The Iron Curtain: Macrophages at the Interface of Systemic and Microenvironmental Iron Metabolism and Immune Response in Cancer

Abstract

Macrophages fulfill central functions in systemic iron metabolism and immune response. Infiltration and polarization of macrophages in the tumor microenvironment is associated with differential cancer prognosis. Distinct metabolic iron and immune phenotypes in tumor associated macrophages have been observed in most cancers. While this prompts the hypothesis that macroenvironmental manifestations of dysfunctional iron metabolism have direct associations with microenvironmental tumor immune response, these functional connections are still emerging. We review our current understanding of the role of macrophages in systemic and microenvironmental immune response and iron metabolism and discuss these functions in the context of cancer and immunometabolic precision therapy approaches. Accumulation of tumor associated macrophages with distinct iron pathologies at the invasive tumor front suggests an "Iron Curtain" presenting as an innate functional interface between systemic and microenvironmental iron metabolism and immune response that can be harnessed therapeutically to further our goal of treating and eliminating cancer.

Keywords: cancer systems; immunotherapy; iron metabolism; macrophage polarization; tumor microenvironment.

Figure 1

Macrophage regulation of systemic iron metabolism. Macrophages are central regulators of iron metabolism systemically throughout the body where they regulate largely unidirectional flux of non-transferrin bound iron NTBI, and red blood cell (RBC) erythrophagocytosis. Macrophages across the body and in tumors share similar uptake, storage and release mechanisms. NTBI iron is taken up by ZIP14, and DMT1. RBC are recognized for phagocytosis via CD163, CD91, and CD47 receptors. NTBI is stored as ferritin heavy chain (FTH) and light chain (FTL) complexes. NTBI is released by ferroportin (FPN). In liver Kupffer cells integrate inflammatory cues with NTBI iron recycling to regulate iron homeostasis. Spleen red-pulp macrophages respond to systemic metabolic iron needs by phagocytosis of senescent red blood cells (RBC) and export of recycled NTBI. Bone marrow central macrophages process NTBI received from the periphery to support heme synthesis during erythropoiesis. In the tumor, tumor associated macrophages similarly recycle NTBI and RBC.

Figure 2

The Iron Curtain. Iron-laden macrophages occupy a unique cellular niche in the tumor where they act as an interfacial boundary mediating systemic and microenvironment metabolic flux and immune response. Prussian Blue iron histochemistry which is specific for ferric iron deposits from endogenous hemosiderin (shown here) or iron nanoparticle contrast agent (not shown) in such macrophages beside pan-macrophage CD68 immunohistochemical staining reveals a distinct spatial pathology of such iron-laden macrophages suggestive of an “Iron Curtain” where colonies of TAMs exhibiting similar iron accumulation phenotypes form physical borders in the TME.

Figure 3

Macrophage iron metabolism and immune response in the tumor microenvironment. Within the microenvironment macrophage phenotype is influenced by iron metabolism, and both iron and immune status are correlated with tumor growth and therapy response. Along a gradient of tumor iron concentration established according to systemic metabolic background and mode of therapy, macrophages can adopt various polarization states spanning a continuum between M1 anti-tumor/proinflammatory activation and M2 pro-tumor wound-healing states. Low tumor iron is associated with reduced tumor growth and favors M2-like macrophage polarization with increased expression of ferroportin, lipocalin 2 and transferrin receptor, and reduced ferritin content. High tumor iron is similarly associated with reduced tumor growth and favors M1-like macrophage polarization with lower expression of ferroportin, lipocalin 2 and transferrin receptor, and increases in ferritin iron storage. Between these two extremes the heterogeneous distribution of macrophage polarization states supports an intermediate iron regime where iron-addicted cancer cells expressing low levels of ferroportin, and high levels of ferritin, lipocalin 2 and transferrin receptor co-opt macrophage’s innate role in iron handling to support malignancy.

Figure 4

TAM iron imaging in cancer. In many studies focusing on iron-laden population of macrophages magnetic resonance imaging (MRI) is used to localize and monitor these cells during tumor growth and immunometabolic therapy response. Here, iron nanoparticle contrast agents are injected intravenously and subsequently are delivered to the tumor where TAM phagocytosis occurs. Quantitative iron MRI provides in vivo quantitative detection of iron containing macrophages in animal models and patients. Cytological imaging confirms associations between iron deposits within macrophage accumulation and vascular infiltration.