Macrophages are derived from what type of blood cells

Your cells around the splinter were calling for help, and when the blood vessels let macrophages in the infected tissue, they also let some blood fluid seep into the area.

This extra fluid and the chemicals released by infected cells can cause inflammation. This hurts, but actually helps your body fight infections better! Macrophages and neutrophils work to keep the body clean of debris and invaders, but they also call for backup when an infection is too big for the two of them to handle alone.

Other immune system cells, like the T-Cells and B-Cells in our story, are alerted that their help is needed by chemicals the macrophages release.

Macrophages are also linked to the presence of other types of cells like basophils and eosinophils, which are most often involved in allergic reactions. These cells also help control the inflammation of tissues. Think of macrophages as cell-eating machines. Macrophages are the biggest type of white blood cells - about 21 micrometers - or 0. Still too small to see with your eyes, but big enough to do the important job of cleaning up unwanted viruses, bacteria, and parts of dead cells.

Instead, the eating machines engulf viruses and bacteria. This is called phagocytosis. First, the macrophage surrounds the unwanted particle and sucks it in. Then, the macrophage breaks it down by mixing it with enzymes stored in special sacs called lysosomes. The leftover material is then pushed out of the cell as waste. Here, we discuss these protocols and argue for a better understanding of the type of macrophages made in vitro; we also encourage recognition of the importance of tissue identity of macrophages, which cannot be recapitulated by cytokine-dependent protocols.

We suggest that a two-step model - in which iPSC-derived macrophages are first generated based on their ontogeny and then conditioned by their tissue-specific environment - offers immense potential for generating biologically relevant macrophages for future studies.

Abstract Macrophages are immune cells with important roles in tissue homeostasis, inflammation and pathologies. In this review, we will focus on new insights in the pro-tumor functions of TAMs and describe how understanding these functions can benefit anti-tumor therapy.

It is becoming increasingly clear that chronic unresolved inflammation is the underlying cause of many types of cancer [ 63 , 64 , 66 ]. In sites of chronic unresolved inflammation, macrophages initially triggered by a pathogen or tissue stress, recruit monocytes that develop into additional inflammatory macrophages, producing cytokines and chemokines propagating and amplifying the inflammatory cascade [ 66 ].

Activated macrophages, located in the sub-epithelial spaces, can contribute to genetic mutations in the adjacent epithelial cells through the production of DNA-damaging reactive nitrogen and oxygen species [ 69 — 71 ].

During the next stage of tumor development, recruited monocytes differentiate into macrophage subpopulations, unlike those found in the acute inflammatory environment, which support tissue remodeling and thereby promote tumor growth. TAMs are well-documented producers of trophic and activating factors that directly promote the proliferation and survival of tumor and stromal cells [ 66 ]. In addition, TAMs secrete proteolytic enzymes that degrade the ECM and facilitate the diffusion of growth factors in the tumor microenvironment [ 40 , 66 ].

One of the most important roles for macrophages in tumor growth seems to be in promoting angiogenesis. As the tumor becomes larger, the metabolic demands increase and a more developed vascular infrastructure is required. Of note, it might be a very standard physiological reaction of macrophages to respond to tissue hypoxia and initiate, or support, angiogenesis and not at all specific to the tumor environment. TEMs are a small subset of tumor-associated myeloid cells characterized by the expression of the Ang-2 receptor Tie2 [ 41 , 77 , 78 ].

They derive from circulating Tie2-expressing monocytes, which are recruited into the hypoxic areas of solid tumors by hypoxia-induced, endothelial-derived chemotactic factors, such as Ang-2 and CXCL12 the CXCR4 ligand [ 76 — 78 ]. TAMs play a role in multiple stages of tumor metastasis, from promoting tumor cell escape from the primary site to facilitating tumor cell arrival and establishment at distant sites.

Wyckoff and colleagues elegantly demonstrated that interactions between macrophages and tumor cells facilitate their simultaneous migration through the primary tumor [ 81 ]. They concluded that tumor-derived factors, like M-CSF, stimulate macrophage migration and production of EGF, which then activates tumor cell migration. Macrophages also produce proteases that facilitate the escape of tumor cells from the ECM at the tumor border through a process called invasion [ 63 ].

At specific stages of tumor development, especially at the transition to metastatic disease, macrophages can be found at locations of basement-membrane breakdown suggesting that tumors could exploit the normal matrix remodeling capacities of macrophages [ 80 ]. TAMs also enhance the ability of tumor cells to enter the blood vessels, a process called intravasation. Intravital multi-photon microscopy showed that tumor cell intravasation occurs through clusters of macrophages located on the abluminal side of the vessels [ 83 ].

Recently, Zervantonakis and colleagues described a three-dimensional micro-fluidic model to test tumor cell intravasation and endothelial barrier permeability [ 84 ]. The tumor microenvironment and TAMs both play crucial roles in the initiation of metastasis at the primary tumor site. These populations were required for extravasation as well as establishment and proliferation of the metastasis.

An ex vivo whole-lung imaging system showed that CCL2 produced by both metastatic tumor cells and target-site stromal cells was critical for this recruitment. Even after successful extravasation into potential metastatic sites, the vast majority of tumor cells are killed in the unfriendly stromal microenvironment.

Chen and colleagues used a mouse metastatic breast cancer model to investigate tumor cell infiltration and survival in the leukocyte-rich microenvironment of the lungs [ 86 ]. They found that vascular cell adhesion molecule-1 VCAM-1 or CD is aberrantly expressed on lung metastatic breast cancer cells. These interactions result in VCAM-1 clustering and activation of downstream signals that lead to protection from pro-apoptotic cytokines, such as TRAIL, in the stromal microenvironment, thus supporting cancer cell survival and establishment of local metastasis [ 86 ].

Having discussed that monocytes and TAMs have multiple pro-tumor functions as well as an anti-tumor repertoire, we want to highlight some findings on how to exploit this for anti-tumor therapy Fig. A more comprehensive view on MDSC-specific studies has recently been published [ 27 ]. Targeting monocytes and macrophages in cancer.

Monocytes Mo and tumor-associated macrophages TAMs are promising targets for a variety of diseases. This figure illustrates some recently developed strategies to target these cell types for immunotherapy of cancer.

Several approaches intend to reduce the local pool of TAMs, thus preventing pro-tumoral functions in situ. In contrast, other therapeutic strategies aim at functional modification of TAMs, thus activating anti-tumoral functions, rather than eliminating TAMs. Such approaches include the cytokine- and antibody-based therapeutic reprogramming of TAMs as well as licensing phagocytosis of targeted tumor cells by TAMs.

Their ability to target proliferating cells has made these compounds attractive general chemotherapeutic agents.

Only recently has their ability to specifically deplete monocytes and macrophages been investigated. Trabectedin or Yondelis , a tetrahydroisoquinoline alkaloid produced by the marine tunicate Ecteinascidia turbinate, was discovered in a large anti-cancer screen of plant and marine material by the National Cancer Institute performed in the s and s.

It is a DNA minor groove binder that blocks cell cycle and interferes with inducible gene transcription in a selective manner. Trabectedin was recently registered in Europe for the treatment of soft tissue sarcoma and ovarian cancer and is currently in a number of clinical trials for other types of cancer [ 87 ].

In addition to its anti-neoplastic activity, Trabectedin was shown to selectively deplete circulating monocytes in a small group of tumor patients, while other cells including neutrophils and lymphocytes were significantly less sensitive to the drug [ 88 ]. Furthermore, sub-cytotoxic doses of Trabectedin inhibited both in vitro and ex vivo differentiation of monocytes to macrophages.

Bisphosphonates are another class of anti-neoplastic compounds being tested for their ability to deplete macrophages in vivo. They are the primary treatment of bone metastases, secondary to several tumor types and have direct effects on different cancer cell lines [ 89 ]. To selectively target macrophages, the drugs are encapsulated into liposomes, which are then specifically endocytosed and degraded by macrophages.

For example, clodronate-encapsulated liposomes have been used for in vivo depletion of macrophages and have shown subsequent reduction of tumor growth in a variety of tumor models [ 63 , 90 ]. Antigen-specific tumor-targeting strategies have been widely investigated and developed for clinical use. They have been used to target, and generally kill, certain tumor cells as well as blocking the factors that promote recruitment or drive tumor progression [ 91 ].

Unfortunately, the tremendous heterogeneity of macrophage populations and redundancy of cell-surface markers has made it difficult to use adaptive immune-based techniques, such as cytotoxic T cells CTLs or monoclonal antibodies, to specifically target TAMs.

However, recent comprehensive gene and protein expression analyses have identified potential TAM-specific profiles that could be used for antigen-specific therapies [ 56 , 92 ]. Legumain is a member of the asparaginyl endopeptidase family and is a stress protein highly over-expressed by TAMs in the tumor microenvironment. In addition, Movahedi and colleagues generated single-domain antibodies sdAb that are specific for the macrophage mannose receptor MMR or CD , which they found to be highly expressed on certain TAM subpopulations [ 56 ].

The MMR-specific sdAb were able to bind TAMs isolated from multiple tumor types ex vivo as well as in vivo following intravenous injection of sdAb [ 93 ].

These pre-clinical results suggest that antigen-specific targeting of TAMs is possible, although it remains to be seen if this will translate to effective therapy. High densities of M2-like TAMs in tumors are often associated with poor clinical outcomes and TAM depletion strategies are successful at improving clinical outcomes.

Therefore, blocking migration of monocytes into the tumor tissue could be an effective, and potentially less harmful, therapeutic strategy. Using a CCL2-specific monoclonal antibody, Qian and colleagues inhibited the tumor recruitment of monocytes, decreased metastases and increased survival in a mammary tumor transgenic mouse system [ 39 ]. In addition, Leuschner and colleagues targeted monocyte recruitment to tumors using siRNA-mediated silencing of the chemokine receptor CCR2 in EL4 lymphoma and CT26 colon carcinoma models in mice, which resulted in decreased TAM accumulation and tumor growth [ 94 ].

M-CSF is critical for recruitment and differentiation of monocytes, and thus an important target for therapy. Many complementary strategies have been used to demonstrate that blocking this pathway significantly reduces monocyte infiltration, tumor growth and metastasis in a variety of tumor models. For example, interrupting this pathway with a CXCR4 antagonist is sufficient to significantly reduce recruitment of monocytes and inhibit tumor growth in multiple tumor models [ 27 , 98 , 99 ].

Chemokines promote monocyte recruitment into tissue, in part, by promoting changes in integrin affinity and avidity that increases attachment to endothelial cells bordering tumor tissue. Manipulation of macrophage polarization is an especially broad topic that has been more comprehensively reviewed [ 27 , 28 ]. In this review, we will highlight some of the more recently described and further developed therapeutic ideas and give examples of two distinct techniques, monoclonal antibodies to surface-expressed proteins and recombinant cytokines, used to reprogram macrophages.

Beatty and colleagues used a human clinical trial and a mouse model to test if CD40 activation could reverse immune suppression and promote the anti-tumor T cell responses in pancreatic ductal adenocarcinoma PDA [ ]. They tested a humanized CD40 agonist antibody in combination with gemcitabine chemotherapy in a small group of patients with advanced PDA and observed tumor regressions in some patients.

Unexpectedly, tumor regression did not correlate with lymphocyte infiltration in primary lesions. In fact, further experiments in the mouse model found that tumor regression required macrophages but not T cells or gemcitabine [ ]. They observed that treatment with the CD40 agonist antibody resulted in reprogramming of TAMs, including up-regulation of MHC class II and the costimulatory molecule CD86, accumulation in tumor tissue and ability to lyse tumor cells ex vivo.

These results demonstrated a novel mechanism for CDmediated tumor elimination involving TAMs [ ]. IL is an important cytokine that is involved in lymphocyte and macrophage polarization and differentiation. Intravenous treatment of tumor-bearing mice with recombinant IL has been shown to induce tumor regression and TAM conversion from a pro- to anti-tumoral phenotype [ 27 , ].

The following two examples are interesting because they describe ILmediated TAM reprogramming using a unique cytokine delivery method. By adoptively transferring these tumor-derived antigen-specific T cells, they were able to deliver IL directly into the tumor tissue. They found that anti-tumor activity depended on the ability of the myeloid-derived cells, but not lymphocytes or NK cells, to respond to IL In addition, this T cell-delivered IL resulted in significant reprogramming of multiple myeloid-derived cell populations, including MDSCs, macrophages, and DCs within the tumor [ ].

Chmielewski and colleagues took a different approach by engineering cytotoxic T cells with a chimeric antigen receptor CAR with specificity for a tumor-associated antigen. Adoptive transfer of these CAR-iIL12 T cells resulted in an accumulation of activated macrophages within the tumor tissue that was critical to the anti-tumor response [ ]. Like the previous examples, this report is particularly interesting because of the delivery method.

This vascular remodeling was mediated, in part, by TAMs, reprogrammed towards a more inflammatory anti-tumor profile [ ]. CD47, a cell surface protein in the immunoglobulin superfamily, is expressed in the majority of normal tissues.

A number of recent reports have described how tumor cells use this pathway to avoid phagocytosis. Tumor cells were shown to constitutively up-regulate CD47 expression in multiple tumor entities and animal models.

Furthermore, over-expression of CD47 was a poor prognostic factor and correlated with increased pathogenicity [ — ]. Importantly, there did not seem to be a significant increase in the phagocytosis of normal cells in vitro or in vivo. Targeting the myeloid immune cell compartment in tumors is a promising approach for immunotherapy. Currently, two main strategies are investigated: reduction of the pool size and functional modification of these myeloid cells Fig.

The number of tumor infiltrating monocytes and macrophages can be reduced by controlling the development, recruitment and survival of these cells. Since their half-life is relatively short, interfering with generation and differentiation may have great potential.

Several tools are available to modify the cellular functions. The overall goal is to activate the anti-tumoral potential of these myeloid cells.

This can be achieved either by agonistic antibodies targeting surface structures such as CD40 or by reprogramming the cytokine profile of the cells. Multiple manipulation strategies have been mentioned in this review and many more have been tested, but unfortunately, could not be discussed in-depth here. In summary, targeting myeloid cells for immunotherapy is very encouraging, but whether a monotherapy will be sufficient or a combination with adoptive immunotherapy or other strategies will be more effective remains to be determined.

The authors declare no competing financial interests. David M. Richards and Jan Hettinger equally contributed. National Center for Biotechnology Information , U. Journal List Cancer Microenviron v. Cancer Microenviron. Published online Nov Richards , Jan Hettinger , and Markus Feuerer. Author information Article notes Copyright and License information Disclaimer. Corresponding author. Received Oct 8; Accepted Oct This article has been cited by other articles in PMC.

Abstract Monocytes and tumor-associated macrophages are part of the myeloid family, a group of hematopoietic derived cells. Keywords: Tumor-associated macrophages, Monocytes, Myeloid cells, Immunotherapy.

Introduction The mononuclear phagocyte system MPS represents a body—wide, specialized system of different phagocytic cell types derived from bone marrow and yolk sac progenitors [ 1 , 2 ]. Steady-State Development of Monocytes Monocytes are found in the blood and spleen, but their largest reservoir under homeostatic conditions is the bone marrow, the primary site of monocyte generation [ 3 , 8 ]. Open in a separate window. Development of Monocytes in Cancer In cancer, many characteristics of myeloid cells, such as migratory and functional properties, are altered, but whether the principal developmental processes in the bone marrow are also affected is currently under investigation.

Table 1 Phenotypic identification of murine monocytes and macrophages. Population Subset Phenotype Ref. Mobilization and Recruitment of Monocytes to Target Sites Monocytes are mobilized from the bone marrow and spleen in response to chemotactic signals and recruited to target tissues guiding their further differentiation [ 32 ]. Development and Functions of Macrophages Following tissue recruitment, monocytes are polarized by the local microenvironment and differentiate into resident macrophages under the control of multiple tissue-specific factors [ 6 , 7 ].

Tumor-Associated Macrophages Tumor-derived factors attract circulating monocytes into the tumor tissue where they differentiate into macrophages Fig.

Inflammation-Induced Genetic Alterations and Instability It is becoming increasingly clear that chronic unresolved inflammation is the underlying cause of many types of cancer [ 63 , 64 , 66 ]. Production of Trophic Growth Factors and Promotion of Angiogenesis During the next stage of tumor development, recruited monocytes differentiate into macrophage subpopulations, unlike those found in the acute inflammatory environment, which support tissue remodeling and thereby promote tumor growth.

Promotion of Metastasis by Monocytes and Tumor-Associated-Macrophages TAMs play a role in multiple stages of tumor metastasis, from promoting tumor cell escape from the primary site to facilitating tumor cell arrival and establishment at distant sites. Intravasation of Cancer Cells TAMs also enhance the ability of tumor cells to enter the blood vessels, a process called intravasation.

Extravasation of Cancer Cells and Establishment of Local Metastasis The tumor microenvironment and TAMs both play crucial roles in the initiation of metastasis at the primary tumor site.