Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications
Abstract
Tumor metastasis is a major contributor to the death of cancer patients. It is driven not only by the intrinsic alterations in tumor cells, but also by the implicated cross-talk between cancer cells and their altered microenvironment components. Tumor-associated macrophages (TAMs) are the key cells that create an immunosuppressive tumor microenvironment (TME) by producing cytokines, chemokines, growth factors, and triggering the inhibitory immune checkpoint proteins release in T cells. In doing so, TAMs exhibit important functions in facilitating a metastatic cascade of cancer cells and, meanwhile, provide multiple targets of certain checkpoint blockade immunotherapies for opposing tumor progression. In this article, we summarize the regulating networks of TAM polarization and the mechanisms underlying TAM-facilitated metastasis. Based on the overview of current experimental evidence dissecting the critical roles of TAMs in tumor metastasis, we discuss and prospect the potential applications of TAM-focused therapeutic strategies in clinical cancer treatment at present and in the future.
https://jhoonline.biomedcentral.com/art ... 019-0760-3
Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications
Re: Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications
Introduction
Metastasis is a process of tumor cells escaping from the primary sites, spreading through lymphatic and/or blood circulations and ultimately disseminating to the distant sites. As one of the hallmarks of cancer, development of metastasis accounts for more than 90% cancer-related deaths [1]. Usually, the metastasis of tumor cells is a multistep sequence mainly including (a) invasion in the primary sites, (b) intravasation into the vasculature, (c) survival in the circulations, (d) extravasation out of the vasculature, and (e) adaption and growth in the metastatic sites [2, 3]. Failure in any of those steps will prevent the formation of metastasis. In addition to the alterations of the intrinsic properties in tumor cells, the “seed and soil” concept, firstly proposed by Stephen Paget in 1889, has been widely accepted as a critical theory to do with metastasis [4]. In this theory, tumor cells themselves are not sufficient for the development of metastasis. In fact, both the tumor cells and multiple components of the tumor microenvironment (TME) and their complicated cross talk are closely involved [5, 6]. Macrophages populating in the surrounding TME are usually termed as tumor-associated macrophages (TAMs) [7, 8]. A large volume of studies suggests that TAMs serve as prominent metastasis promoters in the TME, which orchestrate almost all of the 5 cascade steps of tumor metastasis as mentioned above [9, 10]. By producing growth factors, proteolytic enzymes, and various inhibitory immune checkpoint proteins in T cells, TAMs display implicated functions in regulating metastasis. Also, targeting TAMs as therapeutic strategies to prevent tumor progression and metastasis has attracted more and more researchers’ attention in recent years. So far, different types of molecular agents against TAMs are emerging as potential anti-cancer approaches. This review aims to provide an overview of the origin, classification, and polarization of TAMs as well as the mechanisms underlying the TAM-induced metastasis. Also, we will specifically discuss the agents targeting TAMs for cancer therapy. It is hoped that this review will help readers to understand the roles of TAMs in metastasis and their potential in clinic therapeutic applications against tumor progression.
Metastasis is a process of tumor cells escaping from the primary sites, spreading through lymphatic and/or blood circulations and ultimately disseminating to the distant sites. As one of the hallmarks of cancer, development of metastasis accounts for more than 90% cancer-related deaths [1]. Usually, the metastasis of tumor cells is a multistep sequence mainly including (a) invasion in the primary sites, (b) intravasation into the vasculature, (c) survival in the circulations, (d) extravasation out of the vasculature, and (e) adaption and growth in the metastatic sites [2, 3]. Failure in any of those steps will prevent the formation of metastasis. In addition to the alterations of the intrinsic properties in tumor cells, the “seed and soil” concept, firstly proposed by Stephen Paget in 1889, has been widely accepted as a critical theory to do with metastasis [4]. In this theory, tumor cells themselves are not sufficient for the development of metastasis. In fact, both the tumor cells and multiple components of the tumor microenvironment (TME) and their complicated cross talk are closely involved [5, 6]. Macrophages populating in the surrounding TME are usually termed as tumor-associated macrophages (TAMs) [7, 8]. A large volume of studies suggests that TAMs serve as prominent metastasis promoters in the TME, which orchestrate almost all of the 5 cascade steps of tumor metastasis as mentioned above [9, 10]. By producing growth factors, proteolytic enzymes, and various inhibitory immune checkpoint proteins in T cells, TAMs display implicated functions in regulating metastasis. Also, targeting TAMs as therapeutic strategies to prevent tumor progression and metastasis has attracted more and more researchers’ attention in recent years. So far, different types of molecular agents against TAMs are emerging as potential anti-cancer approaches. This review aims to provide an overview of the origin, classification, and polarization of TAMs as well as the mechanisms underlying the TAM-induced metastasis. Also, we will specifically discuss the agents targeting TAMs for cancer therapy. It is hoped that this review will help readers to understand the roles of TAMs in metastasis and their potential in clinic therapeutic applications against tumor progression.
Debbie
Re: Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications
“ Overview: biological information and polarization of TAMs
The definition, origin, and functions of TAMs
Macrophages are a type of versatile immunocytes, executing a broad spectrum of functions that range from modulating tissue homeostasis, defensing against pathogens, and facilitating wound healing [11]. Macrophages infiltrating tumor tissues or populated in the microenvironment of solid tumors are defined as tumor-associated macrophages (TAMs). As a critical component of tumor microenvironment, TAMs affect tumor growth, tumor angiogenesis, immune regulation, metastasis, and chemoresistance. Most of the TAMs gather in the leading edge and avascular areas, while some others align along the abluminal side of the vessels as well [12, 13]. It is generally believed that the blood monocytes derived from bone marrow hematopoietic stem cells are the primary resource of macrophages [14,15,16]. However, recent evidence suggests that a majority of resident macrophages stem from yolk sac progenitors, which proliferate or differentiate in situ and have progeny throughout their life, such as alveolar macrophages, brain macrophages, and Kupffer cells [11, 17,18,19]. They are recruited and activated by various signals in the TME and then exhibit dramatic impacts on the tumor progression and metastasis. The cellular origin of macrophages and TAMs was shown in Fig. 1.”
The definition, origin, and functions of TAMs
Macrophages are a type of versatile immunocytes, executing a broad spectrum of functions that range from modulating tissue homeostasis, defensing against pathogens, and facilitating wound healing [11]. Macrophages infiltrating tumor tissues or populated in the microenvironment of solid tumors are defined as tumor-associated macrophages (TAMs). As a critical component of tumor microenvironment, TAMs affect tumor growth, tumor angiogenesis, immune regulation, metastasis, and chemoresistance. Most of the TAMs gather in the leading edge and avascular areas, while some others align along the abluminal side of the vessels as well [12, 13]. It is generally believed that the blood monocytes derived from bone marrow hematopoietic stem cells are the primary resource of macrophages [14,15,16]. However, recent evidence suggests that a majority of resident macrophages stem from yolk sac progenitors, which proliferate or differentiate in situ and have progeny throughout their life, such as alveolar macrophages, brain macrophages, and Kupffer cells [11, 17,18,19]. They are recruited and activated by various signals in the TME and then exhibit dramatic impacts on the tumor progression and metastasis. The cellular origin of macrophages and TAMs was shown in Fig. 1.”
Definition of Immunocyte
Our body has cells that control immunity or eat up germs to protect the body against pathogens, foreign materials or viruses. These are called immune cells or immunocytes.
Debbie
Re: Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications
“ Like macrophages perform diverse functions in immune regulation, TAMs also play multi-functional roles in tumor progression, including cancer initiation and promotion, immune regulation, metastasis, and angiogenesis, as shown in Fig. 1. For example, the presence of TAM-derived inflammatory cytokines interleukin (IL)-23 and IL-17 have been shown to trigger tumor-elicited inflammation, which in turn drives tumor growth [20] (Fig. 1). Another study demonstrated that the increased TAM-derived IL-6 exerts an amplifying effect on the inflammation response, thus promoting the occurrence and development of hepatocellular carcinoma via STAT3 signaling [21]. Moreover, TAMs acquire an M2-like phenotype, providing essential support on tumor progression and metastasis, despite their weak antigen presenting ability [22].
The classification and polarization of TAMs
It is clear that macrophages are capable of displaying very different and even opposing phenotypes, depending on the microenvironment they embedded in. Activated macrophages are often classified into M1 (classical-activated macrophages) and M2 (alternative-activated macrophages) phenotype [23] (Fig. 2). In general, M1 macrophages foster inflammation response against invading pathogens and tumor cells, whereas M2 macrophages tend to exert an immune suppressive phenotype, favoring tissue repair and tumor progression. These two types of macrophages are distinct in their different markers, metabolic characteristics, and gene expression profiles. M1 macrophages secrete proinflammatory cytokines such as IL-12, tumor necrosis factor (TNF)-α, CXCL-10, and interferon (IFN)-γ and produce high levels of nitric oxide synthase (NOS, an enzyme metabolizing arginine to the “killer” molecule nitric oxide), while M2 macrophages secrete anti-inflammatory cytokines such as IL-10, IL-13, and IL-4 and express abundant arginase-1, mannose receptor (MR, CD206), and scavenger receptors [24, 25] (Fig. 2). The conversion between M1 (anti-tumorigenesis) and M2 (pro-tumorigenesis) is a biological process named “macrophage polarization” in response to microenvironmental signals [26]. Though studies found that TAMs are able to exhibit either polarization phenotype, researchers tend to consider TAMs as M2-like phenotype-acquired macrophages [22, 26,27,28]. It is consistent with these clinical observations that the accumulation of macrophages in the TME is largely associated with worse disease outcome [13, 29]. However, classification and identification of TAMs should be correlated mainly to their function such as metastasis, angiogenesis, and immune regulation. Expression of CD68, CD14, HLA-DR, and CD204 have been used for macrophage classification, and other proteins such as MMP2/9, B7-H4, STAT-3, CD163, and CD206 have been used for classification of TAMs [30]. We have listed these characterized biomarkers, CDs, and cytokines for TAM identification in Table 1. To better understand the correlation between TAMs, metastasis, and clinical applications in cancer therapy, we will further characterize the molecular mechanisms underlying TAMs polarization from M1-like to M2-like in detail below, also as shown in Fig. 2.”
The classification and polarization of TAMs
It is clear that macrophages are capable of displaying very different and even opposing phenotypes, depending on the microenvironment they embedded in. Activated macrophages are often classified into M1 (classical-activated macrophages) and M2 (alternative-activated macrophages) phenotype [23] (Fig. 2). In general, M1 macrophages foster inflammation response against invading pathogens and tumor cells, whereas M2 macrophages tend to exert an immune suppressive phenotype, favoring tissue repair and tumor progression. These two types of macrophages are distinct in their different markers, metabolic characteristics, and gene expression profiles. M1 macrophages secrete proinflammatory cytokines such as IL-12, tumor necrosis factor (TNF)-α, CXCL-10, and interferon (IFN)-γ and produce high levels of nitric oxide synthase (NOS, an enzyme metabolizing arginine to the “killer” molecule nitric oxide), while M2 macrophages secrete anti-inflammatory cytokines such as IL-10, IL-13, and IL-4 and express abundant arginase-1, mannose receptor (MR, CD206), and scavenger receptors [24, 25] (Fig. 2). The conversion between M1 (anti-tumorigenesis) and M2 (pro-tumorigenesis) is a biological process named “macrophage polarization” in response to microenvironmental signals [26]. Though studies found that TAMs are able to exhibit either polarization phenotype, researchers tend to consider TAMs as M2-like phenotype-acquired macrophages [22, 26,27,28]. It is consistent with these clinical observations that the accumulation of macrophages in the TME is largely associated with worse disease outcome [13, 29]. However, classification and identification of TAMs should be correlated mainly to their function such as metastasis, angiogenesis, and immune regulation. Expression of CD68, CD14, HLA-DR, and CD204 have been used for macrophage classification, and other proteins such as MMP2/9, B7-H4, STAT-3, CD163, and CD206 have been used for classification of TAMs [30]. We have listed these characterized biomarkers, CDs, and cytokines for TAM identification in Table 1. To better understand the correlation between TAMs, metastasis, and clinical applications in cancer therapy, we will further characterize the molecular mechanisms underlying TAMs polarization from M1-like to M2-like in detail below, also as shown in Fig. 2.”
M1/M2 describes the two major and opposing activities of macrophages. M1 activity inhibits cell proliferation and causes tissue damage while M2 activity promotes cell proliferation and tissue repair.
M1 and M2 Macrophages: Oracles of Health and Disease - PubMed
Debbie
Re: Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications
TAMs were suspected in cases of the hyper progression syndrome that happens in rare cases with ICI and sometimes with the wrong radiation timing when it is added to ICI as an attempt to improve the immune system recognition. There were cases when adding the SBRT to ICI in the middle of the treatment cycle (which is 21 day with Keytruda if I remember correctly) caused this very unintended effect. From reading the articles posted it is obvious that their dual nature, the ability either to protect the tumor or to hunt it, depending on innate factors, is a double edged sword.
Olga
Re: Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications
Hi Olga
I’ve been pondering on the SBRT and ICI failure verses success scenario , you’ve presented with your response above .
I’m remembering the toxcity Nhi experienced with the close sbrt and Keytruda dosing, and wondering what the answer is in creating a successful response that creates an antigen recognition via the concurrent use of the 2 .
Found this write up on SBRT and ICI usage.
A narrative review of combined stereotactic ablative radiotherapy and immunotherapy in metastatic non-small cell lung cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264312/
Ps I certainly agree that it is a doubled edged sword, in using the two modalities ( SBRT and ICI) to “unclothe” the hidden cancer so the immune system can do what it was meant to do , attack the cancer by virtue of antigen presentation , OR possibility create more deregulation ( immune suppression) and cause progression.
I’ve been pondering on the SBRT and ICI failure verses success scenario , you’ve presented with your response above .
I’m remembering the toxcity Nhi experienced with the close sbrt and Keytruda dosing, and wondering what the answer is in creating a successful response that creates an antigen recognition via the concurrent use of the 2 .
Found this write up on SBRT and ICI usage.
A narrative review of combined stereotactic ablative radiotherapy and immunotherapy in metastatic non-small cell lung cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264312/
Ps I certainly agree that it is a doubled edged sword, in using the two modalities ( SBRT and ICI) to “unclothe” the hidden cancer so the immune system can do what it was meant to do , attack the cancer by virtue of antigen presentation , OR possibility create more deregulation ( immune suppression) and cause progression.
Debbie