Introduction and major histocompatibility complex class II





is well known that high levels of macrophages are found circulating with the
tumour microenvironment. These macrophages are initiated by tumours and
contribute to tumour progression (1). Within the tumour microenvironment,
macrophages present different phenotypes depending on signals produced by the
tumours (2). These phenotypes can be M1 or M2 (3). M1 macrophages are
associated with anti-tumour and pro-inflammatory immune responses, whereas M2 macrophages
are associated with pro-tumour and anti-inflammatory immune responses (4, 5).

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Within most tumours, macrophages usually present the M2 phenotype and have been
described as tumour-associated macrophages. Tumour associated macrophages have
various roles in tumour progression, these include metastasis, angiogenesis and
tumour survival (6-8). It has been well documented and assumed that
tumour-associated macrophages solely derived from inflammatory monocytes but
there is increasing evidence that this may not the case and that some types of
tissue-resident macrophages can also be the source of tumour associated
macrophages (9-11).




are two main groups of activated macrophages, M1 (classically activated
macrophages) and M2 (alternatively activated macrophages) (12). M1 macrophages
are known to express high levels of pro-inflammatory cytokines such as IL-12
and major histocompatibility complex class II (MHC II) but express low levels
of anti-inflammatory cytokines such as IL-10 and the enzyme arginase (13). They
are present after activation by IFN-g  with either lipopolysaccharide (LPS) or tumour
necrosis factor alpha (TNF-a) with infected and
inflamed tissues (14). They are also known to increase the expression of
intracellular protein suppressor of cytokine signalling 3 (SOCS3) and activate inducible
nitric oxide synthase (iNOS) (15,16). In contrast to M1 macrophages, M2 macrophages
express high levels of IL-10 and low levels of IL-12 (17). M2 macrophages are
activated in response to high levels of IL-4 or IL-13 (18). M2 macrophages
which are activated in response to IL-4, have been shown to be involved in
tumour progression, tissue repair and immunoregulation (4). They have low
antigen presentation and produce various immunosuppressive cytokines such IL-10
and transforming growth factor beta (TGF-b) (5,19).


Polarization of M1 and M2 sub-types


transcription factors are involved in macrophage polarization (20). Suppressor
of cytokine signalling proteins (SOCS), interferon regulatory factor (IRF) and
signal transducers and activators of transcription (STAT) are involved in
determining the M1 or M2 phenotype. Interferons and toll-like receptor
signalling activate the IRF/STAT pathways, which polarizes macrophage to the M1
phenotype via STAT1, in contrast IL-4 and IL-13 polarize macrophage to the M2
phenotype via STAT6 (4). M1 macrophages have been shown to increase IRF5, which
is required for the polarization of M1 macrophages and the activation of IL-12,
IL-23 and tumour necrosis factor and the initiation of TH1 and TH17 immune
responses (21). Bruton’s tyrosine kinase (Btk) has also been shown to be
involved in M1 macrophage polarization in response to lipopolysaccharide (LPS) (22).

In M1 macrophages, granulocyte macrophage colony stimulating factor (GM-CSF) has
been shown to increase antigen presentation and leukocyte chemotaxis as well as
inducing phagocytosis. GM-CSF also increase the production of cytokines which
including IL-6, granulocyte colony stimulating factor (G-CSF), macrophage
colony stimulating factor (M-CSF) and tumour necrosis factor (23). Other
molecules involved in M1 macrophages polarization are the G-protein couple receptor
P2Y purinoceptor 2, this protein induces nitric oxide (NO) via nitric oxide
synthase 2 (NOS2) (24); suppresser of cytokine signalling 3 (SOCS3), this protein
activates NF-kB/PI-3 kinase pathway
to produce nitric oxide (25) and Activin A, which increase M1 markers and
decrease IL-10 (26). The production of arginase 1 is necessary for M2
polarization and translated by STAT6 after activation of IL-4/IL-13 signalling (27).

The nuclear receptor, peroxisome proliferator-activated receptor g
has been shown to increase the genes which are required for oxidative
metabolism and the activation of the M2 macrophage polarization (28, 29). Cytokine
IL-21 plays a role in M2 polarization by down-regulating nitric oxide synthase
2 (NOS2) expression and regulating STAT3 phosphorylation (30). M2 macrophages
produce high levels of IL-10 in response to toll like receptors,
glucocorticoids and C-type lectin signalling (31).


Polarization of tumour-associated macrophages


associated macrophages are associated with the M2 macrophage phenotype. Several
factors are involved in the polarization of tumour associated macrophages. Various
chemokines such as CCL2, CCL3 and CCL14 have been shown to activate the
proliferation of macrophages in multiple myeloma (32). Prostate
cancer-derived cathelicidin-related antimicrobial peptide and hypoxic cancer
cell-derived Oncostatin M and Eotaxin both induce macrophages within the
tumour microenvironment into the M2 macrophage phenotype (33, 34). IL-10
produced from regulatory T cells and immunoglobulin from B cells induces
macrophages towards the M2 phenotype within the tumour microenvironment (35,
36). Both hypoxia-inducible factor 1-a
and hypoxia-inducible factor 2-a induce
M2 polarization and function (37).



Functions of tumour-associated macrophages


previously mentioned, it is well known that there are high numbers of
macrophages circulating within the tumour microenvironment (1). Tumour-associated
macrophages have various functions within the tumour microenvironment. Tumour-associated
macrophages promote angiogenesis via stimulatory and inhibitory mediators, such
as basic fibroblast growth factor (bFGF), vascular endothelial growth factor
(VEGF), angiopoietins 1 and 2, IL-8, tumour necrosis factor-a
(TNF-a) and matrix metalloproteinases MMP-9 and MMP-2
(38, 39). All of these molecules induce the proliferation and migration of
endothelial cells and formation of structured vessels within tumours (40). Vascular
endothelial growth factor is essential in the process of angiogenesis Macrophages
are suitably designed to activate and induce the process of angiogenesis (41).

a study looking at human breast cancer, it was shown that tumour-associated
macrophages accumulate in avascular areas (42), within these avascular areas
there were increased levels of angiogenesis resulting in poor survival and
increased relapse after treatment, it was proposed that hypoxia, which induces
hypoxia-inducible factor 2, which in turn activates vascular endothelial growth
factor (VEGF) or that cytokines produced in breast cancer tissue is the reason
for the accumulation of the tumour-associated macrophages within the tissue
(43). Macrophage colony stimulating factor is shown to induce vascular
endothelial growth factor (VEGF) in tumour-associated macrophages (44).

Vascular endothelial growth factor is a chemoattractant towards macrophages and
could be the reason for a positive feedback loop resulting in fast and
increased vascularization in tumours (45).

macrophages produce various cytokines which promote angiogenesis (39). They
produce tumour necrosis factor-a, which has been seen
in high levels in tumour-associated macrophages in tumours which has metastasised

macrophages has been shown to produce tumour promoting IL-6 in mouse tumour
models, this production of IL-6 has been shown to promote tumour progression
and inhibit apoptosis in colon cancer cells via the induction of STAT3 (47, 48).

This has also been seen pancreatic cancer, IL-6 induces tumour progression
epithelial lesion via STAT3 (49).

macrophages has recently been shown to play a role in chemo-resistance (50). Macrophages
has been shown to increase levels of cytidine deaminase, which is a
metabolising enzyme in the chemotherapy drug gemcitabine, specifically in
pancreatic adenocarcinoma (51). Tumour associated macrophages has also been
shown to promote resistance to chemotherapy in pancreatic ductal adenocarcinoma
via insulin-like growth factor 1 and insulin-like growth factor 2 (52).



Origin and development of tumour-associated


It has been well documented and assumed that
macrophages derived solely from monocytes that differentiated from precursors
blood and stem cells originated from the bone marrow. Although, recently there
have studies in mouse models which have shown that macrophages which have
derived from embryonic progenitors can maintain through-out adulthood in
various organs (9-11, 53). It seems that macrophage populations derived from
monocytes are specific to certain tissues, this includes the intestine (54),
the skin (55), the mammary gland (56) and the heart (57) and that these tissues
need precursors that have originated from the bone marrow, in contrast to other
tissues which can produce macrophages without the need for circulating
monocytes (58).

Yolk sac erythro-myeloid progenitors have been
recently shown as precursors of yolk sac macrophages, a c-Myb+
pathway produced macrophages without any involvement of monocytes within the
yolk sac (10, 59).

Haematopoiesis occurs in waves during embryonic
development which produces haematopoietic stem cells within the bone marrow (60).

In mice, the first progenitors begin to develop in the embryonic yolk sac on
embryonic 7-7-5, this process is defined as primitive haematopoiesis. It has
been shown recently that erythro-myeloid progenitors (EMPs) develop from blood
islands within the yolk sac and classed as early erythro-myeloid progenitors
(59, 61). After the primitive stage, definitive haematopoiesis occurs which produces
late erythro-myeloid progenitors (EMPs) and lympho-myeloid progenitors (LMPs) (62,
63). At embryonic day 8.5, the following progenitors establish the foetal liver,
where they reproduce and subsequently produce foetal monocytes, at embryonic
day 10.5, these precursor and mature haematopoietic stem cells inhabit the
liver and this becomes the primary organ for haematopoiesis (60, 64, 65).

The first mouse model which demonstrated that
tissue-resident macrophages were developed in embryonic development by yolk sac
erythro-myeloid progenitors in yolk sac as opposed to monocytes derived from
haematopoietic stem cells was Runx1-MERCre-MER, the specific population of tissue-resident macrophages identified
were microglia (66). These findings were consistent with a study using the
mouse model Csf1rMer-iCre-Mer, the study showed that tissue-resident
macrophages, microglia, were still present within the Myb -/- mice
(11) even though the Myb proto-onogene protein is needed in the process of murine
definitive haematopoiesis (67). The embryonic origin of macrophages has been
further confirmed by studies that have shown that adult monocytes do not
contribute to the development to tissue-resident macrophages in homeostatic
conditions (53, 69). The study by Yona et al. (53) highlighted that there may be
a CX3CR1+ precursor for tissue-resident macrophages that have
derived independently from monocytes as yolk sac macrophages do express CX3CR1 (68,
71) but this has not yet been established. In a study by Gomez et al. (10), it
was suggested that the origin of tissue-resident macrophages was
erythro-myeloid progenitors within the yolk sac, this further confirmed by
Hoffel G, et al. (59) using yolk sac macrophage depletion and multiple mouse
models that the majority of tissue-resident macrophages may derive from late
erythro-myeloid progenitors that have been developed from foetal monocytes in
the liver. This is the opposite to microglia, which are said to derive from
yolk sac macrophages without the need for monocyte precursors (10, 11, 66, 70).