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LYVE-1-expressing macrophages modulate the extracellular matrix in the mammary gland and contribute to mammary tumor growth

ABSTRACT: Macrophages represent a heterogeneous myeloid population with diverse functions in normal tissues and tumors. While LYVE-1 macrophages have been identified in stromal regions of the normal mammary gland and mammary tumor, their functions in these regions remain unknown. Using a genetic LYVE-1+ macrophage deletion model, we demonstrate that loss of LYVE-1+ macrophages leads to accumulation of the extracellular matrix glycosaminoglycan hyaluronan. Consistent with this finding, we demonstrate that LYVE-1 expression correlates with an increased ability of macrophages to bind, internalize, and degrade hyaluronan. Furthermore, we demonstrate that deletion of LYVE-1+ macrophages results in increased hyaluronan accumulation in mammary tumors, which correlates with reduced tumor growth. Finally, using scRNA-seq, we demonstrate that deletion of LYVE-1 macrophages in tumors results in a shift in the remaining macrophages towards a pro-inflammatory phenotype. Together, these findings demonstrate that LYVE-1+ macrophages represent an anti-inflammatory macrophage population that contributes to tissue remodeling in the tumor microenvironment.

ORGANISM(S): Mus musculus

PROVIDER: GSE241469 | GEO | 2024/06/05

REPOSITORIES: GEO

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Project description:The tumor microenvironment (TME) plays a crucial role in cancer progression and represents an appealing target for cancer treatment. Tumor-associated macrophages (TAMs) are an abundant stromal cell type in the TME and, due to their plasticity, TAMs can be exploited to promote a pro-tumoral response. TAMs have been implicated in facilitating a variety of pro-tumoral pathways including resistance to anti-cancer therapeutics, immune suppression, angiogenesis, and metastasis. However, pan-TAM depleting approaches have not delivered robust clinical outcomes as single agents. This might be explained due to their non-selective targeting of both pro- and anti-tumoral macrophage subsets. As such, therapeutically targeting key pro-tumoral TAM subsets may be a more desirable and efficacious strategy. Our group has recently characterised a subpopulation of pro-angiogenic and immune-suppressive TAMs which can be identified by their expression of the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1). LYVE-1+ TAMs reside spatially proximal to blood vasculature and adopt a collaborative multi-cellular ‘nest’ arrangement which supports their biological activity. LYVE-1+ TAMs selectively express high levels of the immunomodulatory enzyme heme oxygenase-1 (HO-1), an enzyme which catabolizes heme to generate the biologically active catabolites carbon monoxide (CO), biliverdin and ferrous iron. Genetic inactivation of HO-1 in LYVE-1+ TAMs improve anti-tumor CD8+ T-cell infiltration into the TME and enhances the immune-stimulating effects of chemotherapy, resulting in sustain control of tumor growth in a spontaneous MMTV-PyMT murine model of breast cancer. This highlights that HO-1 represents a key effector pathway of these cells that prevents immune-elimination of tumors. Considering translation of these observations, unfortunately, current HO-1 inhibitors are not orally bioavailable, which limits their utility for chronic diseases, such as cancer, where daily administration would be required. In response to this hurdle, we developed a next generation HO-1 inhibitor called KCL-HO-1i. We demonstrate in pharmacokinetic studies that KCL-HO-1i is orally bioavailable in murine models with a serum half-life of around 3hours. Furthermore, oral delivery of KCL-HO-1i alongside standard of care chemotherapy delivers durable tumor control in MMTV-PyMT mice. We have characterised the response of the TME to KCL-HO-1i using flow cytometry, immunofluorescence and RNA sequencing approaches and demonstrate that KCL-HO-1i targeting perivascular LYVE-1+ TAM function supports a broader switch from an immunological ‘cold’ to ‘hot’ TME which provides a more favourable immune landscape for improving the response to chemotherapeutic drugs. Taken together, our data support the use of KCL-HO-1i as novel immunotherapeutic for targeting the function of perivascular TAMs in cancer.

Project description:In adult mice, “heart attack” or myocardial infarction (MI) activates the cardiac lymphatics, which undergo sprouting angiogenesis (lymphangiogenesis) and function to drain interstitial fluid and traffic macrophages to mediastinal lymph nodes (MLNs). This prevents oedema and reduces inflammatory/fibrotic immune cell content to improve cardiac function. Given the importance of the adult cardiac lymphatics in macrophage clearance after injury, we investigated their role across the neonatal “regenerative window”. At post-natal day 1 (P1) neonatal mice fully regenerate their heart following MI, in a pro-regenerative macrophage-dependent manner, whereas equivalent injury at post-natal day 7 (P7) leads to scarring driven by pro-fibrotic macrophages. We hypothesised that lymphatics respond and function differently during this “window” to clear macrophage-specific subtypes, depending upon their requirement for regeneration versus fibrotic repair. Normal lymphatic growth and sprouting was evident in intact neonatal hearts until P16, with strain-dependent developmental differences. The response to injury revealed limited lymphangiogenesis (lymphatic vessel growth and sprouting) and minimal clearance of macrophages from P1 compared to P7 infarcted hearts, as determined by adoptive transfer, and monitoring of cleared macrophages to MLNs. This is coincident with maturation of lymphatic endothelial cell junctions across the neonatal period via transition from “zipper” (impermeable) to “button” (permeable) -type junctions and altered signalling between lymphatic endothelial cells and macrophages, including differential expression of the lymphangiocrine factor Reelin (RELN). Finally, in mice lacking the lymphatic endothelial receptor-1 (LYVE-1), that exhibit impaired transmigration of interstitial macrophages to lymphatic vessels, magnetic resonance imaging (MRI) revealed a surprising impaired functional outcome in P1 mice 28 days post-MI. Given our observations that pro-regenerative macrophages at P1 are not trafficked, this suggested a distinct role for LYVE-1 in tissue-resident macrophages, consistent with its expression pattern in developing and post-natal hearts. Macrophage-specific deletion of Lyve1 during neonatal heart injury revealed impaired heart regeneration, characterised by persistent fibrosis, a reduced neovascular response and reduced function. ScRNA-seq of Lyve1 deficient CD45+ cells revealed a loss of tissue-resident macrophages and an increase in recruited monocytes which is predicted to increase inflammation and fibrosis, worsening the outcome post-MI. Collectively, this study reveals that cardiac lymphatics are developmentally compromised for clearance in early neonates, which enables retention of pro-regenerative tissue-resident macrophages, and that LYVE-1 plays an essential role in maintaining this population to promote heart regeneration and prevent inflammation and fibrotic repair.

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LYVE-1-expressing macrophages modulate the extracellular matrix in the mammary gland and contribute to mammary tumor growth

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