EVI2A has emerged as a significant biomarker in various diseases;however,its biological role and mechanism in kidney renal clear cell carcinoma(KIRC)remains unexplored.We used TCGA and GEO databases to analyze EVI2A g...EVI2A has emerged as a significant biomarker in various diseases;however,its biological role and mechanism in kidney renal clear cell carcinoma(KIRC)remains unexplored.We used TCGA and GEO databases to analyze EVI2A gene expression comprehensively and performed pan-cancer assessments.Clinical relevance was evaluated through Kaplan-Meier analysis and ROC curves.The gene’s immune relevance was explored through analyses of the tumor microenvironment(TME),Tumor Immune Single-cell Hub(TISCH),immune checkpoints,and immunotherapy sensitivity.Our results indicate that EVI2A expression is upregulated in KIRC,showing correlations with tumor grade and T/N/M stage.EVI2A demonstrates high diagnostic accuracy(AUC=0.906)and predicts poor overall and progression-free survival in KIRC patients.Furthermore,EVI2A expression exhibits significant associations with immunity,including TME scores and specific immune cell types such as Tfh cells,CD4 memory T cells,and CD8+T cells.Elevated EVI2A expression suggests increased sensitivity to PD-1/CTLA-4 and tyrosine kinase inhibitors.In vitro assays confirmed the impact of EVI2A on KIRC behavior,with its knockdown resulting in reduced cell proliferation and migration.In conclusion,our comprehensive analysis identifies EVI2A as a promising biomarker and a novel therapeutic target for intervening in KIRC.These findings hold significant implications for further research and potential clinical applications.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)ranks as the fourth leading cause of cancerrelated deaths in China,and the treatment options are limited.The cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS...BACKGROUND Hepatocellular carcinoma(HCC)ranks as the fourth leading cause of cancerrelated deaths in China,and the treatment options are limited.The cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)activates the stimulator of interferon gene(STING)signaling pathway as a crucial immune response pathway in the cytoplasm,which detects cytoplasmic DNA to regulate innate and adaptive immune responses.As a potential therapeutic target,cGASSTING pathway markedly inhibits tumor cell proliferation and metastasis,with its activation being particularly relevant in HCC.However,prolonged pathway activation may lead to an immunosuppressive tumor microenvironment,which fostering the invasion or metastasis of liver tumor cells.AIM To investigate the dual-regulation mechanism of cGAS-STING in HCC.METHODS This review was conducted according to the PRISMA guidelines.The study conducted a comprehensive search for articles related to HCC on PubMed and Web of Science databases.Through rigorous screening and meticulous analysis of the retrieved literature,the research aimed to summarize and elucidate the impact of the cGAS-STING pathway on HCC tumors.RESULTS All authors collaboratively selected studies for inclusion,extracted data,and the initial search of online databases yielded 1445 studies.After removing duplicates,remaining 964 records were screened.Ultimately,55 articles met the inclusion criteria and were included in this review.CONCLUSION Acute inflammation can have a few inhibitory effects on cancer,while chronic inflammation generally promotes its progression.Extended cGAS-STING pathway activation will result in a suppressive tumor microenvironment.展开更多
BACKGROUND Hepatitis B virus(HBV)infection is a major factor responsible for HBV+hepatocellular carcinoma(HCC).AIM An immunological classification of HBV+HCC may provide both biological insights and clinical implicati...BACKGROUND Hepatitis B virus(HBV)infection is a major factor responsible for HBV+hepatocellular carcinoma(HCC).AIM An immunological classification of HBV+HCC may provide both biological insights and clinical implications for this disease.METHODS Based on the enrichment of 23 immune signatures,we identified two immunespecific subtypes(Imm-H and Imm-L)of HBV+HCC by unsupervised clustering.We showed that this subtyping method was reproducible and predictable by analyzing three different datasets.RESULTS Compared to Imm-L,Imm-H displayed stronger immunity,more stromal components,lower tumor purity,lower stemness and intratumor heterogeneity,lower-level copy number alterations,higher global methylation level,and better overall and disease-free survival prognosis.Besides immune-related pathways,stromal pathways(ECM receptor interaction,focal adhesion,and regulation of actin cytoskeleton)and neuro-related pathways(neuroactive ligand-receptor interaction,and prion diseases)were more highly enriched in Imm-H than in Imm-L.We identified nine proteins differentially expressed between Imm-H and Imm-L,of which MYH11,PDCD4,Dvl3,and Syk were upregulated in Imm-H,while PCNA,Acetyl-a-Tubulin-Lys40,ER-α_pS118,Cyclin E2,andβ-Catenin were upregulated in Imm-L.CONCLUSION Our data suggest that“hot”tumors have a better prognosis than“cold”tumors in HBV+HCC and that“hot”tumors respond better to immunotherapy.展开更多
AIM: To investigate the role of tumor inf iltrating lym-phocytes (TIL) in primary hepatocellular and cholangio-lar carcinomas of the liver.METHODS: Immunohistochemical analysis was per-formed including antibodies to C...AIM: To investigate the role of tumor inf iltrating lym-phocytes (TIL) in primary hepatocellular and cholangio-lar carcinomas of the liver.METHODS: Immunohistochemical analysis was per-formed including antibodies to CD3, CD4, CD8, CD20, CD56 and TIA-1 in formalin-f ixed and paraff in-embed-ded tissue of 35 liver resection specimens of hepatocel-lular or cholangiocellular carcinomas. Semiquantitative evaluation was performed with emphasis on the area of the tumor itself and of the tumor/liver interface.RESULTS: All hepatocellular carcinomas showed in-filtration of lymphocytes predominantly around the tumor in the tumor/liver interface consisting mainly of CD3+ CD4+ T lymphocytes [164.3/10 high power f ields (HPF)] and in the tumor itself of CD8+ cells (54.9/10 HPF). Cholangiocarcinomas contained a heterogeneous amount of TIL, composed mainly of CD3+ T cells with a predominance of CD8+ cells in the tumor tissue (52.6/10 HPF) and of CD4+ cells in the interface region (223.1/10 HPF). CD56+ cells of the innate immune system were scarce. There was no significant difference between hepatocellular or cholangiolar carcinoma. No correlation with the clinicopathological data was seen. CONCLUSION: Liver TIL consists of intratumoral CD8+ T cells and peritumoral CD4+ T cells indepen-dent of histogenetic origin. Different functions of lym-phocytes in these regions seem possible.展开更多
BACKGROUND Esophageal cancer is a common cause of cancer-related death worldwide.Cutaneous metastasis of esophageal squamous cell carcinoma is rare,particularly in diffuse skin metastasis.CASE SUMMARY In this case rep...BACKGROUND Esophageal cancer is a common cause of cancer-related death worldwide.Cutaneous metastasis of esophageal squamous cell carcinoma is rare,particularly in diffuse skin metastasis.CASE SUMMARY In this case report,we describe an 82-year-old male who was diagnosed with esophageal squamous cell carcinoma.The tumor was staged as T4N3M1(Stage IVB).The pathological findings revealed poorly differentiated squamous cell carcinoma of the esophagus.Four months after diagnosis,the patient began chemotherapy,and symptoms were relieved after four cycles of chemotherapy.After that,the patient returned home without a systematic physical examination.One year after diagnosis,the patient realized that the skin of the abdominal wall was hard and rough without pain,and the color became darker than normal skin.Thirteen months after diagnosis,a biopsy of the patient’s abdominal lesion revealed that the skin metastasis was derived from the esophagus.Then the patient received two cycles of apatinib combined with docetaxel,but the abdominal lesion worsened.Two cycles of nivolumab were administered,but the patient eventually died of multiple organ failure.CONCLUSION This report highlights cutaneous metastasis as a late and untreatable metastasis of esophageal cancer.展开更多
Spontaneous tumor regression is an extremely rare phenomenon in the oncology field. However, there are several case reports resulted in the regression of hepatocellular carcinoma(HCC) and the accumulation of clinical ...Spontaneous tumor regression is an extremely rare phenomenon in the oncology field. However, there are several case reports resulted in the regression of hepatocellular carcinoma(HCC) and the accumulation of clinical information and analyses of the mechanism can contribute to the development of a novel therapy. For this purpose, we have carefully reviewed 23 cases of spontaneously regressed HCC published in recent 5 years and our case. The information regarding the tumor size, tumor marker, treatments, etc., have been summarized. The mechanism of spontaneous regression has been discussed to date and presumed to be due to many factors, including hypoxia and immunological reactions. In this careful review of the 24 cases based on the clinical information, hypoxia, systemic inflammation, and both upon spontaneous regression were seen in 3, 8, and 4 cases, respectively amo ng t he 15 c as e s f or w hic h t he inf o r mat io n regarding the proposed mechanisms are available. Recent development of immunotherapeutic approaches in oncology shows promising results, therefore, accumulation of additional cases and analysis of mechanisms underlying the spontaneous regression of HCC are essential and could lead to the development of a new generation of immunotherapies including antibodies directed against immune reactions.展开更多
AIM: To characterize the anticancer function of cytokine-induced killer cells (CIK) and develop an adoptive immunotherapy for the patients with primary hepatocellular carcinoma (HCC), we evaluated the proliferation ra...AIM: To characterize the anticancer function of cytokine-induced killer cells (CIK) and develop an adoptive immunotherapy for the patients with primary hepatocellular carcinoma (HCC), we evaluated the proliferation rate, phenotype and the antitumor activity of human CIK cells from healthy donors and HCC patients in vitro and in vivo. METHODS: Peripheral blood mononuclear cells (PBMC) from healthy donors and patients with primary HCC were incubated in vitro and induced into CIK cells in the presence of various cytokines such as interferon-gamma (IFN-gamma), interleukin-1 (IL-1), IL-2 and monoclonal antibody (mAb) against CD3. The phenotype and characterization of CIK cells were identified by flow cytometric analysis. The cytotoxicity of CIK cells was determined by (51)Cr release assay. RESULTS: The CIK cells were shown to be a heterogeneous population with different cellular phenotypes. The percentage of CD3+/CD56+ positive cells, the dominant effector cells, in total CIK cells from healthy donors and HCC patients, significantly increased from 0.1-0.13% at day 0 to 19.0-20.5% at day 21 incubation, which suggested that the CD3+ CD56+ positive cells proliferated faster than other cell populations of CIK cells in the protocol used in this study. After 28 day in vitro incubation, the CIK cells from patients with HCC and healthy donors increased by more than 300-fold and 500-fold in proliferation cell number, respectively. CIK cells originated from HCC patients possessed a higher in vitro antitumor cytotoxic activity on autologous HCC cells than the autologous lymphokine-activated killer (LAK) cells and PBMC cells. In in vivo animal experiment, CIK cells had stronger effects on the inhibition of tumor growth in Balb/c nude mice bearing BEL-7402-producing tumor than LAK cells (mean inhibitory rate, 84.7% vs 52.8%, P【0.05) or PBMC (mean inhibitory rate, 84.7% vs 37.1%, P【0.01). CONCLUSION: Autologous CIK cells are of highly efficient cytotoxic effector cells against primary hepatocellular carcinoma cells and might serve as an alternative adoptive therapeutic strategy for HCC patients.展开更多
Hepatocellular carcinoma(HCC)is one of the most prevalent cancers and one of the main causes of cancer-related deaths worldwide.Most HCCs develop in an inflammatory microenvironment,and mounting evidence emphasizes th...Hepatocellular carcinoma(HCC)is one of the most prevalent cancers and one of the main causes of cancer-related deaths worldwide.Most HCCs develop in an inflammatory microenvironment,and mounting evidence emphasizes the importance of immune aspects in hepatocarcinogenesis.In normal physiology,both innate and adaptive immune responses are responsible for eliminating malignantly transformed cells,thus preventing the development of liver cancer.However,in the setting of impaired natural killer cells and exhaustion of T cells,HCC can develop.The immunogenic features of HCC have relevant clinical implications.There is a large number of immune markers currently being studied for the early detection of liver cancer,which would be critical in order to improve surveillance programs.Moreover,novel immunotherapies have recently been proven to be effective,and the combination of atezolizumab and bevacizumab is currently the most effective treatment for advanced HCC.It is expected that in the near future different subgroups of patients will benefit from specific immunotherapy.The better we understand the immune aspects of HCC,the greater the benefit to patients through surveillance aiming for early detection of liver cancer,which allows for curative treatments,and,in cases of advanced disease,through the selection of the best possible therapy for each individual.展开更多
Purpose: A series of clinical studies have established the safety and efficacy of transcatheter arterial chemoembolization(TACE) with gelatin sponge microparticles(GSMs) in treating hepatocellular carcinoma(HCC). HCC ...Purpose: A series of clinical studies have established the safety and efficacy of transcatheter arterial chemoembolization(TACE) with gelatin sponge microparticles(GSMs) in treating hepatocellular carcinoma(HCC). HCC can lead to obvious necrosis inside tumors, especially larger ones, although it is unclear whether such necrotic tumor tissue can induce favorable immune reactions against the tumor. Myeloid-derived suppressor cells(MDSCs)have immunosuppressive functions and are currently considered a very important cell type affecting tumor immunity. This study observed changes in MDSC frequency in peripheral blood before and after GSM–TACE to evaluate the effect on the immune function of HCC patients.Methods: Eight patients diagnosed with HCC underwent GSM–TACE treatment in the Hepatobiliary Interventional Department of Beijing Tsinghua Chang Gung Hospital, Beijing, China;we followed up with the patients over a period of 30 days post-surgery. We used flow cytometry(FCM) to quantify the frequency of MDSCs in peripheral blood before TACE, 10 days after surgery and 30 days after surgery.Results: MDSC frequency after GSM–TACE had a significant downward trend. Pre-TACE, it was 30.73% ? 11.93%,decreasing to 18.60% ? 11.37% at 10 days after operation. This decrease was not statistically significant(P > 0.05). MDSC frequency was even lower 30 days after TACE(7.63% ? 7.32%) than at 10 days after TACE(P < 0.05), and there was a significant difference compared with pre-TACE(P < 0.001). We evaluated tumor response at 30 days after GSM–TACE according to the Modified Response Evaluation Criteria in Solid Tumors(mRECIST), and all eight patients showed partial response(PR).Conclusion: Our results confirmed that GSM–TACE was beneficial for improving anti-tumor immunity in the treatment of HCC.展开更多
The specimens of 135 cases of primary hepatic carcinoma were obtained from the Pathological Laboratory of the First Affiliated Hospital of the Fourth Military Medical University, Xi' an, PRC. Ten percent formalin-...The specimens of 135 cases of primary hepatic carcinoma were obtained from the Pathological Laboratory of the First Affiliated Hospital of the Fourth Military Medical University, Xi' an, PRC. Ten percent formalin-fixed and paraffin- embedded sections were stained by HE and by ABC and PAP immunohistochemical methods. Positive rates of pre- S1 and pre- S2 antigens in cancerous tissue were 22. 2% and 20. 0%, respectively, while those in surrounding hepatic tissue were 60.6% and 59.6%, separately. The pre- S1 and pre- S2 antigens were found to coexist In 16. 3% of cancerous tissue and in 55. 6% of surrounding hepatic tissue. In all the 135 cases of hepatic carcinoma, the cancerous tissue showed positive HBsAg in 16. 3%, HBxAg in 55. 6% and HBcAg in 8. 9%; in the surrounding hepatic tissue, positive HBsAg was 59.6%, HBxAg 78.8% and HBcAg 24.2%. The results of this study suggestes that positive rates of pre- S1 and pre-S2 antigens in cancerous tissue were slightly higher than that of HBsAg, but markedly lower than that of HBxAg. The positive rate of pre-S1 and pre- S2 antigens in surrounding hepatic tissue was nearly the same as HBsAg, but slightly lower than that of HBxAg. Antigens of pre-S1 and pre-S2 are the new markers of HBV infection. The same as other antigens, they may play an important role in the development of hepatic carcinoma. The mechanism of their effect will be further investigated,展开更多
Hepatocellular carcinoma(HCC)is among the most common cancers and it is a major cause of cancer-related deaths.Non-alcoholic fatty liver disease(NAFLD)affects approximately one fourth of individuals worldwide and it i...Hepatocellular carcinoma(HCC)is among the most common cancers and it is a major cause of cancer-related deaths.Non-alcoholic fatty liver disease(NAFLD)affects approximately one fourth of individuals worldwide and it is becoming one of the most important causes of HCC.The pathogenic mechanisms leading to NAFLD-related HCC are complex and not completely understood.However,metabolic,fibrogenic,oncogenic,inflammatory and immunological pathways seem to be involved.First-line therapy of advanced HCC has recently undergone major changes,since the combination of atezolizumab and bevacizumab was proven to increase survival when compared to sorafenib.Other immune-oncology drugs are also demonstrating promising results in patients with advanced HCC when compared to traditional systemic therapy.However,initial studies raised concerns that the advantages of immunotherapy might depend on the underlying liver disease,which seems to be particularly important in NAFLD-related HCC,as these tumors might not benefit from it.This article will review the mechanisms of NAFLD-related hepatocarcinogenesis,with an emphasis on its immune aspects,the efficacy of traditional systemic therapy for advanced NAFLD-related HCC,and the most recent data on the role of immunotherapy for this specific group of patients,showing that the management of this condition should be individualized and that a general recommendation cannot be made at this time.展开更多
Liver cancer is one of the most common causes of cancer death globally,and its incidence in the United States is increasing.Patients with advanced hepatocellular carcinoma(HCC)who are not candidates for surgical resec...Liver cancer is one of the most common causes of cancer death globally,and its incidence in the United States is increasing.Patients with advanced hepatocellular carcinoma(HCC)who are not candidates for surgical resection,liver transplant,or locoregional therapies can be treated with systemic therapies.Multiple agents,including sorafenib,lenvatinib,and regorafenib are approved for use as either first-or second-line therapy in this patient population,but all have relatively modest survival benefits.HCC is potentially susceptible to therapy with checkpoint inhibitors,including agents such as nivolumab and pembrolizumab,which are both approved by the Food and Drug Administration for patients previously treated with sorafenib but have not demonstrated superior overall survival in phase III trials.It is clear that more effective approaches are needed to potentiate the effects of checkpoint inhibitors in patients with HCC.This review will outline and appraise the current literature on the use of checkpoint inhibitors in HCC as part of a combination treatment involving an additional mode of therapy.The list of agents that can be paired with checkpoint inhibitors includes an additional checkpoint inhibitor,vascular endothelial growth factor or vascular endothelial growth factor receptor inhibitors,tyrosine kinase inhibitors,OX-40 agonists,and PT-112 inhibitors.The main non-pharmacologic therapies currently being studied for inclusion in a combination strategy include radiation therapy,trans-arterial chemoembolization,and ablation.展开更多
Background Different strategies for hepatocellular carcinoma (HCC) may have distinct effects on the immune system.The aim of this research was to investigate changes in the immunological function after transcatheter...Background Different strategies for hepatocellular carcinoma (HCC) may have distinct effects on the immune system.The aim of this research was to investigate changes in the immunological function after transcatheter arterial chemoembolization (TACE) plus radiofrequency ablation (RFA) in HCC patients.Methods A total of 51 consecutive HCC treatment-naive patients was enrolled in this study and 20 healthy subjects served as controls.The therapeutic strategy was selected according to the tumor stage and general conditions.TACE was performed in 25 cases,TACE plus RFA in 17 and RFA in nine.All the patients underwent routine examinations and peripheral blood was harvested for the detection of lymphocyte subset by flow cytometry 1 day before,and 2 and 4 weeks after the treatment.The serum levels of alpha-fetoprotein (AFP),ALT and AST were also measured before and 4 weeks after treatment for the evaluation of therapeutic efficacy and liver function impairment.Results When compared with healthy controls,the CD4/CD8 ratio and the number of B cells and natural killer (NK) cells were significantly decreased in HCC patients before treatment (P 〈0.05).When compared with before treatment,the CD4+ cells and CD4/CD8 ratio decreased but CD8+ cells increased in the TACE group (P 〈0.05); the CD4/CD8 ratio and NK cells decreased but CD8+ cells increased in the TACE-RFA group (P 〈0.05); the CD3+ cells,CD4+ cells,CD4/CD8 ratio and NK cells increased in the RFA group (P 〈0.05).Significant differences in the CD3+ cells,CD8+ cells,CD4/CD8 ratio and NK cells were observed among groups (P 〈0.05).Moreover,the AFP level decreased and transaminase level increased in all groups (P 〈0.05).Differences of pre and post treatment between groups were statistically significant (P =0.016,0.025,0.018 respectively).Conclusions Immunity was compromised in HCC patients; TACE and TACE plus RFA lowered immunologic function to a certain extent.RFA improved it accompanied by a protective effect on liver function.展开更多
Hepatocellular carcinoma(HCC)carries an unfavorable prognosis and novel therapeutic strategies are needed.Until now,only few systemic agents have improved survival in patients with advanced stage disease.Immunotherapy...Hepatocellular carcinoma(HCC)carries an unfavorable prognosis and novel therapeutic strategies are needed.Until now,only few systemic agents have improved survival in patients with advanced stage disease.Immunotherapy changed the landscape in several tumor types by producing unprecedented clinical outcomes with a favorable safety profile.Liver presents a particular immune-suppressive microenvironment and HCC develops in a background of chronic inflammation in the vast majority of cases.In this regard,immunotherapy may be a suitable strategy.Preliminary research focused on therapies involving immune cells and anti-tumor immune response for HCC has shown encouraging preliminary results.Immune checkpoint inhibitors,such the anti-PD-1/PD-L1 monoclonal antibodies,have provided durable responses in patients with advanced stage disease,although the pioneers phaseⅢtrials did not confirm survival superiority over the available agents.Cancer vaccines,adoptive cellular therapies and combinations of local modalities with immunotherapy are promising approaches under active research.展开更多
基金the Ethics Committee of the First Affiliated Hospital of Nanchang University(Approval:(2023)CDYFYYLK(03-013)).
文摘EVI2A has emerged as a significant biomarker in various diseases;however,its biological role and mechanism in kidney renal clear cell carcinoma(KIRC)remains unexplored.We used TCGA and GEO databases to analyze EVI2A gene expression comprehensively and performed pan-cancer assessments.Clinical relevance was evaluated through Kaplan-Meier analysis and ROC curves.The gene’s immune relevance was explored through analyses of the tumor microenvironment(TME),Tumor Immune Single-cell Hub(TISCH),immune checkpoints,and immunotherapy sensitivity.Our results indicate that EVI2A expression is upregulated in KIRC,showing correlations with tumor grade and T/N/M stage.EVI2A demonstrates high diagnostic accuracy(AUC=0.906)and predicts poor overall and progression-free survival in KIRC patients.Furthermore,EVI2A expression exhibits significant associations with immunity,including TME scores and specific immune cell types such as Tfh cells,CD4 memory T cells,and CD8+T cells.Elevated EVI2A expression suggests increased sensitivity to PD-1/CTLA-4 and tyrosine kinase inhibitors.In vitro assays confirmed the impact of EVI2A on KIRC behavior,with its knockdown resulting in reduced cell proliferation and migration.In conclusion,our comprehensive analysis identifies EVI2A as a promising biomarker and a novel therapeutic target for intervening in KIRC.These findings hold significant implications for further research and potential clinical applications.
基金Supported by the National Natural Science Foundation of China,No.81973840the Sichuan Provincial Administration of Traditional Chinese Medicine Major Science and Technology projects,No.2021XYCZ004。
文摘BACKGROUND Hepatocellular carcinoma(HCC)ranks as the fourth leading cause of cancerrelated deaths in China,and the treatment options are limited.The cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)activates the stimulator of interferon gene(STING)signaling pathway as a crucial immune response pathway in the cytoplasm,which detects cytoplasmic DNA to regulate innate and adaptive immune responses.As a potential therapeutic target,cGASSTING pathway markedly inhibits tumor cell proliferation and metastasis,with its activation being particularly relevant in HCC.However,prolonged pathway activation may lead to an immunosuppressive tumor microenvironment,which fostering the invasion or metastasis of liver tumor cells.AIM To investigate the dual-regulation mechanism of cGAS-STING in HCC.METHODS This review was conducted according to the PRISMA guidelines.The study conducted a comprehensive search for articles related to HCC on PubMed and Web of Science databases.Through rigorous screening and meticulous analysis of the retrieved literature,the research aimed to summarize and elucidate the impact of the cGAS-STING pathway on HCC tumors.RESULTS All authors collaboratively selected studies for inclusion,extracted data,and the initial search of online databases yielded 1445 studies.After removing duplicates,remaining 964 records were screened.Ultimately,55 articles met the inclusion criteria and were included in this review.CONCLUSION Acute inflammation can have a few inhibitory effects on cancer,while chronic inflammation generally promotes its progression.Extended cGAS-STING pathway activation will result in a suppressive tumor microenvironment.
文摘BACKGROUND Hepatitis B virus(HBV)infection is a major factor responsible for HBV+hepatocellular carcinoma(HCC).AIM An immunological classification of HBV+HCC may provide both biological insights and clinical implications for this disease.METHODS Based on the enrichment of 23 immune signatures,we identified two immunespecific subtypes(Imm-H and Imm-L)of HBV+HCC by unsupervised clustering.We showed that this subtyping method was reproducible and predictable by analyzing three different datasets.RESULTS Compared to Imm-L,Imm-H displayed stronger immunity,more stromal components,lower tumor purity,lower stemness and intratumor heterogeneity,lower-level copy number alterations,higher global methylation level,and better overall and disease-free survival prognosis.Besides immune-related pathways,stromal pathways(ECM receptor interaction,focal adhesion,and regulation of actin cytoskeleton)and neuro-related pathways(neuroactive ligand-receptor interaction,and prion diseases)were more highly enriched in Imm-H than in Imm-L.We identified nine proteins differentially expressed between Imm-H and Imm-L,of which MYH11,PDCD4,Dvl3,and Syk were upregulated in Imm-H,while PCNA,Acetyl-a-Tubulin-Lys40,ER-α_pS118,Cyclin E2,andβ-Catenin were upregulated in Imm-L.CONCLUSION Our data suggest that“hot”tumors have a better prognosis than“cold”tumors in HBV+HCC and that“hot”tumors respond better to immunotherapy.
基金Supported by Centre of Molecular Medicine Cologne (CMMC), Kln, Germany
文摘AIM: To investigate the role of tumor inf iltrating lym-phocytes (TIL) in primary hepatocellular and cholangio-lar carcinomas of the liver.METHODS: Immunohistochemical analysis was per-formed including antibodies to CD3, CD4, CD8, CD20, CD56 and TIA-1 in formalin-f ixed and paraff in-embed-ded tissue of 35 liver resection specimens of hepatocel-lular or cholangiocellular carcinomas. Semiquantitative evaluation was performed with emphasis on the area of the tumor itself and of the tumor/liver interface.RESULTS: All hepatocellular carcinomas showed in-filtration of lymphocytes predominantly around the tumor in the tumor/liver interface consisting mainly of CD3+ CD4+ T lymphocytes [164.3/10 high power f ields (HPF)] and in the tumor itself of CD8+ cells (54.9/10 HPF). Cholangiocarcinomas contained a heterogeneous amount of TIL, composed mainly of CD3+ T cells with a predominance of CD8+ cells in the tumor tissue (52.6/10 HPF) and of CD4+ cells in the interface region (223.1/10 HPF). CD56+ cells of the innate immune system were scarce. There was no significant difference between hepatocellular or cholangiolar carcinoma. No correlation with the clinicopathological data was seen. CONCLUSION: Liver TIL consists of intratumoral CD8+ T cells and peritumoral CD4+ T cells indepen-dent of histogenetic origin. Different functions of lym-phocytes in these regions seem possible.
文摘BACKGROUND Esophageal cancer is a common cause of cancer-related death worldwide.Cutaneous metastasis of esophageal squamous cell carcinoma is rare,particularly in diffuse skin metastasis.CASE SUMMARY In this case report,we describe an 82-year-old male who was diagnosed with esophageal squamous cell carcinoma.The tumor was staged as T4N3M1(Stage IVB).The pathological findings revealed poorly differentiated squamous cell carcinoma of the esophagus.Four months after diagnosis,the patient began chemotherapy,and symptoms were relieved after four cycles of chemotherapy.After that,the patient returned home without a systematic physical examination.One year after diagnosis,the patient realized that the skin of the abdominal wall was hard and rough without pain,and the color became darker than normal skin.Thirteen months after diagnosis,a biopsy of the patient’s abdominal lesion revealed that the skin metastasis was derived from the esophagus.Then the patient received two cycles of apatinib combined with docetaxel,but the abdominal lesion worsened.Two cycles of nivolumab were administered,but the patient eventually died of multiple organ failure.CONCLUSION This report highlights cutaneous metastasis as a late and untreatable metastasis of esophageal cancer.
文摘Spontaneous tumor regression is an extremely rare phenomenon in the oncology field. However, there are several case reports resulted in the regression of hepatocellular carcinoma(HCC) and the accumulation of clinical information and analyses of the mechanism can contribute to the development of a novel therapy. For this purpose, we have carefully reviewed 23 cases of spontaneously regressed HCC published in recent 5 years and our case. The information regarding the tumor size, tumor marker, treatments, etc., have been summarized. The mechanism of spontaneous regression has been discussed to date and presumed to be due to many factors, including hypoxia and immunological reactions. In this careful review of the 24 cases based on the clinical information, hypoxia, systemic inflammation, and both upon spontaneous regression were seen in 3, 8, and 4 cases, respectively amo ng t he 15 c as e s f or w hic h t he inf o r mat io n regarding the proposed mechanisms are available. Recent development of immunotherapeutic approaches in oncology shows promising results, therefore, accumulation of additional cases and analysis of mechanisms underlying the spontaneous regression of HCC are essential and could lead to the development of a new generation of immunotherapies including antibodies directed against immune reactions.
基金Science and Technology Development Foundation of Beijing Institute of Infectious Diseases,No.01 Z094
文摘AIM: To characterize the anticancer function of cytokine-induced killer cells (CIK) and develop an adoptive immunotherapy for the patients with primary hepatocellular carcinoma (HCC), we evaluated the proliferation rate, phenotype and the antitumor activity of human CIK cells from healthy donors and HCC patients in vitro and in vivo. METHODS: Peripheral blood mononuclear cells (PBMC) from healthy donors and patients with primary HCC were incubated in vitro and induced into CIK cells in the presence of various cytokines such as interferon-gamma (IFN-gamma), interleukin-1 (IL-1), IL-2 and monoclonal antibody (mAb) against CD3. The phenotype and characterization of CIK cells were identified by flow cytometric analysis. The cytotoxicity of CIK cells was determined by (51)Cr release assay. RESULTS: The CIK cells were shown to be a heterogeneous population with different cellular phenotypes. The percentage of CD3+/CD56+ positive cells, the dominant effector cells, in total CIK cells from healthy donors and HCC patients, significantly increased from 0.1-0.13% at day 0 to 19.0-20.5% at day 21 incubation, which suggested that the CD3+ CD56+ positive cells proliferated faster than other cell populations of CIK cells in the protocol used in this study. After 28 day in vitro incubation, the CIK cells from patients with HCC and healthy donors increased by more than 300-fold and 500-fold in proliferation cell number, respectively. CIK cells originated from HCC patients possessed a higher in vitro antitumor cytotoxic activity on autologous HCC cells than the autologous lymphokine-activated killer (LAK) cells and PBMC cells. In in vivo animal experiment, CIK cells had stronger effects on the inhibition of tumor growth in Balb/c nude mice bearing BEL-7402-producing tumor than LAK cells (mean inhibitory rate, 84.7% vs 52.8%, P【0.05) or PBMC (mean inhibitory rate, 84.7% vs 37.1%, P【0.01). CONCLUSION: Autologous CIK cells are of highly efficient cytotoxic effector cells against primary hepatocellular carcinoma cells and might serve as an alternative adoptive therapeutic strategy for HCC patients.
基金Supported by European-Latin American ESCALON consortium,funded by the EU Horizon 2020 Program,No.825510Robert Wood Johnson Foundation,Harold Amos Medical Faculty Development Program(to Debes JD).
文摘Hepatocellular carcinoma(HCC)is one of the most prevalent cancers and one of the main causes of cancer-related deaths worldwide.Most HCCs develop in an inflammatory microenvironment,and mounting evidence emphasizes the importance of immune aspects in hepatocarcinogenesis.In normal physiology,both innate and adaptive immune responses are responsible for eliminating malignantly transformed cells,thus preventing the development of liver cancer.However,in the setting of impaired natural killer cells and exhaustion of T cells,HCC can develop.The immunogenic features of HCC have relevant clinical implications.There is a large number of immune markers currently being studied for the early detection of liver cancer,which would be critical in order to improve surveillance programs.Moreover,novel immunotherapies have recently been proven to be effective,and the combination of atezolizumab and bevacizumab is currently the most effective treatment for advanced HCC.It is expected that in the near future different subgroups of patients will benefit from specific immunotherapy.The better we understand the immune aspects of HCC,the greater the benefit to patients through surveillance aiming for early detection of liver cancer,which allows for curative treatments,and,in cases of advanced disease,through the selection of the best possible therapy for each individual.
基金Supported by a grant from National Natural Science Foundation of China(grant number 81571783)National Major Project for Infectious Diseases of China(2017ZX100203205005)
文摘Purpose: A series of clinical studies have established the safety and efficacy of transcatheter arterial chemoembolization(TACE) with gelatin sponge microparticles(GSMs) in treating hepatocellular carcinoma(HCC). HCC can lead to obvious necrosis inside tumors, especially larger ones, although it is unclear whether such necrotic tumor tissue can induce favorable immune reactions against the tumor. Myeloid-derived suppressor cells(MDSCs)have immunosuppressive functions and are currently considered a very important cell type affecting tumor immunity. This study observed changes in MDSC frequency in peripheral blood before and after GSM–TACE to evaluate the effect on the immune function of HCC patients.Methods: Eight patients diagnosed with HCC underwent GSM–TACE treatment in the Hepatobiliary Interventional Department of Beijing Tsinghua Chang Gung Hospital, Beijing, China;we followed up with the patients over a period of 30 days post-surgery. We used flow cytometry(FCM) to quantify the frequency of MDSCs in peripheral blood before TACE, 10 days after surgery and 30 days after surgery.Results: MDSC frequency after GSM–TACE had a significant downward trend. Pre-TACE, it was 30.73% ? 11.93%,decreasing to 18.60% ? 11.37% at 10 days after operation. This decrease was not statistically significant(P > 0.05). MDSC frequency was even lower 30 days after TACE(7.63% ? 7.32%) than at 10 days after TACE(P < 0.05), and there was a significant difference compared with pre-TACE(P < 0.001). We evaluated tumor response at 30 days after GSM–TACE according to the Modified Response Evaluation Criteria in Solid Tumors(mRECIST), and all eight patients showed partial response(PR).Conclusion: Our results confirmed that GSM–TACE was beneficial for improving anti-tumor immunity in the treatment of HCC.
文摘The specimens of 135 cases of primary hepatic carcinoma were obtained from the Pathological Laboratory of the First Affiliated Hospital of the Fourth Military Medical University, Xi' an, PRC. Ten percent formalin-fixed and paraffin- embedded sections were stained by HE and by ABC and PAP immunohistochemical methods. Positive rates of pre- S1 and pre- S2 antigens in cancerous tissue were 22. 2% and 20. 0%, respectively, while those in surrounding hepatic tissue were 60.6% and 59.6%, separately. The pre- S1 and pre- S2 antigens were found to coexist In 16. 3% of cancerous tissue and in 55. 6% of surrounding hepatic tissue. In all the 135 cases of hepatic carcinoma, the cancerous tissue showed positive HBsAg in 16. 3%, HBxAg in 55. 6% and HBcAg in 8. 9%; in the surrounding hepatic tissue, positive HBsAg was 59.6%, HBxAg 78.8% and HBcAg 24.2%. The results of this study suggestes that positive rates of pre- S1 and pre-S2 antigens in cancerous tissue were slightly higher than that of HBsAg, but markedly lower than that of HBxAg. The positive rate of pre-S1 and pre- S2 antigens in surrounding hepatic tissue was nearly the same as HBsAg, but slightly lower than that of HBxAg. Antigens of pre-S1 and pre-S2 are the new markers of HBV infection. The same as other antigens, they may play an important role in the development of hepatic carcinoma. The mechanism of their effect will be further investigated,
基金European-Latin American ESCALON Consortium,Funded By The EU Horizon 2020 Program,No.825510Robert Wood Johnson Foundation,Harold Amos Medical Faculty Development Program to JDD+2 种基金University of Minnesota Academic Investment Research Program–AIRP Grant to JDDFondo Nacional de Ciencia y Tecnología de Chilex to MA,No.FONDECYT-1191145Agencia Nacional de Investigación y Desarrollo to MA,No.ANID-ACE210009
文摘Hepatocellular carcinoma(HCC)is among the most common cancers and it is a major cause of cancer-related deaths.Non-alcoholic fatty liver disease(NAFLD)affects approximately one fourth of individuals worldwide and it is becoming one of the most important causes of HCC.The pathogenic mechanisms leading to NAFLD-related HCC are complex and not completely understood.However,metabolic,fibrogenic,oncogenic,inflammatory and immunological pathways seem to be involved.First-line therapy of advanced HCC has recently undergone major changes,since the combination of atezolizumab and bevacizumab was proven to increase survival when compared to sorafenib.Other immune-oncology drugs are also demonstrating promising results in patients with advanced HCC when compared to traditional systemic therapy.However,initial studies raised concerns that the advantages of immunotherapy might depend on the underlying liver disease,which seems to be particularly important in NAFLD-related HCC,as these tumors might not benefit from it.This article will review the mechanisms of NAFLD-related hepatocarcinogenesis,with an emphasis on its immune aspects,the efficacy of traditional systemic therapy for advanced NAFLD-related HCC,and the most recent data on the role of immunotherapy for this specific group of patients,showing that the management of this condition should be individualized and that a general recommendation cannot be made at this time.
文摘Liver cancer is one of the most common causes of cancer death globally,and its incidence in the United States is increasing.Patients with advanced hepatocellular carcinoma(HCC)who are not candidates for surgical resection,liver transplant,or locoregional therapies can be treated with systemic therapies.Multiple agents,including sorafenib,lenvatinib,and regorafenib are approved for use as either first-or second-line therapy in this patient population,but all have relatively modest survival benefits.HCC is potentially susceptible to therapy with checkpoint inhibitors,including agents such as nivolumab and pembrolizumab,which are both approved by the Food and Drug Administration for patients previously treated with sorafenib but have not demonstrated superior overall survival in phase III trials.It is clear that more effective approaches are needed to potentiate the effects of checkpoint inhibitors in patients with HCC.This review will outline and appraise the current literature on the use of checkpoint inhibitors in HCC as part of a combination treatment involving an additional mode of therapy.The list of agents that can be paired with checkpoint inhibitors includes an additional checkpoint inhibitor,vascular endothelial growth factor or vascular endothelial growth factor receptor inhibitors,tyrosine kinase inhibitors,OX-40 agonists,and PT-112 inhibitors.The main non-pharmacologic therapies currently being studied for inclusion in a combination strategy include radiation therapy,trans-arterial chemoembolization,and ablation.
文摘Background Different strategies for hepatocellular carcinoma (HCC) may have distinct effects on the immune system.The aim of this research was to investigate changes in the immunological function after transcatheter arterial chemoembolization (TACE) plus radiofrequency ablation (RFA) in HCC patients.Methods A total of 51 consecutive HCC treatment-naive patients was enrolled in this study and 20 healthy subjects served as controls.The therapeutic strategy was selected according to the tumor stage and general conditions.TACE was performed in 25 cases,TACE plus RFA in 17 and RFA in nine.All the patients underwent routine examinations and peripheral blood was harvested for the detection of lymphocyte subset by flow cytometry 1 day before,and 2 and 4 weeks after the treatment.The serum levels of alpha-fetoprotein (AFP),ALT and AST were also measured before and 4 weeks after treatment for the evaluation of therapeutic efficacy and liver function impairment.Results When compared with healthy controls,the CD4/CD8 ratio and the number of B cells and natural killer (NK) cells were significantly decreased in HCC patients before treatment (P 〈0.05).When compared with before treatment,the CD4+ cells and CD4/CD8 ratio decreased but CD8+ cells increased in the TACE group (P 〈0.05); the CD4/CD8 ratio and NK cells decreased but CD8+ cells increased in the TACE-RFA group (P 〈0.05); the CD3+ cells,CD4+ cells,CD4/CD8 ratio and NK cells increased in the RFA group (P 〈0.05).Significant differences in the CD3+ cells,CD8+ cells,CD4/CD8 ratio and NK cells were observed among groups (P 〈0.05).Moreover,the AFP level decreased and transaminase level increased in all groups (P 〈0.05).Differences of pre and post treatment between groups were statistically significant (P =0.016,0.025,0.018 respectively).Conclusions Immunity was compromised in HCC patients; TACE and TACE plus RFA lowered immunologic function to a certain extent.RFA improved it accompanied by a protective effect on liver function.
文摘Hepatocellular carcinoma(HCC)carries an unfavorable prognosis and novel therapeutic strategies are needed.Until now,only few systemic agents have improved survival in patients with advanced stage disease.Immunotherapy changed the landscape in several tumor types by producing unprecedented clinical outcomes with a favorable safety profile.Liver presents a particular immune-suppressive microenvironment and HCC develops in a background of chronic inflammation in the vast majority of cases.In this regard,immunotherapy may be a suitable strategy.Preliminary research focused on therapies involving immune cells and anti-tumor immune response for HCC has shown encouraging preliminary results.Immune checkpoint inhibitors,such the anti-PD-1/PD-L1 monoclonal antibodies,have provided durable responses in patients with advanced stage disease,although the pioneers phaseⅢtrials did not confirm survival superiority over the available agents.Cancer vaccines,adoptive cellular therapies and combinations of local modalities with immunotherapy are promising approaches under active research.