Human Lung-Resident Macrophages Express and Are Targets of Thymic Stromal Lymphopoietin in the Tumor Microenvironment

Abstract

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine highly expressed by epithelial cells and several innate and adaptive immune cells. TSLP exerts its biological effects by binding to a heterodimeric complex composed of TSLP receptor (TSLPR) and IL-7Rα. In humans, there are two TSLP isoforms: the short form (sfTSLP), constitutively expressed, and the long form (lfTSLP), which is upregulated in inflammation. TSLP has been implicated in the induction and progression of several experimental and human cancers. Primary human lung macrophages (HLMs), monocyte-derived macrophages (MDMs), and peripheral blood monocytes consitutively expressed sfTSLP mRNA. Incubation of HLMs, MDMs, and monocytes with lipopolysaccharide (LPS) or IL-4, but not with IL-13, induced TSLP release from HLMs. LPS, but not IL-4 or IL-13, induced CXCL8 release from HLMs. LPS, IL-4 alone or in combination with IL-13, induced the expression of lfTSLP, but not of sfTSLP from HLMs. Preincubation of HLMs with IL-4, alone or in combination with IL-13, but not IL-13 alone, synergistically enhanced TSLP release from LPS-activated macrophages. By contrast, IL-4, alone or in combination with IL-13, inhibited LPS-induced CXCL8 release from HLMs. Immunoreactive TSLP was detected in lysates of HLMs, MDMs, and monocytes. Incubation of HLMs with TSLP induced the release of proinflammatory (TNF-α), angiogenic (VEGF-A, angiopoietin 2), and lymphangiogenic (VEGF-C) factors. TSLP, TSLPR, and IL-7Rα were expressed in intratumoral and peritumoral areas of human lung cancer. sfTSLP and lfTSLP mRNAs were differentially expressed in peritumoral and intratumoral lung cancer tissues. The TSLP system, expressed in HLMs, MDMs, and monocytes, could play a role in chronic inflammatory disorders including lung cancer.

Role of thymic stromal lymphopoietin in allergy and beyond

“…Expression of TSLP protein in tumours was significantly higher than in benign lesions and non-cancer lung tissue, and the prevalence of regulatory T cells in the tumour microenvironment correlated with the expression of TSLP in lung cancer. Furthermore, TSLP and TSLPR are expressed in macrophages purified from the lungs of patients with lung cancer 145 , with a presumed pro-tumorigenic role for TSLP.…”

Neutrophil Extracellular Traps, Angiogenesis and Cancer

“…VEGF-C and VEGF-D are key regulators of lymphangiogenesis by activation of the VEGFR3 receptor on lymphatic endothelial cells (LECs) [ 141 ]. Previous studies have demonstrated that tissue-resident immune cells, such as human macrophages [ 142 , 143 ] and mast cells [ 110 , 112 , 144 ], are a major source of lymphangiogenic factors. When we investigated the effects of sPLA 2 on the release of lymphangiogenic factors from human neutrophils, we found that these cells do not express VEGF-C/VEGF-D mRNAs.…”

“…Macrophages, important resident immune cells in TME [ 143 , 262 ], are critical sentinels in tumor immunity, modulating angiogenesis and lymphangiogenesis [ 21 , 263 ] and surveilling against tumors [ 264 , 265 ]. Recent studies have demonstrated that activated macrophages can release extracellular DNA traps, also called macrophage extracellular traps (METs) [ 95 , 230 , 266 ].…”

“…Mast cells [ 95 , 269 , 270 , 271 , 272 , 273 , 274 ], eosinophils [ 149 , 150 , 183 , 275 , 276 , 277 , 278 ], basophils [ 186 , 275 , 279 ], and macrophages [ 95 , 230 ], which are present in TME [ 143 , 144 , 208 , 248 , 280 , 281 ], can also release extracellular DNA traps. Further studies are needed to evaluate whether immunological stimuli (e.g., ANGPTs) can induce the formation of extracellular DNA traps from human mast cells, macrophages, eosinophils, and basophils.…”

Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities

“…Exposing HLMs to lfTSLP stimulate these cells to produce proinflammatory and angiogenic factors (TNF-α), which can, in turn, promote lung cancer progression. This research indicates the importance of the TSLP system (via the selection of distinct TSLP isoforms) and underlines the ability of the lfTSLP, produced by HLMs, in directing the fate of lung cancer [8].…”