Mechanisms of Macrophage Plasticity in the Tumor Environment: Manipulating Activation State to Improve Outcomes

Abstract

Macrophages are a specialized class of innate immune cells with multifaceted roles in modulation of the inflammatory response, homeostasis, and wound healing. While developmentally derived or originating from circulating monocytes, naïve macrophages can adopt a spectrum of context-dependent activation states ranging from pro-inflammatory (classically activated, M1) to pro-wound healing (alternatively activated, M2). Tumors are known to exploit macrophage polarization states to foster a tumor-permissive milieu, particularly by skewing macrophages toward a pro-tumor (M2) phenotype. These pro-tumoral macrophages can support cancer progression by several mechanisms including immune suppression, growth factor production, promotion of angiogenesis and tissue remodeling. By preventing the adoption of this pro-tumor phenotype or reprogramming these macrophages to a more pro-inflammatory state, it may be possible to inhibit tumor growth. Here, we describe types of tumor-derived signaling that facilitate macrophage reprogramming, including paracrine signaling and activation of innate immune checkpoints. We also describe intervention strategies targeting macrophage plasticity to limit disease progression and address their implications in cancer chemo- and immunotherapy.

Transcriptional Profiling of Mouse Eosinophils Identifies Distinct Gene Signatures Following Cellular Activation

“…Over the past years it has become increasingly apparent that immune cells display marked plasticity ( 43 , 44 ). Within the myeloid lineage, this has been best characterized in macrophages where in vitro modeling of macrophage activations states has been widely applied for molecular and biomarker profiling ( 14 ).…”

The Role of Tumor-Associated Macrophages in Hematologic Malignancies

“…Macrophages are characterized by remarkable plasticity and were initially divided into six subtypes (immunosuppressive, angiogenic, metastasis-associated, invasive, activated and perivascular), depending on the stimuli that trigger their activation [ 20 ]. However, in the currently accepted classification, even if oversimplified, TAM have been divided into M1 (classically activated) and M2 (alternatively activated), probably representing the 2 extremities of a continuous spectrum [ 21 , 22 , 23 ]. Due to this different polarization, which occurs in the tissue, M1 TAM could provoke a Th-1 response and play an antineoplastic effect leading to tumor suppression, while M2 TAM, with a low antigen-presenting capacity, could promote tumor growth and survival by inducing angiogenesis and immunosuppression [ 24 ].…”

“…Due to this different polarization, which occurs in the tissue, M1 TAM could provoke a Th-1 response and play an antineoplastic effect leading to tumor suppression, while M2 TAM, with a low antigen-presenting capacity, could promote tumor growth and survival by inducing angiogenesis and immunosuppression [ 24 ]. In particular, as shown in Figure 1 and Figure 2 , the M1 subtype, triggered by GM-CSF, bacterial products and interferon-γ, could secrete pro-inflammatory molecules, such as interleukin (IL)-1, IL-6, IL-12, IL-23, TNF-α, NO, CXCL9, CXCL10, CXCL11 and reactive oxygen species; conversely, the M2 subtype is activated by IL-4, IL-10, IL-13 and express anti-inflammatory molecules, such as IL-10, tumor growth factor (TGF-β), CCL17, CCL18, CCL22, mannose receptor C type 1 (CD206), class A scavenger receptor (CD204) and hemoglobin scavenger receptor (CD163), which are currently used as M2-associated markers [ 21 , 22 , 23 , 24 ].…”

The Proper Administration Sequence of Radiotherapy and Anti-Vascular Agent—DMXAA Is Essential to Inhibit the Growth of Melanoma Tumors

“…Macrophages play an essential role in obtaining effective cancer therapy. Their polarization from the pro-cancer M2 phenotype to the anti-cancer M1 phenotype is particularly important [59][60][61]. M1 macrophages, besides their phagocytic properties, are responsible for changes in tumor blood vessels and the microenvironment in tumors [62].…”