Tumor-derived thymic stromal lymphopoietin enhances lung metastasis through an alveolar macrophage-dependent mechanism

Abstract

It is well-recognized that macrophages, which arise from circulating precursors, enhance tumor progression in patients and animal models. However, less is known regarding the role of tissue-resident macrophages in metastasis. Moreover, the identification of tumor factors which influence macrophage function in the metastatic niche remains incomplete. Here, we investigated one such cytokine known as thymic stromal lymphopoietin (TSLP). Our rationale to focus on TSLP was based on two non-overlapping findings; first, TSLP exacerbates asthma in part by altering the lung macrophage response and, secondly, TSLP is produced by certain mouse and human tumor systems, although its role in neoplasia remains understudied. Thus, we tested the hypothesis that tumor-derived TSLP augments lung metastasis by rendering alveolar macrophages pro-tumorigenic. To test this hypothesis, we principally employed the 4T1 tumor model, which produces high levels of TSLP and metastasizes to the lung. TSLP loss-of-function significantly reduced spontaneous lung metastasis, as well as lung colonization. Moreover, similar outcomes were observed in both wild-type and immune-deficient hosts, suggesting that TSLP acted on innate immune cells such as macrophages. To test this notion, pharmacologic depletion of alveolar macrophages significantly reduced lung tumor growth of the TSLP-expressing, but not TSLP-deficient tumor population. In contrast, depleting macrophages originating from the circulation did not impact lung tumor growth. Lastly, TSLP increased the invasive and angiogenic gene expression profile of the alveolar macrophage population. Altogether, our study identified a novel TSLP-alveolar macrophage axis in lung metastasis, which offers new insights into mechanisms of metastasis and potential therapeutic targets.

Thymic Stromal Lymphopoietin and Cancer: Th2-Dependent and -Independent Mechanisms

“…Experiments in TSLP KO mice then showed that TSLP signaling was required for metastatic disease progression to the lung. In another study (33), tumor cell-derived TSLP induced invasive and angiogenic gene expression profiles in alveolar macrophages. Depletion of alveolar macrophages but not macrophages from the circulation impacted lung lesion growth.…”

Lung Macrophages: Multifunctional Regulator Cells for Metastatic Cells

“…Thymic stromal lymphopoietin (TSLP) was abundantly expressed by several mouse and human breast cancer cell lines. Tumor cell-derived TSLP induced AMs to express VEGF-A, platelet-derived growth factor-A, and MMP-9 thereby promoting lung metastasis [61]. In this model, intratracheal CLL injection reduced AMs but not IMs, together with reduced metastatic burden.…”

Tumor-Derived Thymic Stromal Lymphopoietin Expands Bone Marrow B-cell Precursors in Circulation to Support Metastasis

“…Although TSLP is expressed by epithelial cells, keratinocytes, mast cells, and basophils in response to a range of stimuli, including cancer cell-derived IL1a, IL1b, TNFa, IL13, and TGFb (18), progression and metastasis of some cancers also require TSLP production from cancer cells themselves. TSLP's purpose is to induce production of survival factors (19) or to activate invasive and angiogenic properties of alveolar macrophages (20). We reported that 4T1 cancer cell-produced TSLP induces Th2-skewed and CCL17-elevated lung environment (16) to enable coinfiltration of CCR4 þ cancer cells and their protector CCR4 þ Tregs in the lungs (6,16,21).…”