The Innate Immune Microenvironment in Metastatic Breast Cancer

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1		Chiara Tommasi	--	3113	2022-11-21 15:03:53	\|
2	format correct	Vivi Li	Meta information modification	3113	2022-11-23 05:33:05	\|

This entry is adapted from the peer-reviewed paper 10.3390/jcm11205986

The immune system plays a fundamental role in neoplastic disease. In the era of immunotherapy, the adaptive immune response has been in the spotlight whereas the role of innate immunity in cancer development and progression is less known. The tumor microenvironment influences the terminal differentiation of innate immune cells, which can explicate their pro-tumor or anti-tumor effect. Different cells are able to recognize and eliminate no self and tumor cells: macrophages, natural killer cells, monocytes, dendritic cells, and neutrophils are, together with the elements of the complement system, the principal players of innate immunity in cancer development and evolution. Metastatic breast cancer is a heterogeneous disease from the stromal, immune, and biological point of view and requires deepened exploration to understand different patient outcomes.

innate immunity metastatic breast cancer tumor-immune microenvironment tumor-associated macrophages dendritic cells tumor-associated neutrophiles

1. Introduction: Immune Response and Metastatic Spread

Metastatic disease is the major cause of morbidity and mortality in breast cancer (BC) patients ^[1]. From the very early phases of tumor development, interactions between tumor cells and the immune environment are remarkably tight. The immune system is first able to recognize and eliminate malignant cells, and the sole cells that are able to escape from immune surveillance will survive and proliferate. Immune cells and soluble factors are also important players in the following phases of dormancy, when disseminated tumor cells (DTCs) remain in a latent state as micrometastases, that afterwards will undergo progression, invasiveness, and metastasis ^[2].

Metastatic organotropism of BC is directed to the bones, liver, lung, brain, and skin. Organ-specific tissue-resident stromal cells (e.g., fibroblasts and epithelial cells in lung, liver Kuppfer cells, and brain endothelial cells) play a crucial role in homing metastatic cells and preparing the pre-metastatic niche ^[3], where immune cells are recruited and are able to create a permissive growth environment before the arrival of tumor cells ^[4].

Myeloid cells such as tumor-associated macrophages (TAMs) and neutrophils (TANs) can promote metastatic spread through blood and lymphatic vessels via the production of matrix metalloproteinases (MMPs) involved in the degradation of extracellular substrates such as collagen. Cytokines, such as interleukin (IL)-1, tumor necrosis factor (TNF)-α, and IL-6, can also determine invasiveness and metastasis. Transforming growth factor-β (TGF-β) produced by TAMs, myeloid-derived suppressor cells (MDSCs), and cancer-associated fibroblasts (CAFs) are regulators of the epithelial–mesenchymal transition and metastasis. TNF-α and IL-6 sustain the survival of tumor cells that reach blood and lymphatic circulation. The increased levels of circulating cytokines in the serum of cancer patients are thought to increase the expression of adhesion molecules on the endothelium or in target organs and chemokine–chemokine receptor interactions are responsible for the guided migration of tumor cells to future specific target metastatic sites. Homing to specific sites is followed by extravasation into tissues, and the adaptation of tumor cells to a foreign environment through interactions with immune, inflammatory, and stromal cells of the new niche. After reaching the secondary organ site, metastatic cells can either proliferate or enter a dormant state. By creating a pre-metastatic niche ^[5], delivering site-specific chemo-attractants ^[6], and forming a favorable milieu ^[7]^[8]^[9], the tumor immune environment (TIM) plays a major role in determining whether tumor cells will progress towards clinically manifested metastases ^[10].

2. The Cells of Innate Immunity and Their Role According to the Site of Metastases

In physiological conditions, myeloid cells maintain homeostasis during the processes of tissue repair and remodeling. They are released in the bloodstream from hematopoietic stem cells. In the bone marrow microenvironment, a multistep process leads to the formation of common lymphoid progenitors and common myeloid progenitors (CMPs) ^[11]. Granulocyte/macrophage lineage-restricted progenitors (GMPs) are born from CMPs and are precursors of macrophages, dendritic cells, and granulocytes (basophils, eosinophils, and neutrophils) ^[11]. The terminally differentiated myeloid cells are essential to combat infections and in the scavenger process through antigen presentation ^[12].

In tumors, myeloid cells enhance tumor growth through the secretion of soluble factors, playing a role in the promotion of angiogenesis, invasion, and metastases. The release of factors by tumor and stromal cells from TIM generates MDSCs, which influence the adaptive immune response. On the other hand, TIM is able to convert terminally differentiated myeloid cells into potent immunosuppressive cells ^[13].

Malignant transformation, tumor vascularization, and neoplastic cell migration can be driven by bone marrow-derived cells (BMDCs).

Figure 1 shows the different cells of the innate immune system involved in the BC metastatic niche.

Figure 1. The role of the tumor microenvironment in the composition of the tumor niche in breast cancer. Abbreviations: N1: tumor-associated neutrophil type 1; N2: tumor-associated neutrophil type 2; M1: tumor-associated macrophage type 1; M2: tumor-associated macrophage type 2; NK cell: natural killer cell.

2.1. Monocytes (M-DSCs)

Monocyte-derived suppressor cells (M-DSCs) originate from hematopoietic stem cells and then localize within TIM ^[7]. Different signals are involved in the recruitment of circulating monocytes in tissues, where they can differentiate into monocyte-derived macrophages or monocyte-derived dendritic cells ^[14].

M-DSCs are able to suppress in vitro T cell activation ^[15]: they can influence innate and adaptive immune responses by depleting nutrients that are essential for lymphocytes, generating oxidative stress, influencing lymphocyte trafficking and viability, and activating and expanding regulatory T cells (Treg) ^[7] while suppressing CD8⁺ T cell activity ^[16]. The imbalance between host anti-tumor immunity and tumor tolerance is mediated by monocyte chemoattractant protein-1 (MCP-1) ^[17]. CD14⁺CD16⁺ monocytes are stimulated by MCP-1: they are elevated in the serum of BC patients and their levels are associated with the tumor size and stage ^[17].

Colony-stimulating factor-1 (CSF-1), released from invasive BC cells, induces monocytes’ secretion of chemokine C–X–C motif ligand 7 (CXCL7), which enhances the chemotaxis of monocytes in BC sites. Recruited monocytes into TMI enhance the invasive behavior of BC cells, resulting in the progression of tumor size and distant metastases ^[18].

The immunosuppressive intrahepatic environment restricts the endogenous anti-tumor immunity. In addition, liver M-DSCs expand in response to granulocyte-macrophage colony-stimulating factor (GM-CSF), suppressing anti-tumor immunity in BC liver metastases ^[19]. The majority of liver M-DSCs co-express GM-CSF receptor (GM-CSF-R), indoleamine 2,3-dioxygenase (IDO), and programmed death-ligand 1 (PD-L1): a reduction in IDO and PD-L1 expression has been observed through the GM-CSF or GM-CSF-R blockade or with the use of small-molecule inhibitors of Janus-activated kinase 2 (JAK2) and STAT3 ^[20].

CD137 is a member of the TNF receptor superfamily, and it was found to increase the adherence of monocytes, regulating the migration of monocytes/macrophages to TIM both in vitro and in vivo. Moreover, CD137 promoted their differentiation into osteoclasts, favoring the colonization of BC cells in the bone ^[21].

2.2. Macrophages

Macrophages are a group of tissue-resident myeloid cells derived from circulating or tissue-resident macrophages originating from Yolk sac precursor cells ^[13]^[22]. Resident macrophages from different tissues are specific and different according to the corresponding organ site ^[23]: for example, they produce TGF-β in the brain ^[24], PPAR-γ in the alveoli ^[25], and GM-CSF in the liver (where they are called Kupffer cells) ^[26].

TAMs act on primary tumor growth, the anti-tumor adaptive immune response, and angiogenesis, stromal remodeling, and metastatic genesis and evolution (Figure 2) ^[27]. Hypoxia, cytokines such as IL-4 and IL-13 (produced by T helper (Th)2 cells) or IL-10 (produced by Treg), metabolic products of tumor cells, and immune complexes may determine the functional phenotype of TAMs: they can be polarized within “classical” or “pro-inflammatory” M1 macrophages, which switch their metabolism towards enhanced anaerobic glycolysis, pentose phosphate pathway activation, and protein and fatty acid synthesis under the influence of interferon (IFN)-γ, NF-κB, STAT-1, and IRF-5. On the other hand, cytokines such as IL-4, IL-13, and MYC influence the development of “alternative” M2 macrophages, having pro-tumor activity, with angiogenesis induction. M2 polarization of TAMs can also be induced by other signals, such as the presence of immune complexes with or without lipopolysaccharide or IL-1, IL-10, and TGF-β ^[28]. CSF-1 and C-C motif ligand 2 (CCL2) are the most important factors involved in M2 polarization and are involved in the recruitment of TAMs in TIM ^[29].

Figure 2. Cytokines and chemokines involved in macrophagic polarization. Tumoral and stromal cells secrete growth factors involved in monocyte attraction and macrophagic differentiation in M1 pro-inflammatory macrophages, with anti-tumor function, and M2 alternative macrophages, with pro-apoptotic activity.

Elevated macrophage CSF-1 levels are correlated with marked M2 macrophage infiltration in human metastatic BC ^[30]. In fact, metastasized primary BC had higher tumor epithelial and stromal expressions of CSF-1 (p < 0.001 and p = 0.002, respectively) and CSF-1R (both p = 0.03) compared to non-metastatic cancers ^[31]. A high expression of CSF-1/CSF-1R and a high density of TAMs and CD3⁺ T-lymphocytes create an immunosuppressive tumour milieu ^[32] that is related to tumoral immune escape through the inhibition of T lymphocytes and to BC progression ^[31].

Chemokine MCP-1 and CCL2 synthesis, produced by both tumor and stromal cells ^[33], mediates the recruitment of C-C chemokine receptor 2 (CCR2) monocytes (receptor for CCL2) and their subsequent differentiation into metastasis-associated macrophages (MAMs) ^[34]^[35].

2.3. Dendritic Cells (DCs)

DCs are professional antigen-presenting cells (APCs) that can positively or negatively influence the adaptive immune response ^[36]. As terminally differentiated myeloid cells, DCs specialize in antigen processing and presentation and monocytes are their major precursors in humans. These cells reside in tissues in an immature, non-active state ^[7]. They become activated and undergo maturation in response to stimuli associated with bacteria, viruses, and tissue damage ^[7]. Only functional activated DCs are able to stimulate an effective T cell response. In cancer, DCs undergo abnormal differentiation, with decreased production of mature functionally competent DCs, increased accumulation of immature DCs at the tumor site, and increased production of immature myeloid cells ^[37]. DCs and macrophages first recognize and bind to the dying BC cells or release tumor-associated antigens through pattern recognition receptors (PRRs) ^[38]. PRRs can identify and recognize the damage-associated molecular patterns (DAMPs), which are derived from the tumor or dying cells to drive intrinsic tumor inflammation ^[38].

GM-CSF with IL-4 is a potent growth factor for DCs ^[39]. BC-derived GM-CSF has a pro-tumor role and high levels of endogenous GM-CSF are associated with metastasis, progression, and reduced survival in patients with BC ^[40]. On the other hand, patients treated with neoadjuvant chemotherapy and exogenous GM-CSF showed a significantly higher mean percentage of DCs in TIM, with a longer disease-free survival ^[41].

RANKL augments the ability of DCs to stimulate naïve T lymphocyte proliferation ^[42], whereas activated T lymphocytes that express RANKL enhance the survival of DCs, increasing inflammation ^[43]^[44]. On the other hand, RANKL induced in keratinocytes can regulate the activation of DCs and induce immunosuppression, which is crucial for the peripheral homeostasis of Tregs ^[45].

2.4. Tumor-Associated Neutrophils (TANs)

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature ^[46]. The presence of granulocytes, particularly neutrophils, has been linked with tumor angiogenesis and metastases ^[47]. Tumors may polarize neutrophil phenotypes during tumor progression, resulting in either tumor destruction or survival at metastatic sites ^[47].

The precise role of neutrophils in metastasis remains uncertain ^[47]. In fact, neutrophils can have dichotomic polarization, being able to shift from an anti-tumor (N1) to a pro-tumor (N2) profile ^[48]. TGF-β in TIM mediates the transformation between the N1, which involves pro-inflammatory neutrophiles with the capacity to stimulate effector T lymphocytes, and the N2 phenotype, which has pro-tumor activity with immunosuppressive and angiogenic features ^[49]. Of interest, the tumor-promoting activity of TANs can be reversed to an anti-tumor role with TGF-β blockade ^[50].

N1 neutrophils can exert anti-tumor functions through an antibody-dependent cellular cytotoxicity (ADCC) effect, producing radical oxygen species (ROS), TNF-α, and nitric oxide with a direct killing effect, and inhibiting suppressive cells, such as IL-17-producing γδ T lymphocytes. To the contrary, N2 can produce CCL2 and CCL17 to recruit CD4⁺ T cells and anti-inflammatory macrophages together with arginase-1 to inhibit CD8⁺ T lymphocyte activation, promoting an immunosuppressive TIM. They also promote tumor angiogenesis, releasing MMP9 and VEGF, and promote tumor cell proliferation and EMT via IL-6, IL-1β, and IL-17 release ^[51].

Upon arrival in the pre-metastatic niche, BMDCs secrete factors that facilitate tumor cell survival and growth ^[6]^[52]. In a preclinical BC study, TANs were the predominant population in the early/pre-metastatic lung, and their depletion reduced metastases to the lung ^[52]. In a mice model, the administration of G-CSF increased neutrophil recruitment and accumulation in primary tumors and blood, leading to an increased metastatic capacity and reduced survival ^[52].

2.5. Mast Cells and Natural Killer (NK) Cells

Mast cells are derived from hematopoietic stem cells. They secrete cytokines that are involved in T lymphocyte responses. In addition, mast cells are able to influence natural killer (NK) activity through the release of granzyme B ^[53]. They also play a role in tissue remodeling by releasing enzymes in the microenvironment and by interacting with fibroblasts and myofibroblasts. They secrete TGF-β1, an enhancer of fibrogenesis and extracellular matrix production, and proteases activate MMPs ^[54]. A high mast cell density has been correlated with lymph-node metastases ^[55]^[56]. Mediators released by mast cells (histamine, TNF, VEGF, and tryptase) can increase vascular permeability, enhancing the extravasation and metastatic spread by tumor cells ^[57]. In a BC cell line model, human mast cells were shown to enhance the invasive property of tumor cells through the HLA-G–KIR2DL4 axis ^[53].

Among the cells of the innate immunity, NK cells are able to recognize and kill tumor cells expressing stress-ligands and non-expressing MHC-I on their surface. NK are activated by MHC-I-negative cells, priming local DCs and stimulating a strong protective response by CD8⁺ T lymphocytes. Given that the disseminated metastatic cells recovered MHC-I cell surface expression, they might be recognized and kept in dormancy by CD8⁺ T lymphocytes ^[2].

NK cells play different roles in the various stages of tumor development ^[58]. In the primary tumor, they can promote potent anti-tumor functions and can be inhibited by M-MDSCs and Tregs. In peripheral blood, they are able to recognize and kill DTCs that are not coated by platelets. In the pre-metastatic niche, NK cells can be part of tumor-infiltrating leukocytes before CTCs seeding; in metastatic lesions, NK cells can be suppressed by IL-10, TGF-β, and adenosine, leading to increased tumor growth ^[58]. NK cells can also induce the activation of DCs, stimulating the adaptive immune response. These cells are also involved in keeping a check on DTCs during the phases of tumor dormancy. In bone marrow from BC patients, DTCs and several immune subpopulations, including NK cells, macrophages, and T lymphocytes, were observed. They had increased expression of markers of activation, proliferation, co-stimulation, and memory ^[59].

The percentages of conventional regulatory NK cells in BC tissue were positively correlated with the tumor size (higher percentages in T3 compared with smaller T1) ^[60]. The percentages of NK cells expressing activation markers such as NKG2A, CXCR3, Granzyme B, and Perforin, were not significantly different between patients based on the clinicopathological characteristics and different BC phenotypes ^[60]. The accumulation of NK cells and the expression of activating NKG2D receptor by tumor-infiltrating NK cells may play roles in BC regression. Indeed, NKG2D was expressed in about half of the NK cells accumulated at the site of tumor and was observed to be more frequent in node-negative BC patients ^[60].

In an immunocompetent BALB/c mice model, the rupture of the balance between NK cells and hepatic stellate cells (HSCs) results in the reversal of dormancy of the BC milieu in the liver. Increased levels of IL-15 induce the proliferation of NK cells, and the dormancy of BC cells is achieved through IFN-γ-induced quiescence. The activation of HSCs and the secretion of CXCL12 act on CXCR4 in NK cells and determines their quiescency. CXCL12 expression and HSC abundance are closely correlated in patients with liver metastases, mirroring the interplay between the immune response and the hepatic microenvironment ^[61].

In tumor-bearing immunocompetent mice, NK cells may promote the development of a cytotoxic immune response, independent of CD4⁺ T lymphocytes, as the depletion of CD8⁺ T lymphocytes promoted the onset of lung metastases ^[2].

In a mice model, the administration of an antibody targeting CD96 in NK cells protected against the experimental development of lung metastases, and this repression required the presence of NK and IFN-γ ^[62]. Of note, a combination of an anti-CD96 with the cytotoxic T lymphocyte-associated protein-4 (CTLA-4) or with the anti-programmed cell death protein-1 (PD-1) immune checkpoint-blocking agents showed an anti-metastatic activity. Particularly, anti-PD-1 in association with anti-CD96 increased the function of lung NK cells, leading to tumor regression. NK cells were critical for the anti-tumor activity of this combination but not T lymphocytes, as shown by the effects exerted by the depletion of CD4⁺ and CD8⁺ T lymphocytes ^[62].

In addition, in a mouse model of BC brain metastases, the administration of EGFR-CAR NK cells alone or in combination with an oncolytic herpes virus-1 resulted in more efficient eradication of tumor cells in vitro and more efficient killing of MDA-MB-231 tumor cells in an intracranial model ^[63].

2.6. Complement System

The complement system is a cascade of serine proteases encoded by genes originating from the same ancestral genes as coagulation proteins. Its activation involves several steps and is tightly regulated. Many complement proteins possess dual functions that provide crosstalk between the complement system and other effector and regulatory systems. As a result, the complement system participates in adaptive immunity, hemostasis, and organ development in addition to its role in innate immunity ^[64]. The extracellular body compartment is the main environment for the activation of the plasmatic complement system cascade ^[65].

The complement system is known to play a dual role in cancer ^[66]. As a fundamental part of the innate immunity, it is capable of targeting tumor cells and managing the immune response against the tumor ^[66]. On the other hand, as a potent pro-inflammatory mechanism, the complement system is thought to substantially contribute to tumor growth by generating a chronic inflammation state that facilitates mobilization of immune suppressor cells and supports angiogenesis ^[66].

In BC, local expression of complement inhibitors was reported as a mechanism of evading cytotoxic complement function ^[65]. In primary BC, the expression of factor I of complement and CD46 correlated with a larger tumor size, higher grade, and poor prognosis ^[65]. Moreover, in animal models of BC, the complement system has a role in lung premetastatic niche formation ^[67]. Anaphylatoxin C5a, released from C5 by tumor cells, binds to C5a receptor (C5aR) and acts as a leukocyte chemoattractant and inflammatory mediator. C5aR expression in BC is associated with poor prognosis and more extensive nodal involvement ^[68].

Using two murine BC models (EMT6 and 4T1), treatment with a dual C3aR/C5aR1 agonist significantly slowed mammary tumor development and progression, suggesting that complement activation peptides can influence the anti-tumor response in different ways ^[69].

Over-sulfated glycosaminoglycans (GAGs) induce thrombin generation through contact system activation. Plasma from BC patients contains activated contact systems for the absence of high-molecular-weight kininogen and processed C1-inh (molecules of the complement system), abnormal kallikrein and thrombin activities, and increased glucosamine, galactosamine, and GAG levels. These data suggest that GAGs or other molecules produced by tumors induce abnormal thrombin generation through contact system activation, resulting in the hypercoagulable state of cancer patients ^[70]^[71].

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Chiara Tommasi

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Michele Orditura

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Update Date: 23 Nov 2022

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