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Tumor, Tumor-Associated Macrophages, and Therapy

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Published Papers

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (20 May 2023) | Viewed by 25273

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Special Issue Editors

Dr. Parthasarathy Chandrakesan

E-Mail Website
Guest Editor

Division of Digestive Diseases and Nutrition, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Interests: immuno-oncology; tumor immunotherapy; tumor stem cells; tumor immunosuppression; targeted therapy; drug resistance; metastasis; cell of origin of cancer; metabolomics and cancer; microbial dysbiosis and cancer

Dr. Janani Panneerselvam

E-Mail Website
Co-Guest Editor

Division of Heamotology-Oncology, Department of Medicine, University of Oklahoma Health Sciences Center, BRC West, Oklahoma City, OK 73104, USA
Interests: cancer biology and Immunotherapy

Special Issue Information

Dear Colleagues,

Macrophages are innate immunocytes and have exceptionally diverse functions that include killing pathogens, tissue homeostasis, and wound healing. Macrophages are extremely plastic cells, and they are two polarization states: classically activated M1 phenotype (pro-inflammatory and antitumor) and alternatively activated M2 (anti-inflammatory and protumorigenic); however, dependent on signaling in the tumor microenvironment (TME), they interchange phenotypes. Tumor-associated macrophages (TAMs) are macrophages that are recruited or infiltrated into the TME, and they are highly immunosuppressive and play major roles in inhibiting active T-cell immune surveillance of tumors, tumor initiation, growth, development, and metastasis by secreting a wide variety of cytokines, growth factors, inflammatory substrates, and proteolytic enzymes. Recent studies have strongly suggested that TAMs can be a potential target in cancers to enhance the host antitumor mechanisms. This Special Issue will highlight the diverse roles of macrophages in cancer, covering high-impact basic and clinical studies on macrophage polarization, macrophage-based immunotherapy in tumors, with an emphasis on macrophage targets, tumor stem cells and macrophages, small molecules targeting macrophages, and immune signaling axes that offer novel ideas and strategies to develop and improve approaches targeting these cells in tumors

Dr. Parthasarathy Chandrakesan
Dr. Janani Panneerselvam
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 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

tumor-associated macrophages
macrophage polarization
tumor stem cells
tumor microenvironment
immunosuppression
host immunity
innate immunity
adaptive immunity
immune escape
immunotherapy
immunotherapy resistance
cytokines/chemokines
T-cell activity
immune checkpoint inhibitors
translational and clinical research
immuno-modulation and cancer
immune infiltration
tumor metastasis
antitumor immunity

Published Papers (7 papers)

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Research

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16 pages, 4646 KiB

Open AccessCommunication

Functionally and Metabolically Divergent Melanoma-Associated Macrophages Originate from Common Bone-Marrow Precursors

by Gabriela A. Pizzurro, Kate Bridges, Xiaodong Jiang, Aurobind Vidyarthi, Kathryn Miller-Jensen and Oscar R. Colegio

Cancers 2023, 15(13), 3330; https://doi.org/10.3390/cancers15133330 - 24 Jun 2023

Cited by 1 | Viewed by 1479

Abstract

Tumor-associated macrophages (TAMs) can be widely heterogeneous, based on their ontogeny and function, and driven by the tissue-specific niche. TAMs are highly abundant in the melanoma tumor microenvironment (TME), usually correlating with worse prognoses. However, the understanding of their diversity may be harnessed for therapeutic purposes. Here, we used the clinically relevant YUMM1.7 model to study melanoma TAM origin and dynamics during tumor progression. In i.d. YUMM1.7 tumors, we identified distinct TAM subsets based on F4/80 expression, with the F4/80^high fraction increasing over time and displaying a tissue-resident-like phenotype. While skin-resident macrophages showed mixed ontogeny, F4/80⁺ TAM subsets in the melanoma TME originated almost exclusively from bone-marrow precursors. A multiparametric analysis of the macrophage phenotype showed a temporal divergence of the F4/80⁺ TAM subpopulations, which also differed from the skin-resident subsets and their monocytic precursors. Overall, the F4/80⁺ TAMs displayed co-expressions of M1- and M2-like canonical markers, while RNA sequencing showed differential immunosuppressive and metabolic profiles. Gene-set enrichment analysis (GSEA) revealed F4/80^high TAMs to rely on oxidative phosphorylation, with increased proliferation and protein secretion, while F4/80^low cells had high pro-inflammatory and intracellular signaling pathways, with lipid and polyamine metabolism. Overall, we provide an in-depth characterization of and compelling evidence for the BM-dependency of melanoma TAMs. Interestingly, the transcriptomic analysis of these BM-derived TAMs matched macrophage subsets with mixed ontogeny, which have been observed in other tumor models. Our findings may serve as a guide for identifying potential ways of targeting specific immunosuppressive TAMs in melanoma. Full article

(This article belongs to the Special Issue Tumor, Tumor-Associated Macrophages, and Therapy)

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19 pages, 2912 KiB

Open AccessArticle

Inhibition of DCLK1 with DCLK1-IN-1 Suppresses Renal Cell Carcinoma Invasion and Stemness and Promotes Cytotoxic T-Cell-Mediated Anti-Tumor Immunity

by Ling Ding, Yuning Yang, Yang Ge, Qin Lu, Zixing Yan, Xuzheng Chen, Jian Du, Sassan Hafizi, Xiaohui Xu, Jiannan Yao, Jian Liu, Zhiyun Cao and Nathaniel Weygant

Cancers 2021, 13(22), 5729; https://doi.org/10.3390/cancers13225729 - 16 Nov 2021

Cited by 16 | Viewed by 3137

Abstract

The approval of immune checkpoint inhibitors has expanded treatment options for renal cell carcinoma (RCC), but new therapies that target RCC stemness and promote anti-tumor immunity are needed. Previous findings demonstrate that doublecortin-like kinase 1 (DCLK1) regulates stemness and is associated with RCC disease progression. Herein, we demonstrate that small-molecule kinase inhibitor DCLK1-IN-1 strongly inhibits DCLK1 phosphorylation and downregulates pluripotency factors and cancer stem cell (CSC) or epithelial-mesenchymal transition (EMT)-associated markers including c-MET, c-MYC, and N-Cadherin in RCC cell lines. Functionally, DCLK1-IN-1 treatment resulted in significantly reduced colony formation, migration, and invasion. Additionally, assays using floating or Matrigel spheroid protocols demonstrated potent inhibition of stemness. An analysis of clinical populations showed that DCLK1 predicts RCC survival and that its expression is correlated with reduced CD8+ cytotoxic T-cell infiltration and increases in M2 immunosuppressive macrophage populations. The treatment of RCC cells with DCLK1-IN-1 significantly reduced the expression of immune checkpoint ligand PD-L1, and co-culture assays using peripheral blood monocytes (PBMCs) or T-cell expanded PBMCs demonstrated a significant increase in immune-mediated cytotoxicity alone or in combination with anti-PD1 therapy. Together, these findings demonstrate broad susceptibility to DCLK1 kinase inhibition in RCC using DCLK1-IN-1 and provide the first direct evidence for DCLK1-IN-1 as an immuno-oncology agent. Full article

(This article belongs to the Special Issue Tumor, Tumor-Associated Macrophages, and Therapy)

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19 pages, 4416 KiB

Open AccessArticle

Inflammatory Mediators and Gut Microbial Toxins Drive Colon Tumorigenesis by IL-23 Dependent Mechanism

by Janani Panneerselvam, Venkateshwar Madka, Rajani Rai, Katherine T. Morris, Courtney W. Houchen, Parthasarathy Chandrakesan and Chinthalapally V. Rao

Cancers 2021, 13(20), 5159; https://doi.org/10.3390/cancers13205159 - 14 Oct 2021

Cited by 9 | Viewed by 2043

Abstract

Obesity-associated chronic inflammation predisposes colon cancer risk development. Interleukin-23 (IL-23) is a potential inflammatory mediator linking obesity to chronic colonic inflammation, altered gut microbiome, and colon carcinogenesis. We aimed to elucidate the role of pro-inflammatory eicosanoids and gut bacterial toxins in priming dendritic cells and macrophages for IL-23 secretion to promote colon tumor progression. To investigate the association of IL-23 with obesity and colon tumorigenesis, we utilized TCGA data set and colonic tumors from humans and preclinical models. To understand IL-23 production by inflammatory mediators and gut microbial toxins, we performed several in vitro mechanistic studies to mimic the tumor microenvironment. Colonic tumors were utilized to perform the ex vivo experiments. Our findings showed that IL-23 is elevated in obese individuals, colonic tumors and correlated with reduced disease-free survival. In vitro studies showed that IL-23 treatment increased the colon tumor cell self-renewal, migration, and invasion while disrupting epithelial barrier permeability. Co-culture experiments of educated dendritic cells/macrophages with colon cancer cells significantly increased the tumor aggression by increasing the secretory levels of IL-23, and these observations are further supported by ex vivo rat colonic tumor organotypic experiments. Our results demonstrate gut microbe toxins and eicosanoids facilitate IL-23 production, which plays an important role in obesity-associated colonic tumor progression. This newly identified nexus represents a potential target for the prevention and treatment of obesity-associated colon cancer. Full article

(This article belongs to the Special Issue Tumor, Tumor-Associated Macrophages, and Therapy)

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16 pages, 6919 KiB

Open AccessArticle

CALD1 Modulates Gliomas Progression via Facilitating Tumor Angiogenesis

by Quan Cheng, Anliu Tang, Zeyu Wang, Ning Fang, Zhuojing Zhang, Liyang Zhang, Chuntao Li and Yu Zeng

Cancers 2021, 13(11), 2705; https://doi.org/10.3390/cancers13112705 - 30 May 2021

Cited by 15 | Viewed by 3604

Abstract

Angiogenesis is more prominent in anaplastic gliomas and glioblastoma (GBM) than that in pilocytic and diffuse gliomas. Caldesmon (CALD1) plays roles in cell adhesion, cytoskeletal organization, and vascularization. However, limited information is available on mechanisms underlying the effect of CALD1 on the microvascular facilitation and architecture in glioma. In this study, we explored the role of CALD1 in gliomas by integrating bulk RNA-seq analysis and single cell RNA-seq analysis. A positive correlation between CALD1 expression and the gliomas’ pathological grade was noticed, according to the samples from the TCGA and CGGA database. Moreover, higher CALD1 expression samples showed worse clinical outcomes than lower CALD1 expression samples. Biofunction prediction suggested that CALD1 may affect glioma progression through modulating tumor angiogenesis. The map of the tumor microenvironment also depicted that more stromal cells, such as endothelial cells and pericytes, infiltrated in high CALD1 expression samples. CALD1 was found to be remarkably upregulated in neoplastic cells and was involved in tumorigenic processes of gliomas in single cell sequencing analysis. Histology and immunofluorescence analysis also indicated that CALD1 associates with vessel architecture, resulting in glioma grade progression. In conclusion, the present study implies that CALD1 may serve as putative marker monitoring the progress of glioma. Full article

(This article belongs to the Special Issue Tumor, Tumor-Associated Macrophages, and Therapy)

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Review

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13 pages, 1427 KiB

Open AccessReview

Dynamic CD8⁺ T Cell Cooperation with Macrophages and Monocytes for Successful Cancer Immunotherapy

by Anaïs Vermare, Marion V. Guérin, Elisa Peranzoni and Nadège Bercovici

Cancers 2022, 14(14), 3546; https://doi.org/10.3390/cancers14143546 - 21 Jul 2022

Cited by 7 | Viewed by 7035

Abstract

The essential roles endorsed by macrophages and monocytes are well established in response to infections, where they contribute to launching the differentiation of specific T-lymphocytes for long-term protection. This knowledge is the result of dynamic studies that can inspire the cancer field, particularly now that cancer immunotherapies elicit some tumor regression. Indeed, immune responses to cancer have mainly been studied after tumors have escaped immune attacks. In particular, the suppressive functions of macrophages were revealed in this context, introducing an obvious bias across the literature. In this review, we will focus on the ways inwhich monocytes and macrophages cooperate with T-lymphocytes, leading to successful immune responses. We will bring together the preclinical studies that have revealed the existence of such positive cooperation in the cancer field, and we will place particular emphasis on proposing the underlying mechanisms. Finally, we will give some perspectives to decipher the functional roles of such T-cell and myeloid cell interactions in the frame of human cancer immunotherapy. Full article

(This article belongs to the Special Issue Tumor, Tumor-Associated Macrophages, and Therapy)

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19 pages, 793 KiB

Open AccessReview

Cellular Carcinogenesis: Role of Polarized Macrophages in Cancer Initiation

by Ram Babu Undi, Adrian Filiberti, Naushad Ali and Mark M. Huycke

Cancers 2022, 14(11), 2811; https://doi.org/10.3390/cancers14112811 - 6 Jun 2022

Cited by 4 | Viewed by 2775

Abstract

Inflammation is an essential hallmark of cancer. Macrophages are key innate immune effector cells in chronic inflammation, parainflammation, and inflammaging. Parainflammation is a form of subclinical inflammation associated with a persistent DNA damage response. Inflammaging represents low-grade inflammation due to the dysregulation of innate and adaptive immune responses that occur with aging. Whether induced by infection, injury, or aging, immune dysregulation and chronic macrophage polarization contributes to cancer initiation through the production of proinflammatory chemokines/cytokines and genotoxins and by modulating immune surveillance. This review presents pre-clinical and clinical evidence for polarized macrophages as endogenous cellular carcinogens in the context of chronic inflammation, parainflammation, and inflammaging. Emerging strategies for cancer prevention, including small molecule inhibitors and probiotic approaches, that target macrophage function and phenotype are also discussed. Full article

(This article belongs to the Special Issue Tumor, Tumor-Associated Macrophages, and Therapy)

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21 pages, 3171 KiB

Open AccessReview

Macrophages as a Therapeutic Target in Metastatic Prostate Cancer: A Way to Overcome Immunotherapy Resistance?

by Clara Martori, Lidia Sanchez-Moral, Tony Paul, Juan Carlos Pardo, Albert Font, Vicenç Ruiz de Porras and Maria-Rosa Sarrias

Cancers 2022, 14(2), 440; https://doi.org/10.3390/cancers14020440 - 16 Jan 2022

Cited by 18 | Viewed by 4140

Abstract

Prostate cancer (PC) is the most common malignancy and the fifth cause of cancer death in men. The treatment for localized or locally advanced stages offers a high probability of cure. Even though the therapeutic landscape has significantly improved over the last decade, metastatic PC (mPC) still has a poor prognosis mainly due to the development of therapy resistance. In this context, the use of immunotherapy alone or in combination with other drugs has been explored in recent years. However, T-cell directed immune checkpoint inhibitors (ICIs) have shown limited activity with inconclusive results in mPC patients, most likely due to the highly immunosuppressive PC tumor microenvironment (TME). In this scenario, targeting macrophages, a highly abundant immunosuppressive cell type in the TME, could offer a new therapeutic strategy to improve immunotherapy efficacy. In this review, we summarize the growing field of macrophage-directed immunotherapies and discuss how these could be applied in the treatment of mPC, focusing on their combination with ICIs. Full article

(This article belongs to the Special Issue Tumor, Tumor-Associated Macrophages, and Therapy)

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