Tumor-associated macrophages as major players in the tumor microenvironment.
13 Aug 2014-Cancers (Multidisciplinary Digital Publishing Institute (MDPI))-Vol. 6, Iss: 3, pp 1670-1690
TL;DR: An overview of mechanisms responsible for TAM recruitment is presented and the roles of TAMs in the regulation of tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance are highlighted.
Abstract: During tumor progression, circulating monocytes and macrophages are actively recruited into tumors where they alter the tumor microenvironment to accelerate tumor progression. Macrophages shift their functional phenotypes in response to various microenvironmental signals generated from tumor and stromal cells. Based on their function, macrophages are divided broadly into two categories: classical M1 and alternative M2 macrophages. The M1 macrophage is involved in the inflammatory response, pathogen clearance, and antitumor immunity. In contrast, the M2 macrophage influences an anti-inflammatory response, wound healing, and pro-tumorigenic properties. Tumor-associated macrophages (TAMs) closely resemble the M2-polarized macrophages and are critical modulators of the tumor microenvironment. Clinicopathological studies have suggested that TAM accumulation in tumors correlates with a poor clinical outcome. Consistent with that evidence, experimental and animal studies have supported the notion that TAMs can provide a favorable microenvironment to promote tumor development and progression. In this review article, we present an overview of mechanisms responsible for TAM recruitment and highlight the roles of TAMs in the regulation of tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance. Finally, we discuss TAM-targeting therapy as a promising novel strategy for an indirect cancer therapy.
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TL;DR: As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.
3,131 citations
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...TAMs include both M1 macrophages, which are involved in promoting anti-tumor immunity, and the M2 macrophages, which possess pro-tumorigenic properties (Chanmee et al., 2014)....
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TL;DR: This work focuses on the CSC niche and discusses its contribution to tumor initiation and progression and examines the prospects of targeting the niche components as preferable therapeutic targets.
1,127 citations
Cites background from "Tumor-associated macrophages as maj..."
...TAMs secrete Transforming growth factor beta (TGF-b), which recruits T regulatory cells (Tregs) that also participate in immunosuppression (Chanmee et al., 2014)....
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TL;DR: Overall, the evidence accumulated to date suggests that induction of PD-L1 by inflammatory factors in the tumor microenvironment may be one of the most important factors affecting the therapeutic efficiency of PD -L1/PD-1 blocking.
Abstract: Tumor immune escape is an important strategy of tumor survival. There are many mechanisms of tumor immune escape, including immunosuppression, which has become a research hotspot in recent years. The programmed death ligand-1/programmed death-1 (PD-L1/PD-1) signaling pathway is an important component of tumor immunosuppression, which can inhibit the activation of T lymphocytes and enhance the immune tolerance of tumor cells, thereby achieving tumor immune escape. Therefore, targeting the PD-L1/PD-1 pathway is an attractive strategy for cancer treatment; however, the therapeutic effectiveness of PD-L1/PD-1 remains poor. This situation requires gaining a deeper understanding of the complex and varied molecular mechanisms and factors driving the expression and activation of the PD-L1/PD-1 signaling pathway. In this review, we summarize the regulation mechanisms of the PD-L1/PD-1 signaling pathway in the tumor microenvironment and their roles in mediating tumor escape. Overall, the evidence accumulated to date suggests that induction of PD-L1 by inflammatory factors in the tumor microenvironment may be one of the most important factors affecting the therapeutic efficiency of PD-L1/PD-1 blocking.
676 citations
Cites background from "Tumor-associated macrophages as maj..."
...The first occurs by inducing immunosuppressive cells to accumulate around the tumor and secrete immunosuppressive factors, which inactivate cytolytic T lymphocytes (CTL) to decrease the immune tolerance of tumor cells, such as regulatory T cells (Treg cells) [2, 3], myeloid-derived suppressor cells (MDSCs) [4], dendritic cells (DCs) [5], and M2 macrophages [6, 7]....
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TL;DR: The biochemical events and parameters involved in the metastatic process and tumor microenvironment have been targeted or can be potential targets for metastasis prevention and inhibition and this review provides an overview of them.
640 citations
TL;DR: The findings indicate that the immunotherapeutic fibrin gel ‘awakens’ the host innate and adaptive immune systems to inhibit both local tumour recurrence post surgery and potential metastatic spread.
Abstract: Cancer recurrence after surgical resection remains a significant cause of treatment failure. Here, we have developed an in situ formed immunotherapeutic bioresponsive gel that controls both local tumour recurrence after surgery and development of distant tumours. Briefly, calcium carbonate nanoparticles pre-loaded with the anti-CD47 antibody are encapsulated in the fibrin gel and scavenge H+ in the surgical wound, allowing polarization of tumour-associated macrophages to the M1-like phenotype. The released anti-CD47 antibody blocks the ‘don’t eat me’ signal in cancer cells, thereby increasing phagocytosis of cancer cells by macrophages. Macrophages can promote effective antigen presentation and initiate T cell mediated immune responses that control tumour growth. Our findings indicate that the immunotherapeutic fibrin gel ‘awakens’ the host innate and adaptive immune systems to inhibit both local tumour recurrence post surgery and potential metastatic spread. A gel with therapeutic nanoformulation that can be sprayed at the tumour resection site after surgery activates immune response in the tissue microenviroment, inhibiting tumour recurrence and potential metastasis.
625 citations
References
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TL;DR: The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
Abstract: The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
9,282 citations
"Tumor-associated macrophages as maj..." refers background in this paper
...They are characterized by the production of pro-inflammatory factors such as IL-6, IL-12, IL-23, and tumor necrosis factor-α (TNF-α)....
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...Although several studies have reported that TAMs exhibit an anti-inflammatory phenotype, in recent years, activated TAMs have been shown to produce multiple pro-inflammatory cytokines, such as IL-6 [12], that are involved in the induction of genes important to tumor cell cycle progression and apoptosis suppression [13]....
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TL;DR: Recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues.
Abstract: Heterogeneity of the macrophage lineage has long been recognized and, in part, is a result of the specialization of tissue macrophages in particular microenvironments. Circulating monocytes give rise to mature macrophages and are also heterogeneous themselves, although the physiological relevance of this is not completely understood. However, as we discuss here, recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues. These advances in our understanding have implications for the development of therapeutic strategies that are targeted to modify particular subpopulations of monocytes.
4,861 citations
"Tumor-associated macrophages as maj..." refers background in this paper
...Circulating monocytes, derived from the bone marrow in the adult, give rise to tissue-resident and inflammatory macrophages throughout the body [3,16]....
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TL;DR: It is shown, in detailed studies of CD4+CD25+FOXP3+ Treg cells in 104 individuals affected with ovarian carcinoma, that human tumor T Reg cells suppress tumor-specific T cell immunity and contribute to growth of human tumors in vivo.
Abstract: Regulatory T (T(reg)) cells mediate homeostatic peripheral tolerance by suppressing autoreactive T cells. Failure of host antitumor immunity may be caused by exaggerated suppression of tumor-associated antigen-reactive lymphocytes mediated by T(reg) cells; however, definitive evidence that T(reg) cells have an immunopathological role in human cancer is lacking. Here we show, in detailed studies of CD4(+)CD25(+)FOXP3(+) T(reg) cells in 104 individuals affected with ovarian carcinoma, that human tumor T(reg) cells suppress tumor-specific T cell immunity and contribute to growth of human tumors in vivo. We also show that tumor T(reg) cells are associated with a high death hazard and reduced survival. Human T(reg) cells preferentially move to and accumulate in tumors and ascites, but rarely enter draining lymph nodes in later cancer stages. Tumor cells and microenvironmental macrophages produce the chemokine CCL22, which mediates trafficking of T(reg) cells to the tumor. This specific recruitment of T(reg) cells represents a mechanism by which tumors may foster immune privilege. Thus, blocking T(reg) cell migration or function may help to defeat human cancer.
4,795 citations
"Tumor-associated macrophages as maj..." refers background in this paper
...In human ovarian carcinoma, TAMs produce the chemokine CCL22, which is one of the CCR4 ligands, as a mediator for the trafficking of Tregs to the tumor [93,96] (Figure 4)....
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TL;DR: These functionally polarized cells, and similarly oriented or immature dendritic cells present in tumors, have a key role in subversion of adaptive immunity and in inflammatory circuits that promote tumor growth and progression.
4,728 citations
"Tumor-associated macrophages as maj..." refers background in this paper
...In general, macrophages have been classified into two subsets: the classical M1 and the alternative M2 macrophages [4]....
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TL;DR: The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for Macrophage-centered diagnostic and therapeutic strategies.
Abstract: Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or M2 (alternative) activation, which represent extremes of a continuum in a universe of activation states. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions (e.g., ontogenesis and pregnancy) and in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer). However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies.
4,721 citations
"Tumor-associated macrophages as maj..." refers background in this paper
...During late-stage tumor progression, TAMs generally switch to an M2-like phenotype characterized by an IL-12 IL-10 phenotype and low tumoricidal activity [5]....
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...Reports of recent research have demonstrated that TAMs exhibit functions similar to those of M2 macrophages and can be characterized as the M2d subtype [5,6] (Figure 1)....
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