single-cell atlas of advanced HCC, highlighting the expression patterns of MICA and MMP9 in tumor cells and macrophages, respectively. Activation of the interferon gamma (IFN-γ) signaling pathway was observed in MICA+ tumor cells and MMP9+ macrophages. We identified the existence of an interaction between MICA+ tumor cells and MMP9+ macrophages mediated via the PROS1-AXL axis. Additionally, we found MMP9+ macrophages had a positive correlation with M2-like macrophages. Subsequently, experiments validated that DNA damage not only induced MICA expression in tumor cells via IRF1, but also upregulated PROS1 levels in HCC cells, stimulating macrophages to secrete MMP9. Consequently, MMP9 led to the proteolysis of MICA. Conclusion: MICA+ HCC cells secreted PROS1, which upregulated MMP9 expression in macrophages through AXL receptors. The increased MMP9 activity resulted in the proteolytic shedding of MICA, leading to the release of soluble MICA (sMICA) and the subsequent facilitation of tumor immune escape. Full article
(This article belongs to the Special Issue Macrophages in Cancer Progression, Diagnosis and Treatment)
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18 pages, 2638 KiB  
Article
Flow Cytometric Analysis of Macrophages and Cytokines Profile in the Bronchoalveolar Lavage Fluid in Patients with Lung Cancer
by Iwona Kwiecień, Elżbieta Rutkowska, Agata Raniszewska, Agnieszka Rzeszotarska, Małgorzata Polubiec-Kownacka, Joanna Domagała-Kulawik, Jolanta Korsak and Piotr Rzepecki
Cancers 2023, 15(21), 5175; https://doi.org/10.3390/cancers15215175 - 27 Oct 2023
Viewed by 1281
Abstract
Macrophages play an important role in the suppression and activation of immune anti-cancer response, but little is known about dominant macrophage phenotype in the lung cancer environment, evaluated by bronchoalveolar lavage fluid (BALF). The aim of this study was to characterize macrophages in [...] Read more.
Macrophages play an important role in the suppression and activation of immune anti-cancer response, but little is known about dominant macrophage phenotype in the lung cancer environment, evaluated by bronchoalveolar lavage fluid (BALF). The aim of this study was to characterize macrophages in BALF from a lung affected by cancer (cBALF) and a healthy lung (hBALF) of the same patient regarding their individual macrophage polarization and selected cytokines profile. A total of 36 patients with confirmed lung cancer were investigated. Macrophages markers: CD206 CD163 CD80 CD86 CD40 CD45, Arginase-1, and CD68 were evaluated by flow cytometry. Cytokines (IL-1 RA, IL-6, IL-10, TNF-α, IL-1β, IL-12, IL-23, and TGF-β) profile was analyzed. There was higher median proportion of macrophages in Cbalf than in Hbalf. The population of macrophages presented immunophenotype: Ccd68+bright CD206+bright CD163+bright CD80+ CD86+ CD40+bright CD45+ cArginase+. We observed some trends in the expression of the analyzed antigens in clBALF and hlBLAF. The highest concentrations of IL-1RA and IL-6 were in Cbalf and Hbalf supernatant. There were the correlations between pro- and anti-inflammatory cytokines. The findings showed that macrophages include a diverse and plastic group with the presence of different antigens and cytokines, and determining the target phenotype is a complex and variable process. Full article
(This article belongs to the Special Issue Macrophages in Cancer Progression, Diagnosis and Treatment)
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16 pages, 5741 KiB  
Article
Endotoxin Tolerance Creates Favourable Conditions for Cancer Development
by Konkonika Roy, Henryk Mikołaj Kozłowski, Tomasz Jędrzejewski, Justyna Sobocińska, Bartosz Maciejewski, Artur Dzialuk and Sylwia Wrotek
Cancers 2023, 15(20), 5113; https://doi.org/10.3390/cancers15205113 - 23 Oct 2023
Cited by 3 | Viewed by 1691
Abstract
Endotoxin tolerance (ET) is an adaptive phenomenon of the immune system that protects the host from clinical complications due to repeated exposure of the body to endotoxins such as lipopolysaccharide (LPS). Since ET is an immunosuppressive mechanism in which a significant reprogramming of [...] Read more.
Endotoxin tolerance (ET) is an adaptive phenomenon of the immune system that protects the host from clinical complications due to repeated exposure of the body to endotoxins such as lipopolysaccharide (LPS). Since ET is an immunosuppressive mechanism in which a significant reprogramming of macrophages is observed, we hypothesized that it could influence cancer development by modifying the tumour environment. This study aimed to explore whether ET influences cancer progression by altering the tumour microenvironment. Endotoxin-tolerant macrophages (MoET) were examined for their impact on breast and colon cancer cells via direct interaction and conditioned media exposure. We characterized cancer cell behaviour by viability, clonogenic potential, motility, scratch assays, and 3D spheroidal assays. MoET-derived factors increased cancer cell viability, motility, and clonogenicity, suggesting a conducive environment for cancer development. Remarkably, despite reduced TNFα and IL-6 levels, MoET exhibited M1 polarization. These findings uncover an ET-associated macrophage reprogramming that fosters a favourable context for cancer progression across diverse tumours. Targeting ET could emerge as a promising avenue for cancer therapy and prevention. Full article
(This article belongs to the Special Issue Macrophages in Cancer Progression, Diagnosis and Treatment)
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19 pages, 10709 KiB  
Article
Targeting Proliferating Tumor-Infiltrating Macrophages Facilitates Spatial Redistribution of CD8+ T Cells in Pancreatic Cancer
by Xiaobao Yang, Jinrong Lin, Guanzheng Wang and Dakang Xu
Cancers 2022, 14(6), 1474; https://doi.org/10.3390/cancers14061474 - 14 Mar 2022
Cited by 13 | Viewed by 4564
Abstract
Tumor-associated macrophages (TAMs) play crucial roles in cancer progression, but the contributions and regulation of different macrophage subpopulations remain unclear. Here, we report a high level of TAM infiltration in human and mouse pancreatic ductal adenocarcinoma (PDAC) models and that the targeting of [...] Read more.
Tumor-associated macrophages (TAMs) play crucial roles in cancer progression, but the contributions and regulation of different macrophage subpopulations remain unclear. Here, we report a high level of TAM infiltration in human and mouse pancreatic ductal adenocarcinoma (PDAC) models and that the targeting of proliferating F4/80+ macrophages facilitated cytotoxic CD8+ T-cell-dependent antitumor immune responses. A well-defined KPC-derived PDAC cell line and the murine Panc02 PDAC cell line were used. Treatment of PDAC-bearing mice with clodronate liposomes, an agent that chemically depletes macrophages, did not impact macrophage subpopulations in the local tumor microenvironment (TME). However, further investigation using both BrdU and Ki67 to evaluate proliferating cells showed that clodronate liposomes treatment reduced proliferating macrophages in the KPC and Panc02 models. We further evaluated the distance between CD8+ T cells and PanCK+ tumor cells, and clodronate liposomes treatment significantly increased the number of CD8+ T cells in close proximity (<30 µm) to PanCK+ PDAC cells, with increased numbers of tumor-infiltrating IFN-γ+CD8+ T cells. This study suggests that targeting proliferating tumor-infiltrating macrophages may increase CD8+ cytotoxic lymphocyte (CTL) infiltration and facilitate the spatial redistribution of CD8+ T cells in tumors, contributing to the antitumor effect. Full article
(This article belongs to the Special Issue Macrophages in Cancer Progression, Diagnosis and Treatment)
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