Hepatocellular carcinoma(HCC)is the most common type of primary liver malignancy and the fourth leading cause of cancer-related deaths globally.HCC is often diagnosed in late stage,difficult to treat,and has poor prog...Hepatocellular carcinoma(HCC)is the most common type of primary liver malignancy and the fourth leading cause of cancer-related deaths globally.HCC is often diagnosed in late stage,difficult to treat,and has poor prognosis with a median survival of 6-20 months.Innate and adaptive immunity play a pivotal role in determining tumor control versus progression.Genomic instability and abnormal signaling in the setting of chronic liver inflammation lead to tumorigenesis.Tumor progression occurs due to a sustained inflammatory response that promotes fibrogenesis and angiogenesis.This review discusses the key innate and adaptive cellular players that mediate the anti-tumor response.This review explores the complex interactions that occur within the tumor microenvironment and their clinical implications.HCC is a fastidious malignancy that is able to evade and downregulate the host immune response.Mechanisms of how this occurs are discussed,along with how they may be exploited in the development of novel therapeutics.From our research,it appears that striking a balance between immunotolerance and a robust immune response may yield the best prognosis.This review assesses major and recent developments in HCC immunotherapy,including adoptive cell therapy,cancer vaccines,and targeted therapy such as checkpoint inhibitors.Overall,the importance of the immune response in determining outcomes for HCC cannot be understated.Improved animal models and better characterization of the tumor microenvironment are needed.We determine that a better understanding of the HCC immune profile would facilitate advancements in diagnosis,monitoring,and ultimately treatment.展开更多
The liver plays an important role in both metabolism and immunity.Disruption of the hepatic immune microenvironment is closely associated with various liver diseases.To gain a better understanding of how different typ...The liver plays an important role in both metabolism and immunity.Disruption of the hepatic immune microenvironment is closely associated with various liver diseases.To gain a better understanding of how different types of immune cells contribute to the progression of liver diseases,it is crucial to thoroughly characterize hepatic immune cells.Although direct digestion of liver tissue is a relatively simple method for isolating immune cells,it often induces excessive hepatocyte death,which causes a release of intracellular components that leads to the activation of stress responses and injury in the surrounding cells.This injury can lead to excessive death in the hepatic immune cells,making isolation and accurate characterization of the immune profile challenging,especially in diseased livers.The method described here addresses these challenges by utilizing Phosphate buffered saline(PBS)and digestion buffer perfusions to eliminate contaminating blood cells,ensure a pure hepatic immune population,and minimize hepatic immune cell death.Further ex vivo digestion of the liver enables the isolation of the immune cells from the hepatic tissues and the generation of a single-cell suspension that can be stained for spectral flow cytometry.To enhance intracellular cytokine detection and maintain signaling under different physiological and pathological conditions,this protocol uses an in vivo administration of Brefeldin A,a less toxic inhibitor of cytokine secretion.This in vivo administration of Brefeldin A allows for a more accurate representation of the immune cell function and cytokine expression compared to the traditionally used ex vivo Brefeldin A administration.A comprehensive spectral flow cytometry panel,comprising extracellular and intracellular staining,is used for deep immunophenotyping and immune cell effector function profiling.While this protocol is specifically designed for liver digestion of Mdr2 knockout mice(a model for primary sclerosing cholangitis)and flow cytometry staining,it can also be applied to other liver diseases and sensitive tissues.展开更多
Hepatocellular carcinoma(HCC)is a highly fatal disease,the mortality of which runs parallel to its incidence.Historically,viral hepatitis has been the major cause of HCC(1).Vaccine is available for hepatitis B virus(H...Hepatocellular carcinoma(HCC)is a highly fatal disease,the mortality of which runs parallel to its incidence.Historically,viral hepatitis has been the major cause of HCC(1).Vaccine is available for hepatitis B virus(HBV)and a drug cocktail is effective in bringing down blood hepatitis C virus(HCV)level to zero.With successful application of mRNA vaccine for COVID-19,it is a matter of time before an effective vaccine for HCV is generated.Despite these positive advancements,the incidence of HCC is continuing to rise because of HCC development as a direct consequence of non-alcoholic steatohepatitis(NASH)caused by obesity(1).While viral hepatitis is waning in the Western countries,obesity is now a global problem,requiring impactful treatment regimen for HCC that can provide meaningful survival benefit.展开更多
Liver disease accounts for approximately 2 million deaths per year worldwide with cirrhosis,viral hepatitis,and malignancy being the most common causes.Consequently,the regenerative capacity of the liver is a topic of...Liver disease accounts for approximately 2 million deaths per year worldwide with cirrhosis,viral hepatitis,and malignancy being the most common causes.Consequently,the regenerative capacity of the liver is a topic of extreme interest in the search for curative therapies to end-stage liver disease.Mesenchymal stem cells(MSCs)have emerged as a promising new therapy for hepatic regeneration.MSCs have multiple properties that make them an appropriate treatment option for liver disease including easy accessibility,targeted migration,immunomodulatory potential and antifibrotic/antioxidant effects.Additionally,MSCs have potential clinical applications in acellular therapy and tissue engineering.Liver regeneration with concurrent attenuation of liver injury makes MSCs a compelling therapeutic target in the setting of severe liver disease.This review outlines the mechanisms of MSC-driven liver regeneration and suggests potential clinical applications.展开更多
文摘Hepatocellular carcinoma(HCC)is the most common type of primary liver malignancy and the fourth leading cause of cancer-related deaths globally.HCC is often diagnosed in late stage,difficult to treat,and has poor prognosis with a median survival of 6-20 months.Innate and adaptive immunity play a pivotal role in determining tumor control versus progression.Genomic instability and abnormal signaling in the setting of chronic liver inflammation lead to tumorigenesis.Tumor progression occurs due to a sustained inflammatory response that promotes fibrogenesis and angiogenesis.This review discusses the key innate and adaptive cellular players that mediate the anti-tumor response.This review explores the complex interactions that occur within the tumor microenvironment and their clinical implications.HCC is a fastidious malignancy that is able to evade and downregulate the host immune response.Mechanisms of how this occurs are discussed,along with how they may be exploited in the development of novel therapeutics.From our research,it appears that striking a balance between immunotolerance and a robust immune response may yield the best prognosis.This review assesses major and recent developments in HCC immunotherapy,including adoptive cell therapy,cancer vaccines,and targeted therapy such as checkpoint inhibitors.Overall,the importance of the immune response in determining outcomes for HCC cannot be understated.Improved animal models and better characterization of the tumor microenvironment are needed.We determine that a better understanding of the HCC immune profile would facilitate advancements in diagnosis,monitoring,and ultimately treatment.
基金supported by VA Merit Award 5 I01 BX005730VA Research Career Scientist(IK6BX004477)+1 种基金National Institutes of Health Grant R01 DK104893,R01DK-057543 and 1R01AA030180funding from NIH-NCI Cancer Center Support Grant P30 CA016059.
文摘The liver plays an important role in both metabolism and immunity.Disruption of the hepatic immune microenvironment is closely associated with various liver diseases.To gain a better understanding of how different types of immune cells contribute to the progression of liver diseases,it is crucial to thoroughly characterize hepatic immune cells.Although direct digestion of liver tissue is a relatively simple method for isolating immune cells,it often induces excessive hepatocyte death,which causes a release of intracellular components that leads to the activation of stress responses and injury in the surrounding cells.This injury can lead to excessive death in the hepatic immune cells,making isolation and accurate characterization of the immune profile challenging,especially in diseased livers.The method described here addresses these challenges by utilizing Phosphate buffered saline(PBS)and digestion buffer perfusions to eliminate contaminating blood cells,ensure a pure hepatic immune population,and minimize hepatic immune cell death.Further ex vivo digestion of the liver enables the isolation of the immune cells from the hepatic tissues and the generation of a single-cell suspension that can be stained for spectral flow cytometry.To enhance intracellular cytokine detection and maintain signaling under different physiological and pathological conditions,this protocol uses an in vivo administration of Brefeldin A,a less toxic inhibitor of cytokine secretion.This in vivo administration of Brefeldin A allows for a more accurate representation of the immune cell function and cytokine expression compared to the traditionally used ex vivo Brefeldin A administration.A comprehensive spectral flow cytometry panel,comprising extracellular and intracellular staining,is used for deep immunophenotyping and immune cell effector function profiling.While this protocol is specifically designed for liver digestion of Mdr2 knockout mice(a model for primary sclerosing cholangitis)and flow cytometry staining,it can also be applied to other liver diseases and sensitive tissues.
基金supported in part by The National Cancer Institute(NCI)Grants(Nos.1R01CA230561-01A1,1R01CA240004-01 and 1R01CA244993-01)The National Institute of Diabetes and Digestive and Kidney Diseases(NIDDK)Grant(No.2R01DK107451-05).
文摘Hepatocellular carcinoma(HCC)is a highly fatal disease,the mortality of which runs parallel to its incidence.Historically,viral hepatitis has been the major cause of HCC(1).Vaccine is available for hepatitis B virus(HBV)and a drug cocktail is effective in bringing down blood hepatitis C virus(HCV)level to zero.With successful application of mRNA vaccine for COVID-19,it is a matter of time before an effective vaccine for HCV is generated.Despite these positive advancements,the incidence of HCC is continuing to rise because of HCC development as a direct consequence of non-alcoholic steatohepatitis(NASH)caused by obesity(1).While viral hepatitis is waning in the Western countries,obesity is now a global problem,requiring impactful treatment regimen for HCC that can provide meaningful survival benefit.
文摘Liver disease accounts for approximately 2 million deaths per year worldwide with cirrhosis,viral hepatitis,and malignancy being the most common causes.Consequently,the regenerative capacity of the liver is a topic of extreme interest in the search for curative therapies to end-stage liver disease.Mesenchymal stem cells(MSCs)have emerged as a promising new therapy for hepatic regeneration.MSCs have multiple properties that make them an appropriate treatment option for liver disease including easy accessibility,targeted migration,immunomodulatory potential and antifibrotic/antioxidant effects.Additionally,MSCs have potential clinical applications in acellular therapy and tissue engineering.Liver regeneration with concurrent attenuation of liver injury makes MSCs a compelling therapeutic target in the setting of severe liver disease.This review outlines the mechanisms of MSC-driven liver regeneration and suggests potential clinical applications.
