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      Next frontier in tumor immunotherapy: macrophage-mediated immune evasion

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          Abstract

          Tumor-associated macrophages (TAMs), at the core of immunosuppressive cells and cytokines networks, play a crucial role in tumor immune evasion. Increasing evidences suggest that potential mechanisms of macrophage-mediated tumor immune escape imply interpretation and breakthrough to bottleneck of current tumor immunotherapy. Therefore, it is pivotal to understand the interactions between macrophages and other immune cells and factors for enhancing existing anti-cancer treatments. In this review, we focus on the specific signaling pathways through which TAMs involve in tumor antigen recognition disorders, recruitment and function of immunosuppressive cells, secretion of immunosuppressive cytokines, crosstalk with immune checkpoints and formation of immune privileged sites. Furthermore, we summarize correlative pre-clinical and clinical studies to provide new ideas for immunotherapy. From our perspective, macrophage-targeted therapy is expected to be the next frontier of cancer immunotherapy.

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          Most cited references162

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          Macrophage plasticity, polarization, and function in health and disease.

          Macrophages are heterogeneous and their phenotype and functions are regulated by the surrounding micro-environment. Macrophages commonly exist in two distinct subsets: 1) Classically activated or M1 macrophages, which are pro-inflammatory and polarized by lipopolysaccharide (LPS) either alone or in association with Th1 cytokines such as IFN-γ, GM-CSF, and produce pro-inflammatory cytokines such as interleukin-1β (IL-1β), IL-6, IL-12, IL-23, and TNF-α; and 2) Alternatively activated or M2 macrophages, which are anti-inflammatory and immunoregulatory and polarized by Th2 cytokines such as IL-4 and IL-13 and produce anti-inflammatory cytokines such as IL-10 and TGF-β. M1 and M2 macrophages have different functions and transcriptional profiles. They have unique abilities by destroying pathogens or repair the inflammation-associated injury. It is known that M1/M2 macrophage balance polarization governs the fate of an organ in inflammation or injury. When the infection or inflammation is severe enough to affect an organ, macrophages first exhibit the M1 phenotype to release TNF-α, IL-1β, IL-12, and IL-23 against the stimulus. But, if M1 phase continues, it can cause tissue damage. Therefore, M2 macrophages secrete high amounts of IL-10 and TGF-β to suppress the inflammation, contribute to tissue repair, remodeling, vasculogenesis, and retain homeostasis. In this review, we first discuss the basic biology of macrophages including origin, differentiation and activation, tissue distribution, plasticity and polarization, migration, antigen presentation capacity, cytokine and chemokine production, metabolism, and involvement of microRNAs in macrophage polarization and function. Secondly, we discuss the protective and pathogenic role of the macrophage subsets in normal and pathological pregnancy, anti-microbial defense, anti-tumor immunity, metabolic disease and obesity, asthma and allergy, atherosclerosis, fibrosis, wound healing, and autoimmunity.
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            Macrophage biology in development, homeostasis and disease.

            Macrophages, the most plastic cells of the haematopoietic system, are found in all tissues and show great functional diversity. They have roles in development, homeostasis, tissue repair and immunity. Although tissue macrophages are anatomically distinct from one another, and have different transcriptional profiles and functional capabilities, they are all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted by chronic insults, resulting in a causal association of macrophages with disease states. In this Review, we discuss how macrophages regulate normal physiology and development, and provide several examples of their pathophysiological roles in disease. We define the 'hallmarks' of macrophages according to the states that they adopt during the performance of their various roles, taking into account new insights into the diversity of their lineages, identities and regulation. It is essential to understand this diversity because macrophages have emerged as important therapeutic targets in many human diseases.
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              Tumor-associated macrophages: from mechanisms to therapy.

              The tumor microenvironment is a complex ecology of cells that evolves with and provides support to tumor cells during the transition to malignancy. Among the innate and adaptive immune cells recruited to the tumor site, macrophages are particularly abundant and are present at all stages of tumor progression. Clinical studies and experimental mouse models indicate that these macrophages generally play a protumoral role. In the primary tumor, macrophages can stimulate angiogenesis and enhance tumor cell invasion, motility, and intravasation. During monocytes and/or metastasis, macrophages prime the premetastatic site and promote tumor cell extravasation, survival, and persistent growth. Macrophages are also immunosuppressive, preventing tumor cell attack by natural killer and T cells during tumor progression and after recovery from chemo- or immunotherapy. Therapeutic success in targeting these protumoral roles in preclinical models and in early clinical trials suggests that macrophages are attractive targets as part of combination therapy in cancer treatment. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                xxl413@smu.edu.cn
                liyuhua1974@outlook.com
                Journal
                Biomark Res
                Biomark Res
                Biomarker Research
                BioMed Central (London )
                2050-7771
                9 October 2021
                9 October 2021
                2021
                : 9
                : 72
                Affiliations
                [1 ]GRID grid.284723.8, ISNI 0000 0000 8877 7471, Department of Hematology, Zhujiang Hospital, , Southern Medical University, ; No. 253 GongyeDadaoZhong, Guangzhou, Guangdong 510280 P. R. China
                [2 ]GRID grid.284723.8, ISNI 0000 0000 8877 7471, The Second School of Clinical Medicine, , Southern Medical University, ; No. 1838 GuangzhongDadaoBei, Guangzhou, Guangdong 510515 P. R. China
                [3 ]GRID grid.284723.8, ISNI 0000 0000 8877 7471, Shunde Hospital, , Southern Medical University (The First People’s Hospital of Shunde Foshan), ; Foshan, 528308 China
                [4 ]GRID grid.508040.9, Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), ; Guangzhou, 510005 P. R. China
                Author information
                http://orcid.org/0000-0002-0982-6680
                Article
                327
                10.1186/s40364-021-00327-3
                8501632
                34625124
                1e8cd49f-1899-4ced-896c-88187e4efae3
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 17 June 2021
                : 15 September 2021
                Funding
                Funded by: Guangzhou Regenerative Medicine and Health Guangdong Laboratory
                Award ID: 2018GZR110105014
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003453, Natural Science Foundation of Guangdong Province;
                Award ID: 2018B030311042
                Award Recipient :
                Funded by: the National Key Research and Development Program of China
                Award ID: 2017YFA0105503
                Funded by: Guangdong Basic and Applied Basic Research Foundation
                Award ID: 2019A1515111113
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002858, China Postdoctoral Science Foundation;
                Award ID: 2020M682626
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2021

                tumor-associated macrophages,immune evasion,tumor microenvironment

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