Abstract
Iron-loaded tumor-associated macrophages (iTAMs) show a pro-inflammatory phenotype, hallmarked by anti-tumorigenic activity and an ability to attenuate tumor growth. Here we explored the relevance of these findings in lung cancer patients by investigating the impact of the iTAM content in the tumor microenvironment (TME) on patient survival. We analyzed 102 human non-small cell lung cancer (NSCLC) paraffin-embedded archival tissue samples for iron levels and macrophage numbers. Interestingly, patients with lung adenocarcinoma accumulating iron in the TME show higher numbers of M1-like pro-inflammatory TAMs and a survival advantage compared to iron-negative patients. By contrast, in patients with lung squamous cell carcinoma iron in the TME does not affect survival, suggesting a unique influence of iron on different histological subtypes of non-small cell lung cancer (NSCLC). We conclude that in lung adenocarcinoma iron may serve as a prognostic marker for patient survival and as a potential therapeutic target for anti-cancer therapy.
Highlights
Lung cancer accounts for more than one million deaths each year worldwide, making it the most common cause of cancer-related mortality[1]
Lung adenocarcinoma accumulates more iron in the tumor microenvironment compared to lung squamous cell carcinoma
tumor-associated macrophages (TAMs) located in the tumor microenvironment are predominantly of an M2-like anti-inflammatory phenotype, which is associated with angiogenesis and tumor progression[9,10,22,23,24]
Summary
Lung cancer accounts for more than one million deaths each year worldwide, making it the most common cause of cancer-related mortality[1]. M1 macrophages produce pro-inflammatory cytokines such as interleukin (IL)-1α/β, IL-6, tumor necrosis factor alpha (TNFα), reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), cluster of differentiation (CD) 86, major histocompatibility complex II (MHC II), and CD14 They express high levels of the iron storage protein ferritin, whereas the iron exporter ferroportin is less expressed, causing iron retention. A higher M1-TAM content in NSCLC has been linked to extended survival of patients[14,15], whereby higher numbers of TAMs and especially M2-TAMs correlate with adverse outcomes of NSCLC patients[16,17] Based on these findings experimental therapies aim to modify polarization towards M1-like TAMs to alter the TME in such a way to impact on tumor growth[18]. We asked the following questions (i) do different histotypes of NSCLC differ in terms of their iron and TAM content, and (ii) does iron and/or TAM content alter the overall outcomes of NSCLC patients
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