Role Of Myeloid Derived Hematopoietic Cells In Inflammation And Immune Tolerance To Cancer


Iuliana Shapira1*, Keith S Sultan2, Emanuela Taioli3, Annette Lee4


1Monter Cancer Center, Don Monti Division of Oncology, Division of Hematology, Hofstra North Shore LIJ of Medicine, 450 Lakeville Road, Lake Success, NY 11042 USA

2Department of Gastroenterology North Shore University Hospital 300 Community Drive Manhasset NY 11030;

3Division of Population Health 175 Community Drive Manhasset NY 11030

4Feinstein Institute for Medical Research Robert S. Boas Center for Genomics and Human Genetics and Elmezzi Graduate School of Molecular Medicine 350 Community Drive Manhasset NY 11030



Tumor microenvironment is the collection of cells such as neutrophils, monocytes, lymphocytes, stromal fibroblasts, macrophages, smooth muscle cells and endothelial cells, all embedded in an extracellular matrix that fibroblasts produce. Myeloid derived cells in and around tumor help cancer cells survive, grow and spread to new locations where they seed metastasis. Cancer cells from growing tumors hijack mechanisms used by the normal tissues for wound repair such as the productions of growth and angiogenic factors, matrix metalloproteinases, fibroblasts, cells of myeloid lineage and chemokines to promote their survival and growth. Cells of myeloid lineage origin have a crucial role in malignant organ development by protecting the growing tumor mass from immune recognition hampering the immune rejection of cancer cells. Malignant tumors recruit cells of myeloid derivation to promote the growing tumor and its invasive abilities. Survival of patients with adenocarcinoma of the breast, colon, lung and prostate is inversely proportional to the number of infiltrating cells of myeloid derivation of tumors. Such malignancies are associated with shorter survival and detecting molecular signatures typical for macrophage infiltration such as CD68 in tumors herald poor diverse malignancies. There is two way editing of the growing malignancy and immune system of the affected patient: the malignant process shapes the immune system of the patient and at the same time the immune system of the patient shapes the growing tumor by selecting for the cancer cells resistant to immunodetection to survive and multiply.

Keywords: Immune system, malignancy development, cancer, macrophages, dendritic cells, cancer outcome, T-regulatory cells


Corresponding Author:

Iuliana Shapira, MD

Associate Professor of Medicine, Director Cancer Genetics, Monter Cancer Center, Don Monti Division of Oncology, Division of Hematology, Hofstra North Shore LIJ of Medicine, 450 Lakeville Road, Lake Success, NY 11042

Phone: +1 516-734-8964 ; Fax: +1 516-734-8924



Malignancies are immunoprivileged organs 

Amongst the main actors in metastasis are cells of myeloid lineage such as macrophages, dendritic cells, myeloid suppressor cells and neutrophils. A cradle created by a heterogenous group of hematopoietic cells, fibroblast and stromal cells becomes an immuno-privileged site, the metastatic niche, favorable to the growth of cancer cells.

The immune system employs cells and secreted factors to discriminate between self and non-self antigens allowing for immune mediated destruction of non-self antigens and tolerance to self.

The immune system is made up by cells of hematopoietic derivation and classically was described as having two arms: the innate immunity and the adaptive immunity with distinct cellular components and physiology [1].

The cellular components of the innate immunity include: neutrophils, monocytes, macrophages, dendritic cells (DC) and natural killer (NK) cells. The adaptive immune system consists of lymphocytes B-cells (CD8+ effector, CD4+ helper) and αβ T-cells.

Other cells function both in innate and adaptive immunity such as NK-T cells, regulatory T-cells (CD4+CD25+FOXP3+), and γδ T-cells [1].


Figure 1: Type 1 immune responses require antigen presentation to occur in the presence additional signals. Ag peptide antigen peptide, TCR T-cell receptor: First signal is provided by the interaction between antigen specific signal linked to Major Histocompatibility Complex [MHC] and T-cell receptor [TCR] interaction. The second signal is provided by, the linkage of B7-1 (CD 80) or B7-2 (CD86) on the Antigen Presenting cell (dendritic and others APC) coupling with CD28 on the T-cell an antigen-independent signal and the third signal comes from the interaction of CD40L on APC to CD40 interaction. These interactions result in either CD8+ effector (cytotoxic) T-cells or Th1 CD4+ Helper T-cells maturing the immune response to tumor recognition and elimination [2].


Type 1 immune responses are required for immune surveillance, recognition and elimination of tumor cells

After appropriate activation dendritic cells become antigen presenting cells, potent stimulators of immune responses (type I immunity) recognizing cancer cells as non-self. (Figure 1) They polarize lymphocytes, neutrophils and macrophages to proinflammatory activities. Lymphocytes become effector cells (CD8+-Tcells), capable of recognition and destruction of tumor cells. Macrophages become M1 proinflammatory cells able to recruit other immune cells to the malignant site. Neutrophils acquire an anti-tumor N1 phenotype helping to recognize and kill tumor cells.

Type 1 immune responses require antigen presentation to occur in the presence additional signals. First signal is provided by the interaction between antigen specific signal linked to Major Histocompatibility Complex [MHC] and T-cell receptor [TCR] interaction. The second signal is provided by, the linkage of B7-1 (CD 80) or B7-2 (CD86) on the Antigen Presenting cell (dendritic and others APC) coupling with CD28 on the T-cell an antigen-independent signal and the third signal comes from the interaction of CD40L on APC to CD40 interaction. These interactions result in either CD8+ effector (cytotoxic) T-cells or Th1 CD4+ Helper T-cells maturing the immune response to tumor recognition and elimination. (Figure 1) [2].

CD8+ effector T-cells have a central role in active killing and elimination of the tumor cells, they recognize 8-10 amino acid long peptides buried in the antigen-presenting groove of the major histocompatibility complex class I molecules [3]. Activation of a naïve CD8+ T-cell into an effector is rapid occurring and less than 24 hours of antigen presence and less than 24 hours antigen stimulation induces enough clonal expansion and differentiation of effector cells to elicit protective responses [4].

One key regulator of CD 8+ T-cells is the aminoacid arginine [5] needed for their normal replication and for the production or the zeta chain the principal signal-transduction element of the T-cell receptor (TCR) [6,7]. CD8+ T-cells proliferation and Th-1 responses requires the presence of essential amino acid tryptophan.

Blood monocytes are able to generate human dendritic cells: in the presence of macrophage colony stimulating factor M-CSF they generate macrophages while in the presence of GM-CSF and IL-4 and TNF-they produce DC1 that expresses CD14-CD38+CD68+ and surface major histocompatibility complex (MHC) II.

Microbial products, antigens from specific cancer cells (recognized as non-self) or interferon γ induce antigen presenting cells such as dendritic cells or macrophages to express an M1 phenotype, M1 macrophages promote activity of killer T-cells through their production of interleukin 12 (IL-12), high interleukin 23 (IL-23) and low interleukin 10 (IL-10). M1 macrophages interact with the T-helper 1 cells they produce major histocompatibility complex molecules rendering T-cells capable of killing pathogens and tumor cells. [8] In response to lipopolysaccharides (LPS) M1 macrophages produce reactive oxygen and nitrogen intermediates, interleukin 1 (IL-1), tumor necrosis factor α (TNFα) and thus function as the first line of defense against bacterial invasions [8,9]  (Table 1).



Table 1: Inflammatory Mediators of Malignancy

IL interleukin; TLR toll like receptor; STAT signal transduction and activator of translation; JAK Janus activated kinase; NF-KB nuclear factor KB; MAPK mitogen activated protein kinase; DC dendritic cells; NK natural killer cells [96].


Maturation of monocytes into M1 macrophages induces them to release IL-12 that in turn promotes activation of NK cells and optimal production of interferon γ (INF- γ). [10] Due to their differential expression of the MHC class I, especially HLA-E, immature dendritic cells are uniquely susceptible to NK-induced cell death, whereas mature dendritic cells are protected. [11] Cancer cells take a risk in trying to evade the immune attack through the loss of HLA molecules, cytotoxicity of natural killer cells is the greatest when target cells have lost their HLA molecules.[12] (Table 1).


Type 2 immune responses the immune tolerance to self

The immune system has developed several check-points to control for the potential destructive power of autoimmunity. For example newly formed lymphocytes are eliminated either in the bone marrow (B-cells) or in the thymus (T-cells) if they are strongly autoreactive. Antigens placed in the brain, anterior chamber of the eye, testis or fetus to not elicit type 1 immune responses making these immuno-privileged niches. The immuno-privilege arises from a specific interaction between cells, cytokines and other secreted factors of the immune system collectively called type-2 immune response. 

Type-2 immune responses require at least 3 signals to occur between the antigen presenting cells (APC) and other cells of the immune system. First signal is provided by antigen specific signal linked to the Major Histocompatibility Complex [MHC] and T-cell receptor [TCR]. The second signal is an antigen-independent signals and involves linking of B7-1 (CD 80) or B7-2 (CD86) on the antigen presenting cells (APC) to Cytotoxic-T-Lymphocytes Associated Antigen (CTLA-4) or interaction with Programmed Death-1 (PD-1) receptor on T-cells. The last signal is provided by the CD40L on APC to CD40 interaction. These interactions result in production of maturation of the immune cells towards a self-tolerant phenotype. CD4 Th2 type T-cells (CD4+FOXP3+ Regulatory T-cells), M2 macrophages and N2 neutrophils [13,14] (Figure 2).

Figure 2

Figure 2: Type 2 immune responses requires at least 3 signals to occur between the antigen presenting cells (APC) and other cells of the immune system. First signal is provided by antigen specific signal linked to the Major Histocompatibility Complex [MHC] and T-cell receptor [TCR]. The second signal is an antigen-independent signals and involves linking of B7-1 (CD 80) or B7-2 (CD86) on the APC to Cytotoxic-T-Lymphocytes Associtated Antigen (CTLA-4) or interaction with Programmed Death-1 (PD-1) receptor on T-cells. The last signal is provided by the CD40L on APC to CD40 interaction. These interactions result in production of maturation of the immune cells towards a self-tolerant phenotype. CD4 Th2 type T-cells (CD4+FOXP3+ Regulatory T-cells), M2 macrophages and N2 neutrophils [13,14]. Ag peptide- antigen peptide, TCR-T-cell receptor, PD-1-programmed death 1; TAM-tumor associated macrophages, MDSC-myeloid derived suppressor cell; MHC-major histocompatibility complex protein.


Type 2 immune responses also provide for wound healing and tissue remodeling during growth. Myeloid derived macrophages provide support for developing tissues because of their matrix remodeling abilities, synthesis of growth and angiogenic factors and engulfment of apoptotic cells. In-vivo multiphoton images showed that M2 macrophages aid the invasion of normal epithelial cells during duct development in normal breast and they also help the invasive edge of the mammary tumor [15].


Type 1 or type 2 immune responses depend on local growth factors stimulating the immune cells

Human monocytes, dendritic cells and other antigen presenting cells (APC) are plastic and their type 1 or Type 2 immune response depends on local conditions and cell stimulations.

During the type 1 immune response these cells produce IL-6 and TNF-a, express TLR-1, -2, -4, -5, -8 responding to microbial ligands, or express TLR-7, -9 and respond to bacterial CpG oligonucleotides. Each mature APC has a short lifespan in the uninfected individual and changes over after interacting with T-cells, B-cells and other cells of the immune system. The responses are not static but change, responding to the local conditions [16].

In the bone marrow common, monocytes progenitors give rise to antigen presenting dendritic cell (DC): either early DC progenitors (c-kit+) with high proliferation potential precursors leading to macrophages or late DC progenitors CD11c+ C-kit with low proliferation potential with potential development into plasmacytoid (CD11c-CD45RA+CD123+ blood DC antigen 2 [BDCA2]+) and macrophages [17,18].  Macrophages are monocytes recruited from the circulation at the site of injury, inflammation, infection, or malignancy where they differentiate into scavenging cells

Gr-1+CD11b+ with inflammatory functions [19].

Polarization of immature dendritic cells to activated dendritic cells depends on the local factors. Dendritic cells may become activated dendritic cells producing IL-12 and helping in maturation of Th1 cells to help eliminating non-self antigens or quiescent DC helping to induce tolerance to presented self antigens. Repeated stimulation of activated DC leads DC to produce IL-4, which has a type 2 an immunosuppressive effect (Table 1). 

Activated dendritic cells are able to produce IL-12 when their CD40 binds CD40L expressed on CD4+ T-cells. IL-12 and the interaction between CD40L and CD40 expressed on B-cells and leads to B-cell proliferation, somatic hypermutation of the immunoglobulin heavy chain and allows for the expression of mature immunoglobulins. 

After antigen recognition DC initiate a process, which results in up-regulation of antigen presenting molecules (MHC class I and II) and of co-stimulatory molecules (such as CD40, CD80 and CD86). This stimulates naïve T-cells to become effector cells and eliminate the pathogen or, alternatively in the absence of appropriate signals the DC induces tolerance for that antigen [20] (Figure 1 and 2). 

Dendritic cells are derived either from monocyte lineage of from lymphoid lineage and are classified by their differential responses to toll-like receptors (TLR): signaling through TLR3, TLR4 and TLR8 occurs in monocytoid dendritic cells but not in plasmacytoid ones and signaling through TLR9 occurs in plasmacytoid DC exclusively [21].

The immature monocyte-derived and activated myeloid dendritic cells can become either M1 or M2 macrophages showing great plasticity until late in their differentiation [22]. The environment in which they differentiate determines their ultimate fate. IL-6 mediated maturation favors macrophage development [23,24] while tumor necrosis factor α (TNFα) exposure results in dendritic cells [25]. 

M2 macrophages are called into action for tissue repair, remodeling and angiogenesis that customarily takes place after the bacterial infection resolves.  M2 macrophages interact with T-helper 2 cells and stimulate the production of IL-4, IL-10 and IL-13, they moderate the inflammatory response, promote angiogenesis, tissue remodeling and clear cell debris and promote tumor formation as well as invasion [8,26,27].

M2 cells have high amounts of scavenger-type receptors. They are recruited into areas of hypoxic tissues or tumors via the hypoxia dependent up-regulation of the chemokine C-X-C motif receptor 4 (CXCR4) [28] where they promote angiogenesis [29]. After trauma and infection, M2 monocytes originating in spleen travel to affected sites and clean up the debris and foster tissue rebuilding [30].


Tumor Microenvironment and Metastatic Niche Foster Skewed Type 2 Immune Responses Allowing The Tumor To Develop in an “Immuno-Privileged” Niche

The growing malignancy exerts an immunosuppressive state with a shift towards a skewed type 2 immunity, cytokine production (important for antibody production), and away from type 1 immunity (associated with cell mediated immunity and tumor rejection).

Many factors are released from the malignant cells (collectively referred to as the tumor secretome) are shed from the tumor into the circulation can bind to monocytes and lymphocytes to induce cytokine release from these cells. Factors released by hemotopoietic cells associated with type 2 immunity are: IL-4, IL-10 and IL-14 cytokines. (Table 1) as well as indolamine 2,3 deoxygenase (IDO) and arginine (Figure 3). 


Figure 3

Figure 3: The interactions between tumor cells in brown with cells of hematopoietic derivation. Monocytes originating in the bone marrow are polarized by tumor cells to become M2 macrophages (TAM, MDSC) and travel to the growing malignancy to promote immune anergy.

The tumor secretome recruits myeloid and stromal cells from the bone marrow and polarizes them towards an immunosuppressive phenotype. The immunosuppressive phenotype leads to immune anergy in the tumors. Polarized macrophages (M2), dendritic cells (DC) and neutrophils (monocytes), function as antigen presenting cells to lymphocytes transforming them into T-suppressor (T-regulatory cells) T-reg; In addition cells of myeloid derivation use arginase, indolamine 2,3 deoxygenase (IDO), nitric oxide (NO) and interleukins IL-4, IL-10 and IL-13 and transforming growth factor beta (TGF-beta) leading to immune anergy in the tumor and converting the growing tumor and metastatic sites into an immuno-privileged organ. Ab-(producing B-cell) antibody; M1-dendritic (type 1 immune response polarized dendritic or macrophage cell), NK-cell natural killer cell; TAM tumor associated macrophages, MDSC myeloid derived suppressor cell [97].


In pancreatic cancer, the malignant cells secrete not only immunosuppressive factors such as transforming growth factor beta-1 (TGF-B1) but also VEGF, both factors known to attenuate type 1 immune responses [31].

In the tumors, monocytes are “educated” (i.e. polarized) to acquire a distinct phenotype (M2) and activated status becoming myeloid derived suppressor cells (MDSC) or tumor associated macrophages (TAMs) or, tumors therefore are “wounds that do not heal” [32,33]; after receiving such instructions TAMs down-regulated their major histocompatibility complex (MHC) class II and their ability to present antigen, decrease expression of IL-12 and increase their production of vascular endothelial growth factor (VEGF), cyclo-oxygenase-2 (COX-2) derived prostaglandin E2, arginase-1 (Arg-1), 2,3 indolamine deoxygenase IDO and IL-10 [33].

Tumor associated macrophages (TAMs) have been considered as mandatory helper cells for tumor-cell migration, invasion and metastasis. [34] In the macrophage deficient mouse with breast cancer, tumors developed normally but were unable to develop pulmonary metastasis in the absence of macrophages [35]. In this model metastasis occurred by interactions between tumor cells and TAM and paracrine growth factors: macrophage-colony stimulating factor and macrophage epidermal growth factor [35,36].

There are paracrine effects between malignant cells and monocytes. Cancer cells release chemoattractants such as CCL2, vascular endothelial growth factor and CXCL12 (SDF1) into the blood stream luring monocytes from the blood stream into the tumor microenvironment [37].

Myeloid-derived suppressor cells (MDSCs) are a population of immunosuppressivemyeloid cells markedly increased in patients with head and neck cancer [38], breast [39], hepatocellular carcinoma [40] and renal cancers [41]. MDSCs circulate in higher numbers in patients with higher cancer stages [39]. MDSC share common characteristics: lack or reducedexpression of markers of mature myeloid cells, expression ofboth Gr-1high CD31+ and CD11b+ molecules [42], inability to differentiateinto mature myeloid cells in the presence of tumor-derived factors,high levels of reactive oxygen species, and activation of arginaseI [43]. Cancer patients especially head and neck, non-small cell lung cancer, pancreatic cancer, colon and breast cancer have three to five times more myeloid derived suppressor cells in circulation than normal controls [44-46].

MDSC from human cancer patients have high levels of arginase I that degrades the arginine, high levels of indolamine 2,3 deoxygenase (IDO) which depletes tumor microenvironment of the essential amino acid tryptophan and produce large amounts of nitric oxide synthase (NOS) another enzyme that degrades arginine impairs normal T-cell function [47] (Figure 3). Efforts to decrease the NOS synthesis retard cancer growth for example in mice with colon or mammary tumors experimental treatment with T-cells and sildenafil decreased production of arginase I and NOS from MDSCs and inhibited tumor growth more than the treatment with T-cells alone [38]. The immunosuppressive abilities of the MDSC translate into the inhibition of CD8 T-cell activity by the expression of NOS2 and Arg1 [48], the triggering of development of CD4+FOP3+ T-regulatory cells [49], and the induction of M2 differentiation of macrophages present in the tumor and circulation by releasing high levels of IL-10 [50].

Vascular endothelial growth factor (VEGF) released by the tumor cells promotes the accumulation of MDSCs by blocking signal 3 of antigen presenting cell maturation [51] (Figure 1 and 2).

MDSCs are known to produce VEGF further promoting tumor growth and their own formation. [52] Hypoxia dependent up-regulation of chemokine (C-X-C motif) receptor 4 (CXCR4) induces accumulation of these MDSCs in the hypoxic areas of the tumors promoting angiogenesis. [28,29] CXCR4-CXCL12 signals are implicated in trafficking of myeloid cells into tumors, inducing a skewed type 2 immune responses [53] that increase tumor vascularization [54]and promote metastasis [55]. MDSCs produced VEGF secretion is an important factor the development of a vascular system by the growing tumor and depends on the enzyme matrix metalloproteinase-9 (MMP-9) [56].

A subgroup of bone marrow derived CD11b+ monocytes cells also expressing Carcioembryonic antigen (CEA) related-cell adhesion molecule-1 (CEACAM-1) are involved in resolution of inflammation by promoting the formation of the blood and lymphatic vessels [57]. Mice with a gene knockout for monocytes expression CEACAM-1 have prolonged inflammatory response and edema of the skin when exposed to cutaneous leishmaniasis and decreased angiogenesis and lymphangiogenesis. Transplanting bone marrow cells from normal mice corrected the wound healing process through reintroduction of CD11b+CEACAM-1+ monocytes [57].

Efforts to manipulate the tumor secreted factors tend to improve immune recognition and elimination of malignant cells. For example, in mice with a homozygous null mutation of the gene that encodes the macrophage growth factor colony stimulating factor -1 (CSF-1) not only reduced the rate of tumor progression in a mouse model of breast cancer (induced by polyoma middle T oncoprotein) but completely ablates the metastasis [35].

The tumor microenvironment skews normal immune responses, the antigen presenting cells (dendritic cells or B-cells) a dysfunctional Th1. Common melanoma epitopes for example show low affinity for MHC-Tcell interaction and low co-stimulatory molecules (Figure 1) resulting in maturation of T-lymphocytes that ignores the common melanoma allowing for progression of metastatic disease [58-60].  The initiation of type 1 immune responses and recognition of abnormal melanoma cells occurs when the melanoma antigen is presented in the context of high affinity MHC-Tcell interaction or when antigen presenting cells express high levels of co-stimulatory molecules.

MDSC (CD11b+Gr1+ monocytes) have been implicated in tumor refractoriness to anti-VEGF therapies (Bevacizumab), [61] used in solid tumors [62]. In experimental mouse tumor models mixing anti-VEGF therapy sensitive tumors with MDSC (CD11b+Gr1+cells) from refractory tumors resulted 60% greater new vessel formation compared with levels resulting from mixture with CD11b–Gr1–monocytes [62].

The molecular basis for tumor refractoriness to anti-VEGF therapies was elucidated with help from gene array analysis that identified genes differentially expressed in tumor microenvironment such as: G-CSF, and MCP-1, known to be involved in the mobilization ofbone marrow–derived myeloid cells to the peripheral blood [63]; the number of circulating MDSC (expressing CD11b+Gr1+ cells) increaseafter implantation of tumor cells [64,65] and proinflammatory factors such as MIP-2 and IL-1Rfound to be highly expressed in tumors refractory to anti-VEGF therapies [66].


Support Of Metastasis And Tumor Angiogenesis Originates And Is Sustained By Cells Of Hematopoietic Derivation

Tumor cells spread in the disease process to establish distant micrometastasis [67]. The micrometastatic disease may not always become successful macrometastatic disease unless a vascular supply develops to supply the metastatic niche. New blood vessels formation requires recruitment of circulating endothelial progenitor cells derived from the bone marrow [68-70]. A study of metastatic Lewis lung carcinoma and spontaneous mouse mammary tumor virus (MMTV) breast cancer found that more than 10% of the endothelial cells in the macrometastasis blood vessels were derived from bone marrow monocytes phenotypically CD31+, VGEFR2 +and Id1+ [71].  In the metastasis these cells provide not only structural (vessel incorporation) roles but also paracrine (instructive) roles initiating metastatic colonization [72]. When researchers reduced the Id1 expression on these monocyte progenitor cells their mobilization from the bone marrow decreased 96% and metastatic processed decreased proportionally, animals’ survival improved providing direct evidence that minor manipulation in bone marrow monocyte differentiation leads to major impact in tumor progression [71].

The involvement of MDSC metastatic process and aberrant lymphangiogenesis in, development and progression of ascites places CD11b+ M2 and immature dendritic cells at the center of this process [73]. CD11b+ M2 and immature dendritic cells are able to differentiate into lymphatic endothelial cell [73], produce the lymphatic endothelial cell-specific growth factor VEGF-C and its tyrosin kinase receptor VEGFR-3 [74], express podoplanin, a membrane mucoprotein [75], and the CD-44 related hyaluronic acid receptor LYVE-1 [76].

In a mouse model generated by implantation of human ovarian cancer cell lines (MDAH-2774, SKOV-3, and OVCAR3) into athymic nude mice dysfunctional lymphangiogenesis, progressive chylous ascites formation and disseminated carcinomatosis were mediated by the bone marrow derived CD11b+ monocytes migrating to the tumor areas and producing vascular endothelial growth factors (VEGF-C, -D and -A) [77]. When injections of clodronate liposomes at 25 mg/kg every 3 days was used after tumor implantation to decrease the CD11b+ monocytes [78] apoptosis by 90%, the aberrant lymphatic formation in the mesentery was reduced by 80% [77].

In another mouse model generated by implantation of highly metastatic gastric carcinoma (OCUM-2MLN) cell line, Iwata and his colleagues demonstrated that the major source of vascular endothelialgrowth factor-C (VEGF-C) and VEGF-D were M2 TAM not the carcinoma cells and lymphangiogenesis was driven by bone marrow derived macrophages [79].



Multiple lines of evidence from clinical and translational research show that the malignant tissue is regarded by the immune system as an immune privileged site. Pathways involved in immune suppression in cancer are intimately related to the cells of hematopoietic derivation such as monocytes (macrophages, dendritic cells and neutrophils), lymphocytes and cytokines made by these cells. Factors secreted in the tumor microenvironment such as arginase or nitric oxide from MDSC, IDO from dendritic cells and immunosuppressive cytokines such as TGF-B, VGEF, IL-4, IL-10, IL-13 induce tolerance of the immune system to the growing microenvironment characteristic or many malignancies.

The question remaining from the studies presented is whether the heterogeneous group of immune cells (MDSC, TAM, T-regulatory cells, immature dendritic cells and neutrophils) are unique entities developing in the presence of certain malignancies and in specific patients or represent a functional status of normal myeloid and lymphoid cells, status elicited by inflammation and skewed immune responses in the tumor microenvironment. Characterization of MDSC showed that tumor conditioning of the immune system is dependent of the time and site of tumor progression with the same secreted factors mediating different activities in the innate tolerance to malignant tumors.



We are grateful to the generous support by Manhasset Women’s Coalition Against Breast Cancer and Moms Who Kick.



1. Lanier LL, Sun JC: Do the terms innate and adaptive immunity create conceptual barriers? Nat Rev Immunol 2009, 9:302-303.

2. Deel MD, Kong M, Cross KP, Bertolone SJ: Absolute lymphocyte counts as prognostic indicators for immune thrombocytopenia outcomes in children. Pediatr Blood Cancer 2013, 60:1967-1974.

3. Pamer E, Cresswell P: Mechanisms of MHC class I--restricted antigen processing. Annu Rev Immunol 1998, 16:323-358.

4. Wong P, Pamer EG: CD8 T cell responses to infectious pathogens. Annu Rev Immunol 2003, 21:29-70.

5. Mills CD: Macrophage arginine metabolism to ornithine/urea or nitric oxide/citrulline: a life or death issue. Crit Rev Immunol 2001, 21:399-425.

6. Irving BA, Weiss A: The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell 1991, 64:891-901.

7. Rodriguez PC, Zea AH, DeSalvo J, Culotta KS, Zabaleta J, Quiceno DG, Ochoa JB, Ochoa AC: L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes. J Immunol 2003, 171:1232-1239.

8. Gordon S: Alternative activation of macrophages. Nat Rev Immunol 2003, 3:23-35.

9. Mantovani A, Sica A, Locati M: Macrophage polarization comes of age. Immunity 2005, 23:344-346.

10. Borg C, Jalil A, Laderach D, Maruyama K, Wakasugi H, Charrier S, Ryffel B, Cambi A, Figdor C, Vainchenker W, et al.: NK cell activation by dendritic cells (DCs) requires the formation of a synapse leading to IL-12 polarization in DCs. Blood 2004, 104:3267-3275.

11. Carbone E, Terrazzano G, Ruggiero G, Zanzi D, Ottaiano A, Manzo C, Karre K, Zappacosta S: Recognition of autologous dendritic cells by human NK cells. Eur J Immunol 1999, 29:4022-4029.

12. Stewart TJ, Abrams SI: How tumours escape mass destruction. Oncogene 2008, 27:5894-5903.

13. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, et al.: Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004, 10:942-949.

14. Brown JA, Dorfman DM, Ma FR, Sullivan EL, Munoz O, Wood CR, Greenfield EA, Freeman GJ: Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 2003, 170:1257-1266.

15. Wyckoff J, Wang W, Lin EY, Wang Y, Pixley F, Stanley ER, Graf T, Pollard JW, Segall J, Condeelis J: A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 2004, 64:7022-7029.

16. Zhou Y, Tang L, Lin M, Xu S, Bai J, Song H: Expression of Cytotoxic T-Lymphocyte Antigen 4 on CD4+ and CD8+ T Cells Is Increased in Acute Lung Injury. DNA Cell Biol 2013.

17. Merad M, Manz MG: Dendritic cell homeostasis. Blood 2009, 113:3418-3427.

18. Degli-Esposti MA, Smyth MJ: Close encounters of different kinds: dendritic cells and NK cells take centre stage. Nat Rev Immunol 2005, 5:112-124.

19. Taylor PR, Gordon S: Monocyte heterogeneity and innate immunity. Immunity 2003, 19:2-4.

20. Steinman RM: The control of immunity and tolerance by dendritic cell. Pathol Biol (Paris) 2003, 51:59-60.

21. Jarrossay D, Napolitani G, Colonna M, Sallusto F, Lanzavecchia A: Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur J Immunol 2001, 31:3388-3393.

22. Palucka KA, Taquet N, Sanchez-Chapuis F, Gluckman JC: Dendritic cells as the terminal stage of monocyte differentiation. J Immunol 1998, 160:4587-4595.

23. Chomarat P, Banchereau J, Davoust J, Palucka AK: IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat Immunol 2000, 1:510-514.

24. Iwamoto S, Iwai S, Tsujiyama K, Kurahashi C, Takeshita K, Naoe M, Masunaga A, Ogawa Y, Oguchi K, Miyazaki A: TNF-alpha drives human CD14+ monocytes to differentiate into CD70+ dendritic cells evoking Th1 and Th17 responses. J Immunol 2007, 179:1449-1457.

25. Chomarat P, Dantin C, Bennett L, Banchereau J, Palucka AK: TNF skews monocyte differentiation from macrophages to dendritic cells. J Immunol 2003, 171:2262-2269.

26. Mantovani A, Bottazzi B, Colotta F, Sozzani S, Ruco L: The origin and function of tumor-associated macrophages. Immunol Today 1992, 13:265-270.

27. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A: Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002, 23:549-555.

28. Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, Bernasconi S, Saccani S, Nebuloni M, Vago L, et al.: Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med 2003, 198:1391-1402.

29. De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, Naldini L: Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 2005, 8:211-226.

30. Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, et al.: Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 2009, 325:612-616.

31. Morita Y, Moriai T, Takiyama Y, Makino I: Establishment and characterization of a new hamster pancreatic cancer cell line: the biological activity and the binding characteristics of EGF or TGF-alpha. Int J Pancreatol 1998, 23:41-50.

32. Mantovani A, Allavena P, Sozzani S, Vecchi A, Locati M, Sica A: Chemokines in the recruitment and shaping of the leukocyte infiltrate of tumors. Semin Cancer Biol 2004, 14:155-160.

33. Van Ginderachter JA, Movahedi K, Hassanzadeh Ghassabeh G, Meerschaut S, Beschin A, Raes G, De Baetselier P: Classical and alternative activation of mononuclear phagocytes: picking the best of both worlds for tumor promotion. Immunobiology 2006, 211:487-501.

34. Condeelis J, Pollard JW: Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 2006, 124:263-266.

35. Lin EY, Nguyen AV, Russell RG, Pollard JW: Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 2001, 193:727-740.

36. Wyckoff JB, Wang Y, Lin EY, Li JF, Goswami S, Stanley ER, Segall JE, Pollard JW, Condeelis J: Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 2007, 67:2649-2656.

37. Lewis CE, Pollard JW: Distinct role of macrophages in different tumor microenvironments. Cancer Res 2006, 66:605-612.

38. Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, Dolcetti L, Bronte V, Borrello I: Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 2006, 203:2691-2702.

39. Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ: Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 2009, 58:49-59.

40. Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Kruger C, Manns MP, Greten TF, Korangy F: A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 2008, 135:234-243.

41. Ochoa AC, Zea AH, Hernandez C, Rodriguez PC: Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin Cancer Res 2007, 13:721s-726s.

42. Kusmartsev SA, Li Y, Chen SH: Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation. J Immunol 2000, 165:779-785.

43. Gabrilovich DI, Bronte V, Chen SH, Colombo MP, Ochoa A, Ostrand-Rosenberg S, Schreiber H: The terminology issue for myeloid-derived suppressor cells. Cancer Res 2007, 67:425; author reply 426.

44. Nagaraj S, Gabrilovich DI: Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res 2008, 68:2561-2563.

45. Schmielau J, Finn OJ: Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients. Cancer Res 2001, 61:4756-4760.

46. Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI: Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 2001, 166:678-689.

47. Rodriguez PC, Ochoa AC: T cell dysfunction in cancer: role of myeloid cells and tumor cells regulating amino acid availability and oxidative stress. Semin Cancer Biol 2006, 16:66-72.

48. Serafini P, De Santo C, Marigo I, Cingarlini S, Dolcetti L, Gallina G, Zanovello P, Bronte V: Derangement of immune responses by myeloid suppressor cells. Cancer Immunol Immunother 2004, 53:64-72.

49. Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J, Divino CM, Chen SH: Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res 2006, 66:1123-1131.

50. Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S: Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol 2007, 179:977-983.

51. Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP: Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 1996, 2:1096-1103.

52. Melani C, Chiodoni C, Forni G, Colombo MP: Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity. Blood 2003, 102:2138-2145.

53. Zou W, Machelon V, Coulomb-L'Hermin A, Borvak J, Nome F, Isaeva T, Wei S, Krzysiek R, Durand-Gasselin I, Gordon A, et al.: Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat Med 2001, 7:1339-1346.

54. Kryczek I, Lange A, Mottram P, Alvarez X, Cheng P, Hogan M, Moons L, Wei S, Zou L, Machelon V, et al.: CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res 2005, 65:465-472.

55. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, et al.: Involvement of chemokine receptors in breast cancer metastasis. Nature 2001, 410:50-56.

56. Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, Matrisian LM, Carbone DP, Lin PC: Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 2004, 6:409-421.

57. Horst AK, Bickert T, Brewig N, Ludewig P, van Rooijen N, Schumacher U, Beauchemin N, Ito WD, Fleischer B, Wagener C, et al.: CEACAM1+ myeloid cells control angiogenesis in inflammation. Blood 2009, 113:6726-6736.

58. Palmowski M, Salio M, Dunbar RP, Cerundolo V: The use of HLA class I tetramers to design a vaccination strategy for melanoma patients. Immunol Rev 2002, 188:155-163.

59. Romero P, Dunbar PR, Valmori D, Pittet M, Ogg GS, Rimoldi D, Chen JL, Lienard D, Cerottini JC, Cerundolo V: Ex vivo staining of metastatic lymph nodes by class I major histocompatibility complex tetramers reveals high numbers of antigen-experienced tumor-specific cytolytic T lymphocytes. J Exp Med 1998, 188:1641-1650.

60. Yu P, Lee Y, Liu W, Chin RK, Wang J, Wang Y, Schietinger A, Philip M, Schreiber H, Fu YX: Priming of naive T cells inside tumors leads to eradication of established tumors. Nat Immunol 2004, 5:141-149.

61. Inagaki A, Ishida T, Ishii T, Komatsu H, Iida S, Ding J, Yonekura K, Takeuchi S, Takatsuka Y, Utsunomiya A, et al.: Clinical significance of serum Th1-, Th2- and regulatory T cells-associated cytokines in adult T-cell leukemia/lymphoma: high interleukin-5 and -10 levels are significant unfavorable prognostic factors. Int J Cancer 2006, 118:3054-3061.

62. Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, Fuh G, Gerber HP, Ferrara N: Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol 2007, 25:911-920.

63. Kaser A, Winklmayr M, Lepperdinger G, Kreil G: The AVIT protein family. Secreted cysteine-rich vertebrate proteins with diverse functions. EMBO Rep 2003, 4:469-473.

64. Shojaei F, Singh M, Thompson JD, Ferrara N: Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proc Natl Acad Sci U S A 2008, 105:2640-2645.

65. Shojaei F, Zhong C, Wu X, Yu L, Ferrara N: Role of myeloid cells in tumor angiogenesis and growth. Trends Cell Biol 2008, 18:372-378.

66. Shojaei F, Wu X, Qu X, Kowanetz M, Yu L, Tan M, Meng YG, Ferrara N: G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci U S A 2009, 106:6742-6747.

67. Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich CR, Gastroph S, Wischnik A, Dimpfl T, Kindermann G, et al.: Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 2000, 342:525-533.

68. Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L, et al.: Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 2001, 7:1194-1201.

69. Rafii S, Lyden D, Benezra R, Hattori K, Heissig B: Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat Rev Cancer 2002, 2:826-835.

70. Bertolini F, Shaked Y, Mancuso P, Kerbel RS: The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nat Rev Cancer 2006, 6:835-845.

71. Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal V: Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 2008, 319:195-198.

72. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, et al.: VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005, 438:820-827.

73. Maruyama K, Ii M, Cursiefen C, Jackson DG, Keino H, Tomita M, Van Rooijen N, Takenaka H, D'Amore PA, Stein-Streilein J, et al.: Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J Clin Invest 2005, 115:2363-2372.

74. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K: Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 1997, 276:1423-1425.

75. Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, Diem K, Weninger W, Tschachler E, Alitalo K, et al.: Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 1999, 154:385-394.

76. Kerjaschki D: The crucial role of macrophages in lymphangiogenesis. J Clin Invest 2005, 115:2316-2319.

77. Jeon BH, Jang C, Han J, Kataru RP, Piao L, Jung K, Cha HJ, Schwendener RA, Jang KY, Kim KS, et al.: Profound but dysfunctional lymphangiogenesis via vascular endothelial growth factor ligands from CD11b+ macrophages in advanced ovarian cancer. Cancer Res 2008, 68:1100-1109.

78. Zeisberger SM, Odermatt B, Marty C, Zehnder-Fjallman AH, Ballmer-Hofer K, Schwendener RA: Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br J Cancer 2006, 95:272-281.

79. Iwata C, Kano MR, Komuro A, Oka M, Kiyono K, Johansson E, Morishita Y, Yashiro M, Hirakawa K, Kaminishi M, et al.: Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis. Cancer Res 2007, 67:10181-10189.

80. Yu H, Kortylewski M, Pardoll D: Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 2007, 7:41-51.

81. Dey R, Ji K, Liu Z, Chen L: A cytokine-cytokine interaction in the assembly of higher-order structure and activation of the interleukine-3:receptor complex. PLoS One 2009, 4:e5188.

82. Dedeoglu F, Horwitz B, Chaudhuri J, Alt FW, Geha RS: Induction of activation-induced cytidine deaminase gene expression by IL-4 and CD40 ligation is dependent on STAT6 and NFkappaB. Int Immunol 2004, 16:395-404.

83. Okada E, Yamazaki M, Tanabe M, Takeuchi T, Nanno M, Oshima S, Okamoto R, Tsuchiya K, Nakamura T, Kanai T, et al.: IL-7 exacerbates chronic colitis with expansion of memory IL-7Rhigh CD4+ mucosal T cells in mice. Am J Physiol Gastrointest Liver Physiol 2005, 288:G745-754.

84. Andersson A, Yang SC, Huang M, Zhu L, Kar UK, Batra RK, Elashoff D, Strieter RM, Dubinett SM, Sharma S: IL-7 promotes CXCR3 ligand-dependent T cell antitumor reactivity in lung cancer. J Immunol 2009, 182:6951-6958.

85. Chan DA, Kawahara TL, Sutphin PD, Chang HY, Chi JT, Giaccia AJ: Tumor vasculature is regulated by PHD2-mediated angiogenesis and bone marrow-derived cell recruitment. Cancer Cell 2009, 15:527-538.

86. Hornakova T, Staerk J, Royer Y, Flex E, Tartaglia M, Constantinescu SN, Knoops L, Renauld JC: Acute lymphoblastic leukemia-associated JAK1 mutants activate the Janus kinase/STAT pathway via interleukin-9 receptor alpha homodimers. J Biol Chem 2009, 284:6773-6781.

87. Bollrath J, Phesse TJ, von Burstin VA, Putoczki T, Bennecke M, Bateman T, Nebelsiek T, Lundgren-May T, Canli O, Schwitalla S, et al.: gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 2009, 15:91-102.

88. Hebenstreit D, Wirnsberger G, Horejs-Hoeck J, Duschl A: Signaling mechanisms, interaction partners, and target genes of STAT6. Cytokine Growth Factor Rev 2006, 17:173-188.

89. Correia MP, Cardoso EM, Pereira CF, Neves R, Uhrberg M, Arosa FA: Hepatocytes and IL-15: a favorable microenvironment for T cell survival and CD8+ T cell differentiation. J Immunol 2009, 182:6149-6159.

90. Laurence A, Astoul E, Hanrahan S, Totty N, Cantrell D: Identification of pro-interleukin 16 as a novel target of MAP kinases in activated T lymphocytes. Eur J Immunol 2004, 34:587-597.

91. Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H: IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med 2009, 206:1457-1464.

92. Sattler A, Wagner U, Rossol M, Sieper J, Wu P, Krause A, Schmidt WA, Radmer S, Kohler S, Romagnani C, et al.: Cytokine-induced human IFN-gamma-secreting effector-memory Th cells in chronic autoimmune inflammation. Blood 2009, 113:1948-1956.

93. Chada S, Bocangel D, Ramesh R, Grimm EA, Mumm JB, Mhashilkar AM, Zheng M: mda-7/IL24 kills pancreatic cancer cells by inhibition of the Wnt/PI3K signaling pathways: identification of IL-20 receptor-mediated bystander activity against pancreatic cancer. Mol Ther 2005, 11:724-733.

94. Akamatsu N, Yamada Y, Hasegawa H, Makabe K, Asano R, Kumagai I, Murata K, Imaizumi Y, Tsukasaki K, Tsuruda K, et al.: High IL-21 receptor expression and apoptosis induction by IL-21 in follicular lymphoma. Cancer Lett 2007, 256:196-206.

95. Ziesche E, Bachmann M, Kleinert H, Pfeilschifter J, Muhl H: The interleukin-22/STAT3 pathway potentiates expression of inducible nitric-oxide synthase in human colon carcinoma cells. J Biol Chem 2007, 282:16006-16015.

96. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V: Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12:253-268.

97. Mussai F, De Santo C, Abu-Dayyeh I, Booth S, Quek L, McEwen-Smith RM, Qureshi A, Dazzi F, Vyas P, Cerundolo V: Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment. Blood 2013, 122:749-758.

Author Column

Dr. Shapira

Dr. Iuliana Shapira is the Director of Cancer Genetics at Monter Cancer Center and Associate Professor of Medicine at Hofstra North Shore Long Island Jewish School of Medicine. She served as investigator for the Cancer and Leukemia Group B (CALGB) and serves currently in the Audit Committee and Health Outcomes Committee of the Alliance for Clinical Trials in Oncology. Her major research interests have been the breast cancer, translational epigenetic research in microRNA and genetics. As such, she has published over 90 peer-reviewed articles and abstracts. She serves as an Associate editor for the Molecular Medicine, Translational and Clinical Biology & Onco Reviews and reviewer for five cancer journals.