Therapeutically targeting perivascular macrophage effector function improves CD8+ T-cell infiltration and response to chemotherapeutic drugs in cancer [CD206+LYVE-1+]
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PROVIDER: PRJNA1214841 | ENA |
REPOSITORIES: ENA
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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.
2025-08-06 | GSE287874 | GEO
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.
2025-08-06 | GSE248272 | GEO
Project description:Therapeutically targeting perivascular macrophage effector function improves CD8+ T-cell infiltration and response to chemotherapeutic drugs in cancer
| PRJNA1043144 | ENA
Project description:Hyaluronan receptor LYVE-1 is expressed by liver sinusoidal endothelial cells (LSEC), lymphatic endothelial cells and specialized macrophages. Besides binding hyaluronan, LYVE-1 mediates adhesion of leukocytes and cancer cells to endothelial cells. Here, we analyzed the impact of LYVE-1 on physiological liver functions and metastasis. Mice with deficiency of Lyve-1 (Lyve-1 KO) were analyzed using histology, immunofluorescence, RNA sequencing, plasma proteomics and flow cytometry. Liver metastasis was studied by intrasplenic/intravenous injection of melanoma (B16F10luc2, WT31) or colorectal carcinoma (MC38) cell lines. Results: Hepatic architecture, liver size, endothelial differentiation and angiocrine functions were unaltered in Lyve-1 KO mice. Hyaluronan plasma levels were significantly increased in Lyve-1-KO mice; besides, plasma proteomics revealed increased carbonic anhydrase-2 and decreased FXIIIA, potential modulators of metastatis. Furthermore, gene expression analysis of LSEC indicated regulation of immunological pathways. Therefore, liver metastasis of a highly and of a weekly immunogenic tumor, i.e. melanoma and colorectal carcinoma (CRC), was analyzed in Lyve-1 KO mice. Hepatic metastasis of B16F10 luc2 and WT31 melanoma cells, but not MC38 CRC cells, was significantly reduced in Lyve-1 KO mice. While short-term adhesion assays with B16F10 luc2 cells in vivo did not show differences between Lyve-1 KO and wild-type mice, increased numbers of resident hepatic CD4+, CD8+ and regulatory T cells were detected in Lyve-1 KO livers. In addition, iron deposition was detected in F4/80+ liver macrophages known to exert pro-inflammatory effects. Conclusions: LYVE-1 deficiency controlled hepatic metastasis in a tumor cell-specific manner reducing hepatic metastasis of melanoma, but not CRC. Anti-tumorigenic effects are likely due to enhancement of the resident hepatic immune microenvironment.
2023-03-11 | PXD032717 | Pride
Project description:LYVE-1-positive macrophages were observed to be closely spatially associated with the developing lymphatic vasculature. The role of this population of macrophages in the embryo is uncharacterised. We used microarray analyses to investigate which genes are differentially regulated between LYVE-1-positive and LYVE-1-negative macrophages Macrophage populations were isolated from cell suspensions prepared from digested embryonic day (E) 15.5 skin and prepared for RNA extraction and hybridization on Affymetrix microarrays.
2010-10-02 | E-GEOD-24492 | biostudies-arrayexpress
Project description:Macrophages reside in all organs and participate in homeostatic- and immune regulative processes. Little is known about pancreatic macrophage gene expression. CD206 is an endocytic receptor with prior use in subclassifying macrophages. In the present study, global gene expression was characterized in human pancreatic macrophage subpopulations. Flow cytometry was used to sort CD206- and CD206+ macrophages separately from pancreatic islets and exocrine tissue to high purity. RNA-seq generated transcriptomic profiles were then analyzed. Comparing CD206- with CD206+ macrophages, CD206- showed enrichment in proliferation and nucleic acid processing, glycolysis, pro-inflammatory and SPP1-associated gene sets while CD206+ showed enrichment in complement-, IL-10 and IL-2RA immune regulation, as well as scavenging-related gene sets. Two sets involved in immune regulation were enriched in islet CD206-, while various sets including some proinflammatory sets were enriched in exocrine CD206- macrophages. Fewer differences were found between CD206+ macrophages, with enrichment in two IL2-RA related gene sets in islets and eight gene sets in exocrine samples. Comparing macrophages between individuals with normoglycemia, elevated HbA1c or type 2 diabetes, only a few diverse differentially expressed genes were identified. This work characterizes global gene expression and identifies differences between CD206- and CD206+ macrophage populations within the human pancreas.
2025-04-16 | GSE281600 | GEO
Project description:LYVE-1-positive macrophages were observed to be closely spatially associated with the developing lymphatic vasculature. The role of this population of macrophages in the embryo is uncharacterised. We used microarray analyses to investigate which genes are differentially regulated between LYVE-1-positive and LYVE-1-negative macrophages
2010-10-02 | GSE24492 | GEO
Project description:Beside their role in conventional immune regulation, macrophages are now recognised as essential regulator of local tissue homeostasis depending on the tissue in which they reside. Using phenotyping, we found that LYVE-1+ macrophages are the major resident macrophage population in murine aorta and adipose tissues under steady state. Furthermore, imaging analysis revealed the exclusive association of adipose tissue LYVE-1+ macrophages with smooth muscle positive large blood vessels. Hence, we hypothesize that LYVE-1+ macrophages sustain large vessel functional homeostasis. The present experiment aims to better characterize resident LYVE-1+ vs LYVE-1- macrophages in aorta and adipose tissues.
2018-06-01 | GSE114630 | GEO
Project description: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.
2024-06-05 | GSE241469 | GEO
Project description:Disruption of gut barrier function and intestinal immune cell homeostasis are increasingly considered critical players in pathogenesis of extra-intestinal inflammatory diseases, including multiple sclerosis (MS) and its prototypical animal model, theexperimental autoimmune encephalomyelitis (EAE). Breakdown of epithelial barriers increases intestinal permeability and systemic dissemination of microbiota-derived molecules. However,whetherthe gut-vascular barrier (GVB) is altered during EAE has not been reported. Here, we demonstrate that endothelial cell proliferation and vessel permeability increase before EAE clinical onset, leadingto vascular remodelingand expansion of intestinal villi capillary bed during disease symptomatic phasein an antigen-independent manner. Concomitant to onset of angiogenesis observed prior to neurological symptoms, we identify an increase of intestinal perivascular immune cells characterized by the surface markerlymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1). LYVE-1+is expressed more frequently on B cells that show high levels of CD73 and have proangiogenic properties. B cell depletion was sufficient tomitigate enteric blood endothelial cell proliferation following immunization for EAE. In conclusion, we propose that altered intestinal vasculature driven by a specialized LYVE-1+B cell subset promotes angiogenesis and that loss of GVB function is implicated in EAE development and autoimmunity.
2024-11-13 | GSE271603 | GEO