ABSTRACT
Interleukin 9 (IL-9)-producing helper T (Th9) cells are essential for inducing anti-tumor immunity and inflammation in allergic and autoimmune diseases. Although transcription factors that are essential for Th9 cell differentiation have been identified, other signaling pathways that are required for their generation and functions are yet to be explored. Here, we identify that Epidermal Growth Factor Receptor (EGFR) is essential for IL-9 induction in helper T (Th) cells. Moreover, amphiregulin (Areg), an EGFR ligand, is critical for the amplification of Th9 cells induced by TGF-ß1 and IL-4. Furthermore, our data show that Areg-EGFR signaling induces HIF1α, which binds and transactivates IL-9 and NOS2 promoters in Th9 cells. Loss of EGFR or HIF1α abrogates Th9 cell differentiation and suppresses their anti-tumor functions. Moreover, in line with its reliance on HIF1α expression, metabolomics profiling of Th9 cells revealed that Succinate, a TCA cycle metabolite, promotes Th9 cell differentiation and Th9 cell-mediated tumor regression.
Subject(s)
ErbB Receptors/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Interleukin-9/genetics , Melanoma, Experimental/therapy , Skin Neoplasms/therapy , T-Lymphocytes, Helper-Inducer/immunology , Amphiregulin/metabolism , Animals , Cell Differentiation/immunology , Female , HEK293 Cells , Healthy Volunteers , Humans , Immunotherapy, Adoptive/methods , Melanoma, Experimental/immunology , Mice , Mice, Knockout , Nitric Oxide Synthase Type II/genetics , Primary Cell Culture , RNA-Seq , Signal Transduction/genetics , Signal Transduction/immunology , Skin Neoplasms/immunology , Succinic Acid/metabolism , T-Lymphocytes, Helper-Inducer/transplantation , Transcriptional Activation/immunologyABSTRACT
The epidermal growth factor receptor ligand Amphiregulin has a well-documented role in the restoration of tissue homeostasis after injury; however, the mechanism by which Amphiregulin contributes to wound repair remains unknown. Here we show that Amphiregulin functioned by releasing bioactive transforming growth factor beta (TGF-ß) from latent complexes via integrin-αV activation. Using acute injury models in two different tissues, we found that by inducing TGF-ß activation on mesenchymal stromal cells (pericytes), Amphiregulin induced their differentiation into myofibroblasts, thereby selectively contributing to the restoration of vascular barrier function within injured tissue. Furthermore, we identified macrophages as a critical source of Amphiregulin, revealing a direct effector mechanism by which these cells contribute to tissue restoration after acute injury. Combined, these observations expose a so far under-appreciated mechanism of how cells of the immune system selectively control the differentiation of tissue progenitor cells during tissue repair and inflammation.
Subject(s)
Amphiregulin/metabolism , Macrophages/metabolism , Pericytes/metabolism , Transforming Growth Factor beta/metabolism , Animals , Cell Differentiation/physiology , Female , Male , Mesenchymal Stem Cells/metabolism , Mice , Mice, Inbred C57BL , Myofibroblasts/metabolismABSTRACT
Epidermal Growth Factor Receptor (EGFR) antagonists were one of the first anti-cancer treatments developed targeting a Receptor Tyrosine Kinase. However, the underlying mode of action of how EGFR antagonist application can explain its clinical efficacy in different types of cancers remains largely unresolved. Numerous findings have suggested that a substantial portion of the effects attributed to EGFR antagonist treatment might not be based on direct influence on the tumor itself. Instead it may be based on indirect effects, potentially mediated via the immune system. In this review the role of the EGFR for the functioning of the immune system is discussed, alongside how EGFR antagonist treatment could be impacting tumor growth by blocking macrophage and FoxP3-expressing regulatory CD4+ T cell function. Based on these findings, we consider implications for current treatment schemes and suggest novel approaches to improve the efficacy of EGFR antagonist treatment in the future. Finally, we propose potential ways to improve EGFR antagonists, in order to enhance their clinical efficacy whilst diminishing unwanted side effects.
