Abstract:Iron is both, an essential compound for many metabolic processes, and iron deficiency can impact on the proliferation of cells including lymphocytes but also tumor cells. On the other hand, excess iron-catalyzed radical formation can induce cellular toxicity which has been previously demonstrated for T cells in hereditary iron overload. Despite these interconnections, little is known on the effects of clinically approved intravenous iron supplements for curing cancer-related anemia, on T cell differentiation, … Show more
“…Iron has been shown to trigger CD4+ T cell differentiation and alter CD8+ T cell expansion. Immunosuppressive effects of iron on T cells have been described in individuals with hereditary or transfusion mediated iron overload, where these patients have altered T cell numbers and function ( 118 ). In tumor infiltrating lymphocytes, iron may impair the proliferation, differentiation or maturation by generating mitochondrial ROS, resulting in cell death.…”
Section: Immune Response and Iron Metabolism In Cancer Therapymentioning
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.
“…Iron has been shown to trigger CD4+ T cell differentiation and alter CD8+ T cell expansion. Immunosuppressive effects of iron on T cells have been described in individuals with hereditary or transfusion mediated iron overload, where these patients have altered T cell numbers and function ( 118 ). In tumor infiltrating lymphocytes, iron may impair the proliferation, differentiation or maturation by generating mitochondrial ROS, resulting in cell death.…”
Section: Immune Response and Iron Metabolism In Cancer Therapymentioning
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.
“…First, iron supplementation of anti-CD3-primed splenocytes isolated from naive mice induced a slight decrease in the proliferation and dramatically slowed cell cycle progression of T cells as demonstrated by CFSE dilution ( Figure 1A ) and BrdU pulsing ( Figure 1B ) assays even at concentrations as low as 2.5 to 5 µM ( 39 ). Both effects were independent of the iron source (chloride, sulfate and citrate) and, hence, independent of iron source-inherent differences in solubility, dissociation properties, and cellular iron availability.…”
Section: Resultsmentioning
confidence: 99%
“…According to our in vitro data ( Figure 1 ) iron dose-dependently increased TIM-3 expression, and blocked cell cycle progression and differentiation of Th0 to Th1 cells. Hence, two non-exclusive mechanisms may be proposed: first, interference of iron with the Th1-specific transcription factor network and second, signaling induced by reactive oxygen species, as postulated in our previous report on iron and anti-tumor CD8 + T cells ( 39 ). While iron did not affect the expression of TIM-3-inducing cytokines, IL-12 and IL-27 in vivo , it still could affect signals mediated by those cytokines via the IL-12 receptor or via T-bet, the master switch transcription factor of Th1 cells.…”
Section: Discussionmentioning
confidence: 96%
“…In our model of chronic bacterial infection, the effects of iron were highly specific for Th1 cells as neither the number of Th2, nor Th17 or Treg subsets displayed differences after high iron diet. Interestingly, our previous report provided evidence that the function of the CD8 + IFNγ-producing T cell subset in murine mammary carcinoma was strongly hampered by intravenous iron supplementation ( 39 ).…”
Section: Discussionmentioning
confidence: 99%
“…Our recently published data ( 39 ) indicate that high cellular iron content in CD8 + T cells induces accumulation of reactive oxygen species (ROS) in mitochondria and that treatment with a mitochondria-specific ROS scavenger could restore T cell priming even in the high iron setting. Whether a ROS-mediated mechanism including ferroptosis ( 49 ) or mitochondrial dysfunction ( 50 ) as a consequence of iron loading underly the TIM-3 up-regulation and functional impairment of Th1 cells in high iron-fed Salmonella- infected animals remains to be investigated.…”
Iron plays an important role in host–pathogen interactions, in being an essential element for both pathogen and host metabolism, but also by impacting immune cell differentiation and anti-microbial effector pathways. Iron has been implicated to affect the differentiation of T lymphocytes during inflammation, however, so far the underlying mechanism remained elusive. In order to study the role of iron in T cell differentiation we here investigated how dietary iron supplementation affects T cell function and outcome in a model of chronic infection with the intracellular bacterium Salmonella enterica serovar typhimurium (S. Typhimurium). Iron loading prior to infection fostered bacterial burden and, unexpectedly, reduced differentiation of CD4+ T helper cells type 1 (Th1) and expression of interferon-gamma (IFNγ), a key cytokine to control infections with intracellular pathogens. This effect could be traced back to iron-mediated induction of the negative immune checkpoint regulator T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), expressed on the surface of this T cell subset. In vitro experiments demonstrated that iron supplementation specifically upregulated mRNA and protein expression of TIM-3 in naïve Th cells in a dose-depdendent manner and hindered priming of those T cells towards Th1 differentiation. Importantly, administration of TIM-3 blocking antibodies to iron-loaded mice infected with S. Typhimurium virtually restored Th1 cell differentiation and significantly improved bacterial control. Our data uncover a novel mechanism by which iron modulates CD4+ cell differentiation and functionality and hence impacts infection control with intracellular pathogens. Specifically, iron inhibits the differentiation of naive CD4+ T cells to protective IFNγ producing Th1 lymphocytes via stimulation of TIM-3 expression. Finally, TIM-3 may serve as a novel drug target for the treatment of chronic infections with intracellular pathogens, specifically in iron loading diseases.
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