The Monocyte, a Maestro in the Tumor Microenvironment (TME) of Breast Cancer

Abstract

Breast cancer (BC) is well-known for being a leading cause of death worldwide. It is classified molecularly into luminal A, luminal B HER2-, luminal B HER2+, HER2+, and triple-negative breast cancer (TNBC). These subtypes differ in their prognosis; thus, understanding the tumor microenvironment (TME) makes new treatment strategies possible. The TME contains populations that exhibit anti-tumorigenic actions such as tumor-associated eosinophils. Moreover, it contains pro-tumorigenic populations such as tumor-associated neutrophils (TANs), or monocyte-derived populations. The monocyte-derived populations are tumor-associated macrophages (TAMs) and MDSCs. Thus, a monocyte can be considered a maestro within the TME. Moreover, the expansion of monocytes in the TME depends on many factors such as the BC stage, the presence of macrophage colony-stimulating factor (M-CSF), and the presence of some chemoattractants. After expansion, monocytes can differentiate into pro-inflammatory populations such as M1 macrophages or anti-inflammatory populations such as M2 macrophages according to the nature of cytokines present in the TME. Differentiation to TAMs depends on various factors such as the BC subtype, the presence of anti-inflammatory cytokines, and epigenetic factors. Furthermore, TAMs and MDSCs not only have a role in tumor progression but also are key players in metastasis. Thus, understanding the monocytes further can introduce new target therapies.

Keywords: IL-10; TNBC; breast cancer; monocyte-derived populations; monocytes; tumor microenvironment; tumor-associated macrophages.

Figure 1

TAMs in the breast cancer TME. 1. The effect of TAMs on T cells: 1.a. TAMs can suppress T-cell proliferation via the programmed death-ligand 1 (PDL-1) [42]. 1.b. TGF-beta affects T-cell function by upregulation of PDL-1 on TAMs [42]. 1.c. Tregs are induced by IL-10, TGF-B, and PDGF-2, thus suppressing T cells [45]. 1.d. Treg recruitment happens through CCL7/8/22 [45]. 1.e. Increased activity of arginase enzyme and iNOS result in the increased level of NO and RNOS (ONOO⁻) leading to nitrosylation and thus impairing T-cell self-stimulation by IL-2 in addition to nitration of TCR signaling complex altering T-cell function [23]. 2. The effect of TAMs on NK cells: 2.a. The inhibitory effect of TAMs can be due to the expression of PDL-1 (which is highly expressed on TAMs) or 2.b. it can be due to TGF-B secretion [42]. 2.c. TAMs also suppress NK IFN-Y production [42]. 3. TAMs induce angiogenesis by releasing VEGF, PDGF, and IL-8 [23]. 4. Interaction between TAMs and cancer cells: 4.a. It was observed that VCAM1+ tumor cells have increased survival in a leukocyte-rich environment due to the adhesion of leukocyte receptors on BC cells (VCAM1) to TAM α 4 integrin [21]. 4.b. TGF-B was shown to upregulate PDL-1 on cancer cells, thus inducing an inhibitory effect on immune cells [23]. 4.c. There is a paracrine loop between cancer cells and TAMs. TAMs secrete epidermal growth factor (EGF) that binds to EGFRs on the cancer cells [21]. 4.d. TAMs express M-CSFR, which is a monocyte colony-stimulating factor receptor also known as colony-stimulating factor 1 receptor (CSF-1R or cFMS). The M-CSFR binds to the M-CSF (CSF-1) that is produced by cancer cells [41]. The binding of cancer cells with TAMs allows the co-migration of two different cell types, thus enhancing invasion, motility, and intravasation [21]. 5. CD163 and C206 are considered the commonly used self-markers for TAMs. 6. MCP-1 is a monocyte recruiter that is produced by TAMs; monocytes respond to TME and differentiate into TAMs [46]. 7.a. TAMs coordinate in the extracellular proteolysis through the secretion of tissue-remodeling cysteine cathepsin proteases that contribute to ECM and collagen degradation [47]. 7.b. Moreover, MMPs contribute to collagen degradation. Types I, III, IV, and VI are the major collagens that play an important role in tumors [47]. Myeloid cells remodel ECM by degrading the collagen through matrix metalloproteinases (MMPs) [34].

Figure 2

IL-10: key inducers and key anti-inflammatory mechanisms. a. Inducing agents increase the release of IL-10 from different immune cells [25,54,55] b. IL-10 acts as an inhibitor for a number of pro-inflammatory cytokines released by macrophages/monocytes. c. IL-10 induces a small subset of genes in human monocytes [56]. d. IL-10 is an inhibitor for NF-kB (nuclear localization of nuclear factor kB), a transcriptional factor responsible for the expression of inflammatory genes; however, other transcriptional factors such as NF-IL6, AP-1, and AP-2 were not affected by IL-10 [57].

Figure 3

Role of TAMs and MDSCs in metastasis: 1. Tumor growth and invasion. 1.a. TAMs produce MMPs (MMP1/2/3/7/9) and cathepsin. 1.b. Chemokines such as acidic and rich in cysteine (SPARC), chemokine (C-C motif) ligand 18 (CCL18), αvβ5 integrins, phosphatidylinositol transfer protein 3 (PITPNM3), epidermal growth factor (EGF), EGF receptor (EGFR), colony-stimulating factor 1 (CSF-1), and CSF-1 receptor (CSF-1R) allow the interaction between tumor cells, thus facilitating the invasion step [72].1.c. MDSCs facilitate the invasion step by producing MMPs and TGF-beta [73]. 2. Intravasation. 2.a. TAMs and MDSCs release VEGF-A [72,73]. 3. Extravasation. 3.a. Metastasis-associated macrophages (MAMs) accumulate at the metastatic site and also release VEGF-A. 3.b. The CCL2-CCR2 signaling pathway activates the CCL3-CCR1 signaling pathway in MAMs, leading to their accumulation in the metastatic site and thus attracting more tumor cells and prolonging the process of seeding. 4. Seeding [72]. 5. The metastatic niche in the lungs is induced by MDSCs through the production of CXCL-17 which recruits more MDSCs in the lungs, leading to an increase in the levels of platelet-derived growth factor-beta (PDGF-beta) that will induce angiogenesis, thus creating favorable conditions for metastatic cells [74].