Hepatitis B virus(HBV)infection plays an important role in the occurrence and development of hepatocellular carcinoma(HCC),and the rate of HBV infection in liver cancer patients in China is as high as 92.05%.Due to lo...Hepatitis B virus(HBV)infection plays an important role in the occurrence and development of hepatocellular carcinoma(HCC),and the rate of HBV infection in liver cancer patients in China is as high as 92.05%.Due to long-term exposure to chronic antigens from the gut,the liver needs to maintain a certain level of immune tolerance,both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors.Therefore,HBV infection interacts with the tumor microenvironment(TME)through a highly complex and intertwined signaling pathway,which results in a special TME in HCC.Due to changes in the TME,tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4(CTLA-4)and programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1).Interferons,as a class of immune factors with strong biological activity,can improve the TME of HBV-HCC through various pathways.In recent years,the systematic treatment of HCC has gradually come out of the dilemma.In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs,immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC.At present,immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC,and the disease charac-teristics of patients included in global clinical studies are different from those of Chinese patients.Therefore,whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern.This review aims to elucidate the advances of immuno-therapy for HBV related HCC patients with regard to:(1)Immunotherapy based on interferons;(2)Immunotherapy based on PD-1/L1 inhibitors;(3)Immunotherapy based on CTLA4 inhibitors;(4)Adoptive cell transfer;(5)Combination immunotherapy strategy;and(6)Shortcomings of immunotherapy.展开更多
BACKGROUND As a proteoglycan,VCAN exists in the tumor microenvironment and regulates tumor proliferation,invasion,and metastasis,but its role in hepatocellular carcinoma(HCC)has not yet been elucidated.AIM To investig...BACKGROUND As a proteoglycan,VCAN exists in the tumor microenvironment and regulates tumor proliferation,invasion,and metastasis,but its role in hepatocellular carcinoma(HCC)has not yet been elucidated.AIM To investigate the expression and potential mechanism of action of VCAN in HCC.METHODS Based on The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset,we explored the correlation between VCAN expression and clinical features,and analyzed the prognosis of patients with high and low VCAN expression.The potential mechanism of action of VCAN was explored by Gene Ontology analysis,Kyoto Encyclopedia of Genes and Genomes analysis,and gene set enrichment analysis.We also explored immune cell infiltration,immune checkpoint gene expression,and sensitivity of immune checkpoint[programmed cell death protein 1(PD-1)/cytotoxic T lymphocyte antigen 4(CTLA4)]inhibitor therapy in patients with different VCAN expression.VCAN mRNA expression and VCAN methylation in peripheral blood were tested in 100 hepatitis B virus(HBV)-related patients(50 HCC and 50 liver cirrhosis).RESULTS VCAN was highly expressed in HCC tissues,which was associated with a poor prognosis in HCC patients.No significant difference was found in VCAN mRNA expression in blood between patients with HBV-related cirrhosis and those with HCC,but there was a significant difference in VCAN methylation between the two groups.The correlation between VCAN and infiltrations of several different tumor immune cell types(including B cells,CD8+T cells,and eosinophils)was significantly different.VCAN was strongly related to immune checkpoint gene expression and tumor mutation burden,and could be a biomarker of sensitivity to immune checkpoint(PD1/CTLA4)inhibitors.In addition,VCAN mRNA expression was associated with hepatitis B e antigen,HBV DNA,white blood cells,platelets,cholesterol,and coagulation function.CONCLUSION High VCAN level could be a possible biomarker for poor prognosis of HCC,and its immunomodulatory mechanism in HCC warrants investigation.展开更多
The application of immune checkpoint inhibitors(ICI)in advanced cancer has been a major development in the last decade.The indications for ICIs are constantly expanding into new territory across different cancers,dise...The application of immune checkpoint inhibitors(ICI)in advanced cancer has been a major development in the last decade.The indications for ICIs are constantly expanding into new territory across different cancers,disease stages and lines of therapy.With this increased use,adverse events including immune checkpoint inhibitor-related hepatotoxicity(ICH)have emerged as an important clinical problem.This along with the introduction of ICI as first-and second-line treatments for advanced hepatocellular carcinoma makes ICH very relevant to gastroenterologists and hepatologists.The incidence of ICH varies between 1%-20%depending on the number,type and dose of ICI received.Investigation and management generally involve excluding differential diagnoses and following a stepwise escalation of withholding or ceasing ICI,corticosteroid treatment and adding other immunosuppressive agents depending on the severity of toxicity.The majority of patients with ICH recover and some may even safely recommence ICI therapy.Guideline recommendations are largely based on evidence derived from retrospective case series which highlights a priority for future research.展开更多
BACKGROUND Immune checkpoint inhibitors(ICIs)can lead to immune-related hepatitis(IRH)and severe liver damage,which is life-threatening in the absence of specific treatment.CASE SUMMARY A 75-year-old man was admitted ...BACKGROUND Immune checkpoint inhibitors(ICIs)can lead to immune-related hepatitis(IRH)and severe liver damage,which is life-threatening in the absence of specific treatment.CASE SUMMARY A 75-year-old man was admitted to our hospital complaining of loss of appetite,yellow urine,and abnormal liver function for the past 2 wk.Three months prior to admission,he was treated with two rounds of capecitabine in combination with camrelizumab for lymph node metastasis of esophageal cancer.Although liver function was normal before treatment,abnormal liver function appeared at week 5.Capecitabine and camrelizumab were discontinued.Ursodeoxycholic acid and methylprednisolone 40 mg daily were administered.Liver function continued to deteriorate.Prothrombin time and international normalized ratio were 19 s and 1.8,respectively.The patient was diagnosed with acute liver failure.A pathological analysis of liver biopsy indicated a strongly positive immunohistochemical staining of T8+cells,thereby suggesting that drug-induced liver injury was related to IRH caused by camrelizumab.Subsequently,we performed sequential dual-molecule plasma adsorption system(DPMAS)treatment with plasma exchange(PE).After two rounds of treatment,the patient's appetite significantly improved,the yellow color of urine reduced,and liver function improved(total bilirubin level decreased)after five rounds of treatment.Liver function normalized 4 wk after discharge.CONCLUSION The use of sequential DPMAS with PE can reduce liver injury and systemic toxic reactions by clearing inflammatory mediators and harmful substances from blood,and regulate immune cell activity,which may be effective in the treatment of severe ICI-induced IRH.展开更多
Virus-specific T cells play an important role in the resolution of hepatic infection. However, during chronic hepatitis infection these cells lack their effector functions and fail to control the virus. Hepatitis B vi...Virus-specific T cells play an important role in the resolution of hepatic infection. However, during chronic hepatitis infection these cells lack their effector functions and fail to control the virus. Hepatitis B virus and hepatitis C virus have developed several mechanisms to generate immune tolerance. One of these strategies is the depletion of virus-specific T cells by apoptosis. The immunotolerogenic liver has unique property to retain and activate na ve T cell to avoid the over reactivation of immune response against antigens which is exploited by hepatotropic viruses to persist. The deletion of the virus-specific T cells occurs by intrinsic (passive) apoptotic mechanism. The pro-apoptotic molecule Bcl-2 interacting mediator (Bim) has attracted increasing attention as a pivotal involvement in apoptosis, as a regulator of tissue homeostasis and an enhancer for the viral persistence. Here, we reviewed our current knowledge on the evidence showing critical role of Bim in viral-specific T cell death by apoptotic pathways and helps in the immune tolerance.展开更多
Immune checkpoint inhibitors(ICIs) are monoclonal antibodies that target downregulators of the anti-cancer immune response: Cytotoxic T-lymphocyte antigen-4, programmed cell death protein-1, and its ligand programmed ...Immune checkpoint inhibitors(ICIs) are monoclonal antibodies that target downregulators of the anti-cancer immune response: Cytotoxic T-lymphocyte antigen-4, programmed cell death protein-1, and its ligand programmed death-ligand 1.ICIs have revolutionized the treatment of a variety of malignancies. However,many immune-related adverse events have also been described which mainly occurs as the immune system becomes less suppressed, affecting various organs including the gastrointestinal tract and causing diarrhea and colitis. The incidence of immune-mediated colitis(IMC) ranges from 1%-25% depending on the type of ICI and if used in combination. Endoscopically and histologically there is a significant overlap between IMC and inflammatory bowel disease,however more neutrophilic inflammation without chronic inflammation is usually present in IMC. Corticosteroids are recommended for grade 2 or more severe colitis while holding the immunotherapy. About one third to two thirds of patients are steroid refractory and benefit from infliximab. Recently vedolizumab has been found to be efficacious in steroid and infliximab refractory cases. While in grade 4 colitis, the immunotherapy is permanently discontinued, the decision is controversial in grade 3 colitis.展开更多
The risk of reactivation in patients with chronic or past/resolved hepatitis B virus(HBV)infection receiving chemotherapy or immunosuppressive drugs is a wellknown possibility.The indication of antiviral prophylaxis w...The risk of reactivation in patients with chronic or past/resolved hepatitis B virus(HBV)infection receiving chemotherapy or immunosuppressive drugs is a wellknown possibility.The indication of antiviral prophylaxis with nucleo(t)side analogue is given according to the risk of HBV reactivation of the prescribed therapy.Though the advent of new drugs is occurring in all the field of medicine,in the setting of hematologic malignancies the last few years have been characterized by several drug classes and innovative cellular treatment.As novel therapies,there are few data about the rate of HBV reactivation and the decision of starting or not an antiviral prophylaxis could be challenging.Moreover,patients are often treated with a combination of different drugs,so evaluating the actual role of these new therapies in increasing the risk of HBV reactivation is difficult.First results are now available,but further studies are still needed.Patients with chronic HBV infection[hepatitis B surface antigen(HBsAg)positive]are reasonably all treated.Past/resolved HBV patients(HBsAg negative)are the actual area of uncertainty where it could be difficult choosing between prophylaxis and pre-emptive strategy.展开更多
In Japan,liver biopsies were previously crucial in evaluating the severity of hepatitis caused by the hepatitis C virus(HCV)and diagnosing HCV-related hepatocellular carcinoma(HCC).However,due to the development of ef...In Japan,liver biopsies were previously crucial in evaluating the severity of hepatitis caused by the hepatitis C virus(HCV)and diagnosing HCV-related hepatocellular carcinoma(HCC).However,due to the development of effective antiviral treatments and advanced imaging,the necessity for biopsies has significantly decreased.This change has resulted in fewer chances for diagnosing liver disease,causing many general pathologists to feel less confident in making liver biopsy diagnoses.This article provides a comprehensive overview of the challenges and potential solutions related to liver biopsies in Japan.First,it highlights the importance of considering steatotic liver diseases as independent conditions that can coexist with other liver diseases due to their increasing prevalence.Second,it emphasizes the need to avoid hasty assumptions of HCC in nodular lesions,because clinically diagnosable HCCs are not targets for biopsy.Third,the importance of diagnosing hepatic immune-related adverse events caused by immune checkpoint inhibitors is increasing due to the anticipated widespread use of these drugs.In conclusion,pathologists should be attuned to the changing landscape of liver diseases and approach liver biopsies with care and attention to detail.展开更多
Hepatocellular carcinoma (HCC), chronic hepatitis B (CHB) and chronic hepatitis C (CHC) are characterized by exhaustion of the specific CD8<sup>+</sup> T cell response. This process involves enhancement of...Hepatocellular carcinoma (HCC), chronic hepatitis B (CHB) and chronic hepatitis C (CHC) are characterized by exhaustion of the specific CD8<sup>+</sup> T cell response. This process involves enhancement of negative co-stimulatory molecules, such as programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), 2B4, Tim-3, CD160 and LAG-3, which is linked to intrahepatic overexpression of some of the cognate ligands, such as PD-L1, on antigen presenting cells and thereby favouring a tolerogenic environment. Therapies that disrupt these negative signalling mechanisms represent promising therapeutic tools with the potential to restore reactivity of the specific CD8<sup>+</sup> T cell response. In this review we discuss the impressive in vitro and in vivo results that have been recently achieved in HCC, CHB and CHC by blocking these negative receptors with monoclonal antibodies against these immune checkpoint modulators. The article mainly focuses on the role of CTLA-4 and PD-1 blocking monoclonal antibodies, the first ones to have reached clinical practice. The humanized monoclonal antibodies against CTLA-4 (tremelimumab and ipilimumab) and PD-1 (nivolumab and pembrolizumab) have yielded good results in testing of HCC and chronic viral hepatitis patients. Trelimumab, in particular, has shown a significant increase in the time to progression in HCC, while nivolumab has shown a remarkable effect on hepatitis C viral load reduction. The research on the role of ipilimumab, nivolumab and pembrolizumab on HCC is currently underway.展开更多
Background Immunotherapy shows promise as a treatment option for various cancers.However,there is growing concern over potential complications from hepatitis B virus(HBV)reactivation after checkpoint blockade immunoth...Background Immunotherapy shows promise as a treatment option for various cancers.However,there is growing concern over potential complications from hepatitis B virus(HBV)reactivation after checkpoint blockade immunotherapy.Although most of the previous clinical trials on immune checkpoint inhibitors(ICIs)excluded patients with HBV,a few case reports and retrospective studies of HBV reactivation have been published.The aim of this study is to assess the risk of hepatitis B virus reactivation(HBVr)in patients receiving ICIs for advanced cancer.Methods English and Chinese language literature published prior to April 30,2023,was searched in PubMed,EMBASE,Web of Science,Cochrane,SinoMed,CNKI and Wanfang Data for studies reporting HBVr rates in cancer patients treated with ICIs.A pooled risk estimate was calculated for HBVr rates with 95%confdence intervals(CI).Results Data from 34 studies including 7126 patients were retrieved and analyzed.The pooled HBVr rate in cancer patients treated with ICIs was 1.3%(I^(2)=90.44%,95%CI:0.2-2.9%,P<0.001).Subgroup analysis revealed that patients diagnosed with hepatocellular carcinoma(HCC),HBV carriers,and patients from Asian regions or in developing countries have a higher rate of HBVr.Conclusions Our meta-analysis demonstrated a low risk of HBVr in patients treated with ICIs for advanced cancer.ICI treatment may be safely used in patients with existing HBV infection or chronic hepatitis B,accompanied by regular monitoring and appropriate antiviral prophylaxis if necessary.展开更多
Immune-mediated hepatitis(IMH)induced by immune checkpoint inhibitors(ICIs)is an immune-related adverse event(irAE).IMH usually occurs 8-12 weeks after the first dose of ICI therapy.We report an unusual case of a lung...Immune-mediated hepatitis(IMH)induced by immune checkpoint inhibitors(ICIs)is an immune-related adverse event(irAE).IMH usually occurs 8-12 weeks after the first dose of ICI therapy.We report an unusual case of a lung cancer patient who developed IMH 2 years after initial ICI treatment and relapsed during corticosteroid therapy.A 55-year-old male with stageⅣB lung cancer received ICIs(for over 2 years)and chemotherapy as a second-line therapy.Grade 4 IMH occurred 2 years after initial immunotherapy and was diagnosed as hepatitis via laboratory and imaging tests with the simultaneous exclusion of other causes.The patient responded well to the corticosteroids;however,he decided to discontinue treatment prematurely,meaning that the total treatment period was less than 4 weeks.This led to IMH reoccurrence and the need to readminister corticosteroids at a higher dose than before.Ultimately,the patient's IMH was controlled and did not reoccur.This case illustrates that immune-related toxicity needs to be monitored in patients undergoing long-term ICI therapy.Improving patient education is also essential for the management and treatment of irAEs.展开更多
Hepatitis B virus(HBV)infection is a public health problem that endangers global health and is the leading cause for the occurrence and death due to hepatocellular carcinoma.Although nucleotide analogs are excellent i...Hepatitis B virus(HBV)infection is a public health problem that endangers global health and is the leading cause for the occurrence and death due to hepatocellular carcinoma.Although nucleotide analogs are excellent in controlling virus replication,they have little effect on the production,stability,and transcription of covalently closed circular DNA(cccDNA)in infected hepatocytes.Moreover,only a small fraction of patients with chronic hepatitis B are cured by interferon therapy.During HBV infection,HBV-specific B cells and T cells are produced.HBV-specific T cells exert antiviral effects through cell lysis and non-cytolytic effector functions,reducing viral intermediates and cccDNA.In addition,HBV-specific B cells produce antibodies that eliminate HBV-infected liver cells through antibody-dependent cell-mediated cytotoxicity of natural killer cells.They can also bind to the hepatitis B surface antigen on the surface of the virus particle,inducing antibody-dependent phagocytosis by Kupffer cells.These responses could be combined with immunotherapy based on antiviral therapy,which may achieve a complete cure for hepatitis B.However,patients with chronic hepatitis B have immune dysfunctions,which challenges immunotherapy implementation.This review focuses on advances in adaptive immunotherapy for chronic viral hepatitis B.展开更多
基金Supported by The National Key Research and Development Program,No.2022YFC2603500 and No.2022YFC2603505Beijing Municipal Health Commission High-Level Public Health Technical Personnel Construction Project,No.Discipline leader-03-26+2 种基金The Digestive Medical Coordinated Development Center of Beijing Hospitals Authority,No.XXZ0302The Capital Health Research and Development of Special Public Health Project,No.2022-1-2172and Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support,No.XMLX 202127.
文摘Hepatitis B virus(HBV)infection plays an important role in the occurrence and development of hepatocellular carcinoma(HCC),and the rate of HBV infection in liver cancer patients in China is as high as 92.05%.Due to long-term exposure to chronic antigens from the gut,the liver needs to maintain a certain level of immune tolerance,both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors.Therefore,HBV infection interacts with the tumor microenvironment(TME)through a highly complex and intertwined signaling pathway,which results in a special TME in HCC.Due to changes in the TME,tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4(CTLA-4)and programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1).Interferons,as a class of immune factors with strong biological activity,can improve the TME of HBV-HCC through various pathways.In recent years,the systematic treatment of HCC has gradually come out of the dilemma.In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs,immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC.At present,immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC,and the disease charac-teristics of patients included in global clinical studies are different from those of Chinese patients.Therefore,whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern.This review aims to elucidate the advances of immuno-therapy for HBV related HCC patients with regard to:(1)Immunotherapy based on interferons;(2)Immunotherapy based on PD-1/L1 inhibitors;(3)Immunotherapy based on CTLA4 inhibitors;(4)Adoptive cell transfer;(5)Combination immunotherapy strategy;and(6)Shortcomings of immunotherapy.
基金Supported by the National Natural Science Foundation of China,No.31500650 and 81902449the Key Research&Development Program-Social Development of Shaanxi Province,No.2020SF-063Shaanxi Key Research and Development Plans,No.2021SF-227.
文摘BACKGROUND As a proteoglycan,VCAN exists in the tumor microenvironment and regulates tumor proliferation,invasion,and metastasis,but its role in hepatocellular carcinoma(HCC)has not yet been elucidated.AIM To investigate the expression and potential mechanism of action of VCAN in HCC.METHODS Based on The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset,we explored the correlation between VCAN expression and clinical features,and analyzed the prognosis of patients with high and low VCAN expression.The potential mechanism of action of VCAN was explored by Gene Ontology analysis,Kyoto Encyclopedia of Genes and Genomes analysis,and gene set enrichment analysis.We also explored immune cell infiltration,immune checkpoint gene expression,and sensitivity of immune checkpoint[programmed cell death protein 1(PD-1)/cytotoxic T lymphocyte antigen 4(CTLA4)]inhibitor therapy in patients with different VCAN expression.VCAN mRNA expression and VCAN methylation in peripheral blood were tested in 100 hepatitis B virus(HBV)-related patients(50 HCC and 50 liver cirrhosis).RESULTS VCAN was highly expressed in HCC tissues,which was associated with a poor prognosis in HCC patients.No significant difference was found in VCAN mRNA expression in blood between patients with HBV-related cirrhosis and those with HCC,but there was a significant difference in VCAN methylation between the two groups.The correlation between VCAN and infiltrations of several different tumor immune cell types(including B cells,CD8+T cells,and eosinophils)was significantly different.VCAN was strongly related to immune checkpoint gene expression and tumor mutation burden,and could be a biomarker of sensitivity to immune checkpoint(PD1/CTLA4)inhibitors.In addition,VCAN mRNA expression was associated with hepatitis B e antigen,HBV DNA,white blood cells,platelets,cholesterol,and coagulation function.CONCLUSION High VCAN level could be a possible biomarker for poor prognosis of HCC,and its immunomodulatory mechanism in HCC warrants investigation.
文摘The application of immune checkpoint inhibitors(ICI)in advanced cancer has been a major development in the last decade.The indications for ICIs are constantly expanding into new territory across different cancers,disease stages and lines of therapy.With this increased use,adverse events including immune checkpoint inhibitor-related hepatotoxicity(ICH)have emerged as an important clinical problem.This along with the introduction of ICI as first-and second-line treatments for advanced hepatocellular carcinoma makes ICH very relevant to gastroenterologists and hepatologists.The incidence of ICH varies between 1%-20%depending on the number,type and dose of ICI received.Investigation and management generally involve excluding differential diagnoses and following a stepwise escalation of withholding or ceasing ICI,corticosteroid treatment and adding other immunosuppressive agents depending on the severity of toxicity.The majority of patients with ICH recover and some may even safely recommence ICI therapy.Guideline recommendations are largely based on evidence derived from retrospective case series which highlights a priority for future research.
文摘BACKGROUND Immune checkpoint inhibitors(ICIs)can lead to immune-related hepatitis(IRH)and severe liver damage,which is life-threatening in the absence of specific treatment.CASE SUMMARY A 75-year-old man was admitted to our hospital complaining of loss of appetite,yellow urine,and abnormal liver function for the past 2 wk.Three months prior to admission,he was treated with two rounds of capecitabine in combination with camrelizumab for lymph node metastasis of esophageal cancer.Although liver function was normal before treatment,abnormal liver function appeared at week 5.Capecitabine and camrelizumab were discontinued.Ursodeoxycholic acid and methylprednisolone 40 mg daily were administered.Liver function continued to deteriorate.Prothrombin time and international normalized ratio were 19 s and 1.8,respectively.The patient was diagnosed with acute liver failure.A pathological analysis of liver biopsy indicated a strongly positive immunohistochemical staining of T8+cells,thereby suggesting that drug-induced liver injury was related to IRH caused by camrelizumab.Subsequently,we performed sequential dual-molecule plasma adsorption system(DPMAS)treatment with plasma exchange(PE).After two rounds of treatment,the patient's appetite significantly improved,the yellow color of urine reduced,and liver function improved(total bilirubin level decreased)after five rounds of treatment.Liver function normalized 4 wk after discharge.CONCLUSION The use of sequential DPMAS with PE can reduce liver injury and systemic toxic reactions by clearing inflammatory mediators and harmful substances from blood,and regulate immune cell activity,which may be effective in the treatment of severe ICI-induced IRH.
基金Supported by Grants from "Fiscam" JCCM, Ayuda para proyectos de investigación en salud, PI-2010/022"Fundación de Investigación Médica Mutua Madrilea", Beca Ayudas a la Investigación FMMM, 8922/2011A research grant from "Asociación de Hepatología Translacional", No. AHT 2010-01, to Lokhande MU
文摘Virus-specific T cells play an important role in the resolution of hepatic infection. However, during chronic hepatitis infection these cells lack their effector functions and fail to control the virus. Hepatitis B virus and hepatitis C virus have developed several mechanisms to generate immune tolerance. One of these strategies is the depletion of virus-specific T cells by apoptosis. The immunotolerogenic liver has unique property to retain and activate na ve T cell to avoid the over reactivation of immune response against antigens which is exploited by hepatotropic viruses to persist. The deletion of the virus-specific T cells occurs by intrinsic (passive) apoptotic mechanism. The pro-apoptotic molecule Bcl-2 interacting mediator (Bim) has attracted increasing attention as a pivotal involvement in apoptosis, as a regulator of tissue homeostasis and an enhancer for the viral persistence. Here, we reviewed our current knowledge on the evidence showing critical role of Bim in viral-specific T cell death by apoptotic pathways and helps in the immune tolerance.
文摘Immune checkpoint inhibitors(ICIs) are monoclonal antibodies that target downregulators of the anti-cancer immune response: Cytotoxic T-lymphocyte antigen-4, programmed cell death protein-1, and its ligand programmed death-ligand 1.ICIs have revolutionized the treatment of a variety of malignancies. However,many immune-related adverse events have also been described which mainly occurs as the immune system becomes less suppressed, affecting various organs including the gastrointestinal tract and causing diarrhea and colitis. The incidence of immune-mediated colitis(IMC) ranges from 1%-25% depending on the type of ICI and if used in combination. Endoscopically and histologically there is a significant overlap between IMC and inflammatory bowel disease,however more neutrophilic inflammation without chronic inflammation is usually present in IMC. Corticosteroids are recommended for grade 2 or more severe colitis while holding the immunotherapy. About one third to two thirds of patients are steroid refractory and benefit from infliximab. Recently vedolizumab has been found to be efficacious in steroid and infliximab refractory cases. While in grade 4 colitis, the immunotherapy is permanently discontinued, the decision is controversial in grade 3 colitis.
文摘The risk of reactivation in patients with chronic or past/resolved hepatitis B virus(HBV)infection receiving chemotherapy or immunosuppressive drugs is a wellknown possibility.The indication of antiviral prophylaxis with nucleo(t)side analogue is given according to the risk of HBV reactivation of the prescribed therapy.Though the advent of new drugs is occurring in all the field of medicine,in the setting of hematologic malignancies the last few years have been characterized by several drug classes and innovative cellular treatment.As novel therapies,there are few data about the rate of HBV reactivation and the decision of starting or not an antiviral prophylaxis could be challenging.Moreover,patients are often treated with a combination of different drugs,so evaluating the actual role of these new therapies in increasing the risk of HBV reactivation is difficult.First results are now available,but further studies are still needed.Patients with chronic HBV infection[hepatitis B surface antigen(HBsAg)positive]are reasonably all treated.Past/resolved HBV patients(HBsAg negative)are the actual area of uncertainty where it could be difficult choosing between prophylaxis and pre-emptive strategy.
文摘In Japan,liver biopsies were previously crucial in evaluating the severity of hepatitis caused by the hepatitis C virus(HCV)and diagnosing HCV-related hepatocellular carcinoma(HCC).However,due to the development of effective antiviral treatments and advanced imaging,the necessity for biopsies has significantly decreased.This change has resulted in fewer chances for diagnosing liver disease,causing many general pathologists to feel less confident in making liver biopsy diagnoses.This article provides a comprehensive overview of the challenges and potential solutions related to liver biopsies in Japan.First,it highlights the importance of considering steatotic liver diseases as independent conditions that can coexist with other liver diseases due to their increasing prevalence.Second,it emphasizes the need to avoid hasty assumptions of HCC in nodular lesions,because clinically diagnosable HCCs are not targets for biopsy.Third,the importance of diagnosing hepatic immune-related adverse events caused by immune checkpoint inhibitors is increasing due to the anticipated widespread use of these drugs.In conclusion,pathologists should be attuned to the changing landscape of liver diseases and approach liver biopsies with care and attention to detail.
基金Supported by "Instituto de Salud Carlos Ⅲ",Spain& "European Regional Development Fund(ERDF)a way of making Europe",No.PI12/00130 and No.PI15/00074and"Gilead Spain&Instituto de Salud Carlos Ⅲ",No.GLD14_00217
文摘Hepatocellular carcinoma (HCC), chronic hepatitis B (CHB) and chronic hepatitis C (CHC) are characterized by exhaustion of the specific CD8<sup>+</sup> T cell response. This process involves enhancement of negative co-stimulatory molecules, such as programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), 2B4, Tim-3, CD160 and LAG-3, which is linked to intrahepatic overexpression of some of the cognate ligands, such as PD-L1, on antigen presenting cells and thereby favouring a tolerogenic environment. Therapies that disrupt these negative signalling mechanisms represent promising therapeutic tools with the potential to restore reactivity of the specific CD8<sup>+</sup> T cell response. In this review we discuss the impressive in vitro and in vivo results that have been recently achieved in HCC, CHB and CHC by blocking these negative receptors with monoclonal antibodies against these immune checkpoint modulators. The article mainly focuses on the role of CTLA-4 and PD-1 blocking monoclonal antibodies, the first ones to have reached clinical practice. The humanized monoclonal antibodies against CTLA-4 (tremelimumab and ipilimumab) and PD-1 (nivolumab and pembrolizumab) have yielded good results in testing of HCC and chronic viral hepatitis patients. Trelimumab, in particular, has shown a significant increase in the time to progression in HCC, while nivolumab has shown a remarkable effect on hepatitis C viral load reduction. The research on the role of ipilimumab, nivolumab and pembrolizumab on HCC is currently underway.
文摘Background Immunotherapy shows promise as a treatment option for various cancers.However,there is growing concern over potential complications from hepatitis B virus(HBV)reactivation after checkpoint blockade immunotherapy.Although most of the previous clinical trials on immune checkpoint inhibitors(ICIs)excluded patients with HBV,a few case reports and retrospective studies of HBV reactivation have been published.The aim of this study is to assess the risk of hepatitis B virus reactivation(HBVr)in patients receiving ICIs for advanced cancer.Methods English and Chinese language literature published prior to April 30,2023,was searched in PubMed,EMBASE,Web of Science,Cochrane,SinoMed,CNKI and Wanfang Data for studies reporting HBVr rates in cancer patients treated with ICIs.A pooled risk estimate was calculated for HBVr rates with 95%confdence intervals(CI).Results Data from 34 studies including 7126 patients were retrieved and analyzed.The pooled HBVr rate in cancer patients treated with ICIs was 1.3%(I^(2)=90.44%,95%CI:0.2-2.9%,P<0.001).Subgroup analysis revealed that patients diagnosed with hepatocellular carcinoma(HCC),HBV carriers,and patients from Asian regions or in developing countries have a higher rate of HBVr.Conclusions Our meta-analysis demonstrated a low risk of HBVr in patients treated with ICIs for advanced cancer.ICI treatment may be safely used in patients with existing HBV infection or chronic hepatitis B,accompanied by regular monitoring and appropriate antiviral prophylaxis if necessary.
文摘Immune-mediated hepatitis(IMH)induced by immune checkpoint inhibitors(ICIs)is an immune-related adverse event(irAE).IMH usually occurs 8-12 weeks after the first dose of ICI therapy.We report an unusual case of a lung cancer patient who developed IMH 2 years after initial ICI treatment and relapsed during corticosteroid therapy.A 55-year-old male with stageⅣB lung cancer received ICIs(for over 2 years)and chemotherapy as a second-line therapy.Grade 4 IMH occurred 2 years after initial immunotherapy and was diagnosed as hepatitis via laboratory and imaging tests with the simultaneous exclusion of other causes.The patient responded well to the corticosteroids;however,he decided to discontinue treatment prematurely,meaning that the total treatment period was less than 4 weeks.This led to IMH reoccurrence and the need to readminister corticosteroids at a higher dose than before.Ultimately,the patient's IMH was controlled and did not reoccur.This case illustrates that immune-related toxicity needs to be monitored in patients undergoing long-term ICI therapy.Improving patient education is also essential for the management and treatment of irAEs.
基金This work was supported by the National Science and Technology Major Project of China(2018ZX10302206 and 2017ZX10202203)。
文摘Hepatitis B virus(HBV)infection is a public health problem that endangers global health and is the leading cause for the occurrence and death due to hepatocellular carcinoma.Although nucleotide analogs are excellent in controlling virus replication,they have little effect on the production,stability,and transcription of covalently closed circular DNA(cccDNA)in infected hepatocytes.Moreover,only a small fraction of patients with chronic hepatitis B are cured by interferon therapy.During HBV infection,HBV-specific B cells and T cells are produced.HBV-specific T cells exert antiviral effects through cell lysis and non-cytolytic effector functions,reducing viral intermediates and cccDNA.In addition,HBV-specific B cells produce antibodies that eliminate HBV-infected liver cells through antibody-dependent cell-mediated cytotoxicity of natural killer cells.They can also bind to the hepatitis B surface antigen on the surface of the virus particle,inducing antibody-dependent phagocytosis by Kupffer cells.These responses could be combined with immunotherapy based on antiviral therapy,which may achieve a complete cure for hepatitis B.However,patients with chronic hepatitis B have immune dysfunctions,which challenges immunotherapy implementation.This review focuses on advances in adaptive immunotherapy for chronic viral hepatitis B.
