Previous studies have demonstrated a significant association between sialic acid binding Ig-like lectin 15(SIGLEC15)and both the progression of malignant tumors and immune infiltration.This study comprehensively analy...Previous studies have demonstrated a significant association between sialic acid binding Ig-like lectin 15(SIGLEC15)and both the progression of malignant tumors and immune infiltration.This study comprehensively analyzed and elaborated the function and related mechanism of SIGLEC15 in breast cancer.We analyzed SIGLEC15 expression levels and predicted its functions using mRNA sequencing in a population-based dataset.Single-cell RNA sequencing was utilized to investigate the biological roles of SIGLEC15 within the tumor microenvironment(TME).Finally,we conducted both in vivo and in vitro experiments to validate the findings derived from the RNA sequencing analyses.Elevated SIGLEC15 expression was associated with favorable outcomes in breast cancer patients.Tumor cells exhibiting high SIGLEC15 expression demonstrated reduced epithelial—mesenchymal transition(EMT)tendencies compared to those with lower expression levels,potentially through the regulation of ZEB1 expression.However,anti-tumor immunity was significantly suppressed in the TME containing these tumor cells.Analysis of protein expression in patient samples revealed a negative correlation between SIGLEC15 expression and CD4,CD8 T-cell infiltration.In mouse models,tumor cells overexpressing SIGLEC15 exhibited diminished invasive and migratory capabilities.Furthermore,both in vitro and in vivo experiments confirmed that Nutlin-3a has a more pronounced inhibitory effect on breast cancer cells with elevated SIGLEC15 expression.The expression level of SIGLEC15 can serve as a biomarker to assess the malignancy of breast cancer and the degree of immune infiltration.Monitoring SIGLEC15 expression levels can facilitate more informed and personalized clinical decision-making for the treatment of breast cancer patients.展开更多
cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy.Emerging evidence has shown that interferon-gamma(IFN)could enhance ...cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy.Emerging evidence has shown that interferon-gamma(IFN)could enhance CXCL9 secretion from macrophages to recruit T cells,but Siglec15 expressed on TAMs can attenuate T cell proliferation.Therefore,targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues.We herein developed reductionresponsive nanoparticles(NPs)made with poly(disulfide amide)(PDSA)and lipid-poly(ethylene glycol)(lipid-PEG)for systemic delivery of Siglec15 siRNA(siSiglec15)and IFN for enhanced cancer immunotherapy.After intravenous administration,these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages(TAMs).With the highly concentrated glutathione(GSH)in the cytoplasm to destroy the nanostructure,the loaded IFN and si-Siglec15 could be rapidly released,which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation,leading to significant inhibition of hepatocellular carcinoma(HCC)growth when combining with the immune checkpoint inhibitor.The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.展开更多
基金supported by The First Clinical College Clinical Medicine First-class Discipline Construction Project to Department of Breast and Thyroid Surgery to Lingfeng Tang(China)(No.CYYY-BSYJSCXXM-202322)The First Clinical College Clinical Medicine First-class Discipline Construction Project to Department of Breast and Thyroid Surgery to Zhaofu Tan(China)(No.CYYY-BSYJSCXXM-202333)Innovative Research Group Project of the National Natural Science Foundation of China to Gang Tu(China)(No.81372398).
文摘Previous studies have demonstrated a significant association between sialic acid binding Ig-like lectin 15(SIGLEC15)and both the progression of malignant tumors and immune infiltration.This study comprehensively analyzed and elaborated the function and related mechanism of SIGLEC15 in breast cancer.We analyzed SIGLEC15 expression levels and predicted its functions using mRNA sequencing in a population-based dataset.Single-cell RNA sequencing was utilized to investigate the biological roles of SIGLEC15 within the tumor microenvironment(TME).Finally,we conducted both in vivo and in vitro experiments to validate the findings derived from the RNA sequencing analyses.Elevated SIGLEC15 expression was associated with favorable outcomes in breast cancer patients.Tumor cells exhibiting high SIGLEC15 expression demonstrated reduced epithelial—mesenchymal transition(EMT)tendencies compared to those with lower expression levels,potentially through the regulation of ZEB1 expression.However,anti-tumor immunity was significantly suppressed in the TME containing these tumor cells.Analysis of protein expression in patient samples revealed a negative correlation between SIGLEC15 expression and CD4,CD8 T-cell infiltration.In mouse models,tumor cells overexpressing SIGLEC15 exhibited diminished invasive and migratory capabilities.Furthermore,both in vitro and in vivo experiments confirmed that Nutlin-3a has a more pronounced inhibitory effect on breast cancer cells with elevated SIGLEC15 expression.The expression level of SIGLEC15 can serve as a biomarker to assess the malignancy of breast cancer and the degree of immune infiltration.Monitoring SIGLEC15 expression levels can facilitate more informed and personalized clinical decision-making for the treatment of breast cancer patients.
基金supported by the National Natural Science Foundation of China(82171944,81873899,China)the Natural Science Foundation of Guangdong Province(2021A1515012611,China)+1 种基金the National Natural Science Foundation of China(82171952,81801719,China)Postdoctoral Research and Development Fund Project of West China Hospital(2023HXBH063,China).
文摘cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy.Emerging evidence has shown that interferon-gamma(IFN)could enhance CXCL9 secretion from macrophages to recruit T cells,but Siglec15 expressed on TAMs can attenuate T cell proliferation.Therefore,targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues.We herein developed reductionresponsive nanoparticles(NPs)made with poly(disulfide amide)(PDSA)and lipid-poly(ethylene glycol)(lipid-PEG)for systemic delivery of Siglec15 siRNA(siSiglec15)and IFN for enhanced cancer immunotherapy.After intravenous administration,these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages(TAMs).With the highly concentrated glutathione(GSH)in the cytoplasm to destroy the nanostructure,the loaded IFN and si-Siglec15 could be rapidly released,which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation,leading to significant inhibition of hepatocellular carcinoma(HCC)growth when combining with the immune checkpoint inhibitor.The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.
