Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neu...Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.展开更多
Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune chec...Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints.Thousands of small molecule drugs or biological materials,especially antibody-based ICIs,are actively being studied and antibodies are currently widely used.Limitations,such as anti-tumor efficacy,poor membrane permeability,and unneglected tolerance issues of antibody-based ICIs,remain evident but are thought to be overcome by small molecule drugs.Recent structural studies have broadened the scope of candidate immune checkpoint molecules,as well as innovative chemical inhibitors.By way of comparison,small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features.Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions,including immune regulation,anti-angiogenesis,and cell cycle regulation.In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins,which will lay the foundation for further exploration.展开更多
(Ataxia-telangiectasia mutated gene (ATM) functions in control of cell cycle checkpoints in responding to DNA damage and protects cells from undergoing apoptosis. Knock-out within tumor cells of endogenous ATM will ...(Ataxia-telangiectasia mutated gene (ATM) functions in control of cell cycle checkpoints in responding to DNA damage and protects cells from undergoing apoptosis. Knock-out within tumor cells of endogenous ATM will achieve therapeutic benefits and enable a better understanding of the decisive mechanisms of cell death or survival in response to DNA damaging agents. ) In present paper, we sought to characterize the cell cycle checkpoint profiles in U937-ASPI3K, a U937 cell mutant that was previously established with endogenous ATM knock-out phenotype. Syn- chronized U937-ASPI3K was exposed to 137Cs irradiation, G1, S. G2/M cell cycle checkpoint pro- files were evaluated by determining cell cycle kinetics, p53/p21 protein, cyclin dependent kinase 2 (CDK2) and p34CDC2 kinase activity in response to irradiation. U937-ASPI3K exhibited multiple defects in cell cycle checkpoints as defined by failing to arrest cells upon irradiation. The accumulation of cellular p53/p21 protein and inhibition of CDK kinase was also abolished in U937-ASPI3K. It was concluded that the stable expression of anti-sense PI3K cDNA fragment completely abolished multiple cell cycle checkpoints in U937-ASPI3K, and hence U937-ASPI3K with an AT-like phenotype could serves as a valuable model system for investigating the signal transduction pathway in responding to DNA damaging-based cancer therapy.展开更多
The central nervous system (CNS) is an immune-privileged site with tightly-regulated immune responses, a concept proposed by Nobel Laureate Sir Peter Medawar in 1960. Under physiological conditions, only a few T lymph...The central nervous system (CNS) is an immune-privileged site with tightly-regulated immune responses, a concept proposed by Nobel Laureate Sir Peter Medawar in 1960. Under physiological conditions, only a few T lymphocytes conducting immunosurveillance can infiltrate the CNS.展开更多
Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis(NAFLD and NASH,respectively)are becoming a global epidemic manifested by metabolic syndrome,hepatic fibrosis,and cirrhosis,as well as hepatocellular ca...Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis(NAFLD and NASH,respectively)are becoming a global epidemic manifested by metabolic syndrome,hepatic fibrosis,and cirrhosis,as well as hepatocellular carcinoma(HCC).Natural killer(NK)cells play an important role in the natural history of the disease as anti-fibrotic and anti-tumor protection.NK cells directly kill activated myofibroblasts to prevent fibrosis progression.However,NK cell functional impairment develops along with insulin resistance and deterioration to cirrhosis and HCC.Metabolic checkpoints have been identified that affect NK cell function and killing.Insulin resistance has been directly identified within NK cells,as they decrease expression of insulin receptors.The normal NK cell activation by insulin is therefore effected.Furthermore,Nerologin-4(NLG4)is overexpressed in impaired NK cells from NAFLD donors with advanced fibrosis.NLG4 overexpression impairs NK cell function and contributes to fibrosis progression.Intracellular NK cell depletion of mT OR,NMDAR activation by liver environmental enrich agonists up-regulates NLG4 expression.NLG4 causes a downstream cascade of intracellular scaffolding proteins to depress the killing function via f-actin remodeling.Berra neuroxin is a defined ligand for NLG4 and is found in target cells including activated fibrotic myofibroblasts and HCC cells.This overexpression further enhanced the NLG4 effect to impair NK cell killing.Other NK cells immune checkpoints have been identified.Targeting metabolic checkpoints activate NK cells to reconstitute their killing effects as anti-fibrotic or anti-tumor.Moreover,NLG4 NK expression and an occult urea assay with myofibroblasts has been identified as a biomarker tool in fibrogenesis.展开更多
Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell dea...Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy.展开更多
Survival rates for metastatic lung cancer, including non-small cell lung cancer （NSCLC） and small cell lung cancer （SCLC）, are poor with S-year survivals of less than 5%. The immune system has an intricate and com...Survival rates for metastatic lung cancer, including non-small cell lung cancer （NSCLC） and small cell lung cancer （SCLC）, are poor with S-year survivals of less than 5%. The immune system has an intricate and complex relationship with tumorigenesis; a groundswell of research on the immune system is leading to greater understanding of how cancer progresses and presenting new ways to halt disease progress. Due to the extraordinary power of the immune system-- with its capacity for memory, exquisite specificity and central and universal role in human biology--immunotherapy has the potential to achieve complete, long-lasting remissions and cures, with few side effects for any cancer patient, regardless of cancer type. As a result, a range of cancer therapies are under development that work by turning our own immune cells against tumors. However deeper understanding of the complexity of immunomodulation by tumors is key to the development of effective immunotherapies, especially in lung cancer.展开更多
Myeloid checkpoints are receptors on the myeloid cell surface which can mediate inhibitory signals to modulate anti-tumor immune activities.They can either inhibit cellular phagocytosis or suppress T cells and are thu...Myeloid checkpoints are receptors on the myeloid cell surface which can mediate inhibitory signals to modulate anti-tumor immune activities.They can either inhibit cellular phagocytosis or suppress T cells and are thus involved in the pathogenesis of various diseases.In the tumor microenvironment,besides killing tumor cells by phagocytosis or activating anti-tumor immunity by tumor antigen presentation,myeloid cells could execute protumor efficacies through myeloid checkpoints by interacting with counter-receptors on other immune cells or cancer cells.In summary,myeloid checkpoints may be promising therapeutic targets for cancer immunotherapy.展开更多
In the interaction between a tumor and the immune system,immune checkpoints play an important role,and in tumor immune escape,co-inhibitory immune checkpoints are important.Immune checkpoint inhibitors(ICIs)can enhanc...In the interaction between a tumor and the immune system,immune checkpoints play an important role,and in tumor immune escape,co-inhibitory immune checkpoints are important.Immune checkpoint inhibitors(ICIs)can enhance the immune system's killing effect on tumors.To date,impressive progress has been made in a variety of tumor treatments;PD1/PDL1 and CTLA4 inhibitors have been approved for clinical use in some tumors.However,glioblastoma(GBM)still lacks an effective treatment.Recently,a phase III clinical trial using nivolumab to treat recurrent GBM showed no significant improvement in overall survival compared to bevacizumab.Therefore,the use of immune checkpoints in the treatment of GBM still faces many challenges.First,to clarify the mechanism of action,how different immune checkpoints play roles in tumor escape needs to be determined;which biomarkers predict a benefit from ICIs treatment and the therapeutic implications for GBM based on experiences in other tumors also need to be determined.Second,to optimize combination therapies,how different types of immune checkpoints are selected for combined application and whether combinations with targeted agents or other immunotherapies exhibit increased efficacy need to be addressed.All of these concerns require extensive basic research and clinical trials.In this study,we reviewed existing knowledge with respect to the issues mentioned above and the progress made in treatments,summarized the state of ICIs in preclinical studies and clinical trials involving GBM,and speculated on the therapeutic prospects of ICIs in the treatment of GBM.展开更多
Natural killer(NK)cells are key innate immune lymphocytes,which play important roles against tumors.However,tumor-infiltrating NK cells are always hypofunctional/exhaustive.On the one hand,this state is contributed by...Natural killer(NK)cells are key innate immune lymphocytes,which play important roles against tumors.However,tumor-infiltrating NK cells are always hypofunctional/exhaustive.On the one hand,this state is contributed by context-dependent interactions between inhibitory NK cell checkpoint receptors and their ligands,which usually vary in different tumor types and stages during tumor development.On the other hand,the inhibitory functions of intracellular checkpoint molecules of NK cells are more similar across different tumor types,representing common mechanisms limiting the potential of NK cell therapy.In this review,representative NK cell intracellular checkpoint molecules in different aspects of NK cell biology were reviewed,and therapeutic potentials were discussed by targeting these molecules to promote antitumor NK cell therapy.展开更多
Objective To investigate the combined effects of thymidine phosphorylase(TYMP)and sine oculis homeobox homologue 1(Six1)on the tumor microenvironment and their role in promoting metastasis in gastric cancer(GC).Method...Objective To investigate the combined effects of thymidine phosphorylase(TYMP)and sine oculis homeobox homologue 1(Six1)on the tumor microenvironment and their role in promoting metastasis in gastric cancer(GC).Methods A total of 674 GC patients who underwent surgical resection were enrolled.Correlations between TYMP/Six1 expression and the clinicopathological characteristics and overall survival of patients were analysed.The expression of TYMP,Six1 and vascular endothelial growth factor C(VEGFc)was quantified via immunohistochemistry and quantitative real-time polymerase chain reaction.Cell transfection,wound-healing assays and bioinformatics analyses were used to explore the potential underlying mechanisms involved.Results Compared with the other groups,the Six1+/TYMP+patients exhibited poor differentiation,advanced tumor stage,a higher rate of lymphatic vessel invasion and shorter survival.Additionally,the protein expression of TYMP and Six1 was positively correlated with the VEGFc level.A significant increase in VEGFc expression was observed in cells transfected with TYMP,Six1,and TYMP/Six1 vectors.The results of the wound-healing assay indicated that the synergistic effect of TYMP and Six1 enhanced the migratory ability of GC cells.Furthermore,bioinformatics analysis revealed that TYMP and Six1 were positively correlated with immunosuppressive immune cell subsets and elevated the expression of inhibitory immune checkpoints in GC.Conclusions The combination of TYMP and Six1 is a good predictive and prognostic biomarker for GC.This combination enhances the expression of VEGFc,facilitates the invasion of GC cells,and may be linked to inhibitory immune cells and the tumor immune microenvironment.展开更多
Lung cancer is a common cause of cancer-related death globally.The majority of lung cancer patients initially benefit from chemotherapy and immunotherapy.However,as the treatment cycle progresses and the disease evolv...Lung cancer is a common cause of cancer-related death globally.The majority of lung cancer patients initially benefit from chemotherapy and immunotherapy.However,as the treatment cycle progresses and the disease evolves,the emergence of acquired resistance leads to treatment failure.Many researches have shown that non-coding RNAs(ncRNAs)not only influence lung cancer progression but also act as potential mediators of immunotherapy and chemotherapy resistance in lung cancer,mediating drug resistance by regulating multiple targets and pathways.In addition,the regulation of immune response by ncRNAs is dualistic,forming a microenvironment for inhibits/promotes immune escape through changes in the expression of immune checkpoints.The aim of this review is to understand the effects of ncRNAs on the occurrence and development of lung cancer,focusing on the role of ncRNAs in regulating drug resistance of lung cancer.展开更多
Melanomas are aggressive cancers,with a high rate of metastatic disease.Cutaneous(CM)and uveal(UM)melanomas are intrinsically different diseases,and most cell death inducers effective for CM do not function for UM.Thi...Melanomas are aggressive cancers,with a high rate of metastatic disease.Cutaneous(CM)and uveal(UM)melanomas are intrinsically different diseases,and most cell death inducers effective for CM do not function for UM.This is primarily due to the fact the eye is an immunologically privileged organ,and it fails to achieve the efficacy of immune checkpoint inhibitors(ICIs)comparable to that for CM.However,approaches utilizing specific melanomaassociated antigens are being developed for metastatic forms of CM and UM.The most promising to date are gp100 and tyrosinase related protein 1(TYRP1),primarily for the design of targeting chimeric molecules and for autologous T-/NK-cell products with a chimeric antigen receptor.The difference in the mutational profile of apoptosis-related genes in CM and UM also makes counterproductive the use of the same drugs re-activators of the intrinsic pathway of apoptosis.Therefore,the discovery of novel pathways of regulated cell death such as ferroptosis and cuproptosis may help in the development of new drugs for melanomas resistant to already available inducers of regulated cell death.Here we consistently discuss the latest advances in the therapy of melanomas,and above all-UM,which is classified as an orphan disease.展开更多
NK cells play important roles in innate defenses against viruses and in the control of tumor growth and metastasis.The regulation/induction of NK cell function is mediated by an array of activating or inhibitory surfa...NK cells play important roles in innate defenses against viruses and in the control of tumor growth and metastasis.The regulation/induction of NK cell function is mediated by an array of activating or inhibitory surface receptors.In humans,major activating receptors involved in target cell killing are the natural cytotoxicity receptors(NCRs)and NKG2D.Activating receptors recognize ligands that are overexpressed or expressed de novo upon cell stress,viral infection,or tumor transformation.The HLA-class I-specific inhibitory receptors,including KIRs recognizing HLA-class I allotypic determinants and CD94/NKG2A recognizing the class-Ib HLA-E,constitute a fail-safe mechanism to avoid unwanted NK-mediated damage to healthy cells.Other receptors such as PD-1,primarily expressed by activated T lymphocytes,are important inhibitory checkpoints of immune responses that ensure T-cell tolerance.PD-1 also may be expressed by NK cells in cancer patients.Since PD-1 ligand(PD-L1)may be expressed by different tumors,PD-1/PD-L1 interactions inactivate both T and NK cells.Thus,the reliable evaluation of PD-L1 expression in tumors has become a major issue to select patients who may benefit from therapy with mAbs disrupting PD-1/PD-L1 interactions.Recently,NKG2A was revealed to be an important checkpoint controlling both NK and T-cell activation.Since most tumors express HLA-E,mAbs targeting NKG2A has been used alone or in combination with other therapeutic mAbs targeting PD-1 or tumor antigens(e.g.,EGFR),with encouraging results.The translational value of NK cells and their receptors is evidenced by the extraordinary therapeutic success of haploidentical HSCT to cure otherwise fatal high-risk leukemias.展开更多
Lycii Radicis Cortex(LRC)is a medicinal and food homologous plant with various pharmacological activities,including anti-tumor effects.This study explores the anti-tumor effect of LRC on non-small cell lung cancer(NSC...Lycii Radicis Cortex(LRC)is a medicinal and food homologous plant with various pharmacological activities,including anti-tumor effects.This study explores the anti-tumor effect of LRC on non-small cell lung cancer(NSCLC)and its molecular mechanism using mice bearing Lewis lung carcinoma cells.LRC significantly suppressed the growth of NSCLC.Besides,RNA sequencing of mice tumors and hematoxylin&eosin and immunofluorescence staining revealed that LRC promoted the infiltration of T lymphocytes,specifically GZMB~+CD8~+T lymphocytes,in tumor tissues.The Gene Set Enrichment Analysis of spleen RNA indicated that LRC up-regulated PD-1-downstream pathways,suggesting that LRC exerted its effects through the PDL1/PD-1 pathway.Further experiments revealed that LRC interacted with PD-L1,blocking PD-L1/PD-1 binding and thus restoring the T cell killing activity on tumor cells.Together,these results support using LRC as healthy food to improve anti-tumor immunity in patients with NSCLC.展开更多
BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a ...BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in cancer treatment.While HP infection and PD-L1 expression in GC may be linked,the relationship between them remains unclear,in part because there have been conflicting results reported from various studies.AIM To perform a meta-analysis to assess the relationship between HP and PD-L1 expression in patients with GC.METHODS A systematic literature review was conducted using PubMed,Embase,Cochrane Library,and Web of Science databases.Observational studies that examined the association between HP infection and PD-L1 expression in patients with GC were included.Odds ratios and 95%confidence intervals were calculated to estimate the association.Heterogeneity was assessed using Cochrane’s Q test and I²statistic.A random-effects model was used due to significant heterogeneity across studies.RESULTS Fourteen studies involving a total of 3069 patients with GC were included.The pooled analysis showed a significant association between HP infection and increased PD-L1 expression in GC tissues(odd ratio=1.69,95%confidence interval:1.24-2.29,P<0.001,I^(2)=59%).Sensitivity analyses confirmed the robustness of these findings.Subgroup analyses did not show significant variation based on geographic region,sample size,or method of PD-L1 assessment.Publication bias was minimal,as shown by funnel plots and Egger’s regression test.CONCLUSION HP infection is associated with increased PD-L1 expression in GC,suggesting that HP status may influence the response to programmed cell death protein 1/PD-L1 blockade therapy.展开更多
Primary liver cancer(PLC)is a prevalent malignancy with high incidence and mortality rates globally.Hepatocellular carcinoma(HCC),primarily resulting from hepatitis B virus infections in Asia,constitutes most PLC case...Primary liver cancer(PLC)is a prevalent malignancy with high incidence and mortality rates globally.Hepatocellular carcinoma(HCC),primarily resulting from hepatitis B virus infections in Asia,constitutes most PLC cases.Despite advancements in targeted therapies and localized treatments,the 5-year survival rate remains low,indicating limited efficacy of current approaches.The advent of immunotherapy,particularly immune checkpoint inhibitors(ICIs),has brought new hope for patients with PLC.However,the liver's unique immune microenvironment presents significant challenges to the effectiveness of immunotherapy in HCC.This article reviews recent research developments in liver cancer immunotherapy,focusing on ICIs,combination therapies,emerging treatments,and prospective future directions.展开更多
Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tum...Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tumor effects,they can also trigger immune-related adverse events(irAEs),with ICI-associated colitis being one of the more prevalent forms.This condition can disrupt treatment,necessitate drug discontinuation,and adversely affect therapeutic outcomes.In severe cases,irAEs may even become life-threatening.A recent case report by Hong et al highlights the importance of vigilance for ICI-associated colitis in patients experiencing symptoms such as diarrhea and abdominal pain,which can arise both during and even after completion of ICI treatment.Early identification,multidisciplinary management,and continuous monitoring of patients are essential steps to further improve outcomes.展开更多
CD8^(+)T cell exhaustion,a critical challenge in the immune response to cancer,is characterized by a profound decline in the functionality of effector CD8^(+)T cells.This state of exhaustion is accompanied by the upre...CD8^(+)T cell exhaustion,a critical challenge in the immune response to cancer,is characterized by a profound decline in the functionality of effector CD8^(+)T cells.This state of exhaustion is accompanied by the upregulation of various inhibitory receptors and significant shifts in both transcriptional and epigenetic profiles,thus ultimately leading to inadequate tumor control.Therapeutic strategies aimed at reversing CD8^(+)T cell exhaustion have the potential to rejuvenate immune responses and enhance treatment efficacy.This review compiles current knowledge regarding the molecular mechanisms underlying CD8^(+)T cell exhaustion,including the roles of immune checkpoint molecules,the tumor microenvironment,metabolic reprogramming,transcription factors,and epigenetic modifications.Emerging therapeutic approaches designed to combat CD8^(+)T cell exhaustion are evaluated,with emphasis on the modulation of immune checkpoints;targeting of metabolic and transcriptional changes;and exploration of other innovative strategies,such as epigenetic editing and engineered CAR-T cells.Importantly,we expand the exhaustion concept to immune cells beyond CD8^(+)T cells,such as CD4^(+)T cells,natural killer cells,and myeloid populations,thereby highlighting the broader implications of systemic immunosuppression in the cancer context.Finally,we propose avenues for future research aimed at further elucidating the factors and molecular mechanisms associated with CD8^(+)T cell exhaustion,thereby underscoring the critical need for strategies aimed at reversing this state to improve outcomes in cancer immunotherapy.展开更多
基金Deutsche Forschungsgemeinschaft(DFG,German Research Foundation),project numbers 324633948 and 409784463(DFG grants Hi 678/9-3 and Hi 678/10-2,FOR2953)to HHBundesministerium für Bildung und Forschung-BMBF,project number 16LW0463K to HT.
文摘Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.
基金supported by the National Natural Science Foundation of China(Grant Nos.82203539 and 92259102)Provincial Cooperation Project of Science and Technology Department of Sichuan Province(Grant No.2023YFSY0043)the National Key Research and Development Program of China(Grant No.2023YFC3402100).
文摘Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints.Thousands of small molecule drugs or biological materials,especially antibody-based ICIs,are actively being studied and antibodies are currently widely used.Limitations,such as anti-tumor efficacy,poor membrane permeability,and unneglected tolerance issues of antibody-based ICIs,remain evident but are thought to be overcome by small molecule drugs.Recent structural studies have broadened the scope of candidate immune checkpoint molecules,as well as innovative chemical inhibitors.By way of comparison,small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features.Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions,including immune regulation,anti-angiogenesis,and cell cycle regulation.In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins,which will lay the foundation for further exploration.
基金This project was supported by the National Natural ScienceFoundation of China (No. 39800149)
文摘(Ataxia-telangiectasia mutated gene (ATM) functions in control of cell cycle checkpoints in responding to DNA damage and protects cells from undergoing apoptosis. Knock-out within tumor cells of endogenous ATM will achieve therapeutic benefits and enable a better understanding of the decisive mechanisms of cell death or survival in response to DNA damaging agents. ) In present paper, we sought to characterize the cell cycle checkpoint profiles in U937-ASPI3K, a U937 cell mutant that was previously established with endogenous ATM knock-out phenotype. Syn- chronized U937-ASPI3K was exposed to 137Cs irradiation, G1, S. G2/M cell cycle checkpoint pro- files were evaluated by determining cell cycle kinetics, p53/p21 protein, cyclin dependent kinase 2 (CDK2) and p34CDC2 kinase activity in response to irradiation. U937-ASPI3K exhibited multiple defects in cell cycle checkpoints as defined by failing to arrest cells upon irradiation. The accumulation of cellular p53/p21 protein and inhibition of CDK kinase was also abolished in U937-ASPI3K. It was concluded that the stable expression of anti-sense PI3K cDNA fragment completely abolished multiple cell cycle checkpoints in U937-ASPI3K, and hence U937-ASPI3K with an AT-like phenotype could serves as a valuable model system for investigating the signal transduction pathway in responding to DNA damaging-based cancer therapy.
基金funded by the V Foundation Scholar Award(V2018-023)ACS-IRG(91-022-19)R21(1R21CA230475-01A1)to LZS
文摘The central nervous system (CNS) is an immune-privileged site with tightly-regulated immune responses, a concept proposed by Nobel Laureate Sir Peter Medawar in 1960. Under physiological conditions, only a few T lymphocytes conducting immunosurveillance can infiltrate the CNS.
文摘Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis(NAFLD and NASH,respectively)are becoming a global epidemic manifested by metabolic syndrome,hepatic fibrosis,and cirrhosis,as well as hepatocellular carcinoma(HCC).Natural killer(NK)cells play an important role in the natural history of the disease as anti-fibrotic and anti-tumor protection.NK cells directly kill activated myofibroblasts to prevent fibrosis progression.However,NK cell functional impairment develops along with insulin resistance and deterioration to cirrhosis and HCC.Metabolic checkpoints have been identified that affect NK cell function and killing.Insulin resistance has been directly identified within NK cells,as they decrease expression of insulin receptors.The normal NK cell activation by insulin is therefore effected.Furthermore,Nerologin-4(NLG4)is overexpressed in impaired NK cells from NAFLD donors with advanced fibrosis.NLG4 overexpression impairs NK cell function and contributes to fibrosis progression.Intracellular NK cell depletion of mT OR,NMDAR activation by liver environmental enrich agonists up-regulates NLG4 expression.NLG4 causes a downstream cascade of intracellular scaffolding proteins to depress the killing function via f-actin remodeling.Berra neuroxin is a defined ligand for NLG4 and is found in target cells including activated fibrotic myofibroblasts and HCC cells.This overexpression further enhanced the NLG4 effect to impair NK cell killing.Other NK cells immune checkpoints have been identified.Targeting metabolic checkpoints activate NK cells to reconstitute their killing effects as anti-fibrotic or anti-tumor.Moreover,NLG4 NK expression and an occult urea assay with myofibroblasts has been identified as a biomarker tool in fibrogenesis.
基金supported by the National Key Research and Development Program of China(No.2021YFC2700903)the National Natural Science Foundation of China(Nos.81672791 and 81872300)+2 种基金the Zhejiang Provincial Natural Science Fund for Distinguished Young Scholars of China(No.LR18C060002)the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(No.LHDMY22H160006)the ZJU-QILU Joint Research Institute and Qilu Group.
文摘Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy.
文摘Survival rates for metastatic lung cancer, including non-small cell lung cancer （NSCLC） and small cell lung cancer （SCLC）, are poor with S-year survivals of less than 5%. The immune system has an intricate and complex relationship with tumorigenesis; a groundswell of research on the immune system is leading to greater understanding of how cancer progresses and presenting new ways to halt disease progress. Due to the extraordinary power of the immune system-- with its capacity for memory, exquisite specificity and central and universal role in human biology--immunotherapy has the potential to achieve complete, long-lasting remissions and cures, with few side effects for any cancer patient, regardless of cancer type. As a result, a range of cancer therapies are under development that work by turning our own immune cells against tumors. However deeper understanding of the complexity of immunomodulation by tumors is key to the development of effective immunotherapies, especially in lung cancer.
基金Imported Scholar Project and Startup from Peking University Health Science Center(BMU2021YJ063 to MD)the Biotechnology Innovation Plan from Beijing Sungen Biomedical Technology Co.,Ltd(2022066 to MD)the Excellent Young Scientists Fund Program(overseas)from National Natural Science Fund(HY2021-7 to MD)。
文摘Myeloid checkpoints are receptors on the myeloid cell surface which can mediate inhibitory signals to modulate anti-tumor immune activities.They can either inhibit cellular phagocytosis or suppress T cells and are thus involved in the pathogenesis of various diseases.In the tumor microenvironment,besides killing tumor cells by phagocytosis or activating anti-tumor immunity by tumor antigen presentation,myeloid cells could execute protumor efficacies through myeloid checkpoints by interacting with counter-receptors on other immune cells or cancer cells.In summary,myeloid checkpoints may be promising therapeutic targets for cancer immunotherapy.
文摘In the interaction between a tumor and the immune system,immune checkpoints play an important role,and in tumor immune escape,co-inhibitory immune checkpoints are important.Immune checkpoint inhibitors(ICIs)can enhance the immune system's killing effect on tumors.To date,impressive progress has been made in a variety of tumor treatments;PD1/PDL1 and CTLA4 inhibitors have been approved for clinical use in some tumors.However,glioblastoma(GBM)still lacks an effective treatment.Recently,a phase III clinical trial using nivolumab to treat recurrent GBM showed no significant improvement in overall survival compared to bevacizumab.Therefore,the use of immune checkpoints in the treatment of GBM still faces many challenges.First,to clarify the mechanism of action,how different immune checkpoints play roles in tumor escape needs to be determined;which biomarkers predict a benefit from ICIs treatment and the therapeutic implications for GBM based on experiences in other tumors also need to be determined.Second,to optimize combination therapies,how different types of immune checkpoints are selected for combined application and whether combinations with targeted agents or other immunotherapies exhibit increased efficacy need to be addressed.All of these concerns require extensive basic research and clinical trials.In this study,we reviewed existing knowledge with respect to the issues mentioned above and the progress made in treatments,summarized the state of ICIs in preclinical studies and clinical trials involving GBM,and speculated on the therapeutic prospects of ICIs in the treatment of GBM.
基金supported by the National Key R&D Program of China(No.2020YFA0710802 to Jiacheng Bi)Guangdong Basic and Applied Basic Research Foundation(No.2021A1515110174 to Yingying Huang)the National Natural Science Foundation of China(No.82071768 to Jiacheng Bi).
文摘Natural killer(NK)cells are key innate immune lymphocytes,which play important roles against tumors.However,tumor-infiltrating NK cells are always hypofunctional/exhaustive.On the one hand,this state is contributed by context-dependent interactions between inhibitory NK cell checkpoint receptors and their ligands,which usually vary in different tumor types and stages during tumor development.On the other hand,the inhibitory functions of intracellular checkpoint molecules of NK cells are more similar across different tumor types,representing common mechanisms limiting the potential of NK cell therapy.In this review,representative NK cell intracellular checkpoint molecules in different aspects of NK cell biology were reviewed,and therapeutic potentials were discussed by targeting these molecules to promote antitumor NK cell therapy.
基金supported by the National Natural Science Foundation of China(No.81602104).
文摘Objective To investigate the combined effects of thymidine phosphorylase(TYMP)and sine oculis homeobox homologue 1(Six1)on the tumor microenvironment and their role in promoting metastasis in gastric cancer(GC).Methods A total of 674 GC patients who underwent surgical resection were enrolled.Correlations between TYMP/Six1 expression and the clinicopathological characteristics and overall survival of patients were analysed.The expression of TYMP,Six1 and vascular endothelial growth factor C(VEGFc)was quantified via immunohistochemistry and quantitative real-time polymerase chain reaction.Cell transfection,wound-healing assays and bioinformatics analyses were used to explore the potential underlying mechanisms involved.Results Compared with the other groups,the Six1+/TYMP+patients exhibited poor differentiation,advanced tumor stage,a higher rate of lymphatic vessel invasion and shorter survival.Additionally,the protein expression of TYMP and Six1 was positively correlated with the VEGFc level.A significant increase in VEGFc expression was observed in cells transfected with TYMP,Six1,and TYMP/Six1 vectors.The results of the wound-healing assay indicated that the synergistic effect of TYMP and Six1 enhanced the migratory ability of GC cells.Furthermore,bioinformatics analysis revealed that TYMP and Six1 were positively correlated with immunosuppressive immune cell subsets and elevated the expression of inhibitory immune checkpoints in GC.Conclusions The combination of TYMP and Six1 is a good predictive and prognostic biomarker for GC.This combination enhances the expression of VEGFc,facilitates the invasion of GC cells,and may be linked to inhibitory immune cells and the tumor immune microenvironment.
文摘Lung cancer is a common cause of cancer-related death globally.The majority of lung cancer patients initially benefit from chemotherapy and immunotherapy.However,as the treatment cycle progresses and the disease evolves,the emergence of acquired resistance leads to treatment failure.Many researches have shown that non-coding RNAs(ncRNAs)not only influence lung cancer progression but also act as potential mediators of immunotherapy and chemotherapy resistance in lung cancer,mediating drug resistance by regulating multiple targets and pathways.In addition,the regulation of immune response by ncRNAs is dualistic,forming a microenvironment for inhibits/promotes immune escape through changes in the expression of immune checkpoints.The aim of this review is to understand the effects of ncRNAs on the occurrence and development of lung cancer,focusing on the role of ncRNAs in regulating drug resistance of lung cancer.
基金supported by the Russian Science Foundation,project no.23-14-00285。
文摘Melanomas are aggressive cancers,with a high rate of metastatic disease.Cutaneous(CM)and uveal(UM)melanomas are intrinsically different diseases,and most cell death inducers effective for CM do not function for UM.This is primarily due to the fact the eye is an immunologically privileged organ,and it fails to achieve the efficacy of immune checkpoint inhibitors(ICIs)comparable to that for CM.However,approaches utilizing specific melanomaassociated antigens are being developed for metastatic forms of CM and UM.The most promising to date are gp100 and tyrosinase related protein 1(TYRP1),primarily for the design of targeting chimeric molecules and for autologous T-/NK-cell products with a chimeric antigen receptor.The difference in the mutational profile of apoptosis-related genes in CM and UM also makes counterproductive the use of the same drugs re-activators of the intrinsic pathway of apoptosis.Therefore,the discovery of novel pathways of regulated cell death such as ferroptosis and cuproptosis may help in the development of new drugs for melanomas resistant to already available inducers of regulated cell death.Here we consistently discuss the latest advances in the therapy of melanomas,and above all-UM,which is classified as an orphan disease.
文摘NK cells play important roles in innate defenses against viruses and in the control of tumor growth and metastasis.The regulation/induction of NK cell function is mediated by an array of activating or inhibitory surface receptors.In humans,major activating receptors involved in target cell killing are the natural cytotoxicity receptors(NCRs)and NKG2D.Activating receptors recognize ligands that are overexpressed or expressed de novo upon cell stress,viral infection,or tumor transformation.The HLA-class I-specific inhibitory receptors,including KIRs recognizing HLA-class I allotypic determinants and CD94/NKG2A recognizing the class-Ib HLA-E,constitute a fail-safe mechanism to avoid unwanted NK-mediated damage to healthy cells.Other receptors such as PD-1,primarily expressed by activated T lymphocytes,are important inhibitory checkpoints of immune responses that ensure T-cell tolerance.PD-1 also may be expressed by NK cells in cancer patients.Since PD-1 ligand(PD-L1)may be expressed by different tumors,PD-1/PD-L1 interactions inactivate both T and NK cells.Thus,the reliable evaluation of PD-L1 expression in tumors has become a major issue to select patients who may benefit from therapy with mAbs disrupting PD-1/PD-L1 interactions.Recently,NKG2A was revealed to be an important checkpoint controlling both NK and T-cell activation.Since most tumors express HLA-E,mAbs targeting NKG2A has been used alone or in combination with other therapeutic mAbs targeting PD-1 or tumor antigens(e.g.,EGFR),with encouraging results.The translational value of NK cells and their receptors is evidenced by the extraordinary therapeutic success of haploidentical HSCT to cure otherwise fatal high-risk leukemias.
基金supported by Natural Science Foundation of Guangdong Province,China(2022A1515011575)National Natural Science Foundation of China,China(81873154)President Foundation of Integrated Hospital of Traditional Chinese Medicine,Southern Medical University,China(1202103010)。
文摘Lycii Radicis Cortex(LRC)is a medicinal and food homologous plant with various pharmacological activities,including anti-tumor effects.This study explores the anti-tumor effect of LRC on non-small cell lung cancer(NSCLC)and its molecular mechanism using mice bearing Lewis lung carcinoma cells.LRC significantly suppressed the growth of NSCLC.Besides,RNA sequencing of mice tumors and hematoxylin&eosin and immunofluorescence staining revealed that LRC promoted the infiltration of T lymphocytes,specifically GZMB~+CD8~+T lymphocytes,in tumor tissues.The Gene Set Enrichment Analysis of spleen RNA indicated that LRC up-regulated PD-1-downstream pathways,suggesting that LRC exerted its effects through the PDL1/PD-1 pathway.Further experiments revealed that LRC interacted with PD-L1,blocking PD-L1/PD-1 binding and thus restoring the T cell killing activity on tumor cells.Together,these results support using LRC as healthy food to improve anti-tumor immunity in patients with NSCLC.
文摘BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in cancer treatment.While HP infection and PD-L1 expression in GC may be linked,the relationship between them remains unclear,in part because there have been conflicting results reported from various studies.AIM To perform a meta-analysis to assess the relationship between HP and PD-L1 expression in patients with GC.METHODS A systematic literature review was conducted using PubMed,Embase,Cochrane Library,and Web of Science databases.Observational studies that examined the association between HP infection and PD-L1 expression in patients with GC were included.Odds ratios and 95%confidence intervals were calculated to estimate the association.Heterogeneity was assessed using Cochrane’s Q test and I²statistic.A random-effects model was used due to significant heterogeneity across studies.RESULTS Fourteen studies involving a total of 3069 patients with GC were included.The pooled analysis showed a significant association between HP infection and increased PD-L1 expression in GC tissues(odd ratio=1.69,95%confidence interval:1.24-2.29,P<0.001,I^(2)=59%).Sensitivity analyses confirmed the robustness of these findings.Subgroup analyses did not show significant variation based on geographic region,sample size,or method of PD-L1 assessment.Publication bias was minimal,as shown by funnel plots and Egger’s regression test.CONCLUSION HP infection is associated with increased PD-L1 expression in GC,suggesting that HP status may influence the response to programmed cell death protein 1/PD-L1 blockade therapy.
文摘Primary liver cancer(PLC)is a prevalent malignancy with high incidence and mortality rates globally.Hepatocellular carcinoma(HCC),primarily resulting from hepatitis B virus infections in Asia,constitutes most PLC cases.Despite advancements in targeted therapies and localized treatments,the 5-year survival rate remains low,indicating limited efficacy of current approaches.The advent of immunotherapy,particularly immune checkpoint inhibitors(ICIs),has brought new hope for patients with PLC.However,the liver's unique immune microenvironment presents significant challenges to the effectiveness of immunotherapy in HCC.This article reviews recent research developments in liver cancer immunotherapy,focusing on ICIs,combination therapies,emerging treatments,and prospective future directions.
基金Supported by 2021 Key Topic of Qinghai Provincial Health System–Guiding Plan Topic,No.2021-WJZDX-43.
文摘Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tumor effects,they can also trigger immune-related adverse events(irAEs),with ICI-associated colitis being one of the more prevalent forms.This condition can disrupt treatment,necessitate drug discontinuation,and adversely affect therapeutic outcomes.In severe cases,irAEs may even become life-threatening.A recent case report by Hong et al highlights the importance of vigilance for ICI-associated colitis in patients experiencing symptoms such as diarrhea and abdominal pain,which can arise both during and even after completion of ICI treatment.Early identification,multidisciplinary management,and continuous monitoring of patients are essential steps to further improve outcomes.
基金supported by grants from the National Natural Science Foundation of China(Grant No.82171810)the Program of Shandong Provincial Scientific and Technological Development of Traditional Chinese Medicine(Grant No.M-2023210)。
文摘CD8^(+)T cell exhaustion,a critical challenge in the immune response to cancer,is characterized by a profound decline in the functionality of effector CD8^(+)T cells.This state of exhaustion is accompanied by the upregulation of various inhibitory receptors and significant shifts in both transcriptional and epigenetic profiles,thus ultimately leading to inadequate tumor control.Therapeutic strategies aimed at reversing CD8^(+)T cell exhaustion have the potential to rejuvenate immune responses and enhance treatment efficacy.This review compiles current knowledge regarding the molecular mechanisms underlying CD8^(+)T cell exhaustion,including the roles of immune checkpoint molecules,the tumor microenvironment,metabolic reprogramming,transcription factors,and epigenetic modifications.Emerging therapeutic approaches designed to combat CD8^(+)T cell exhaustion are evaluated,with emphasis on the modulation of immune checkpoints;targeting of metabolic and transcriptional changes;and exploration of other innovative strategies,such as epigenetic editing and engineered CAR-T cells.Importantly,we expand the exhaustion concept to immune cells beyond CD8^(+)T cells,such as CD4^(+)T cells,natural killer cells,and myeloid populations,thereby highlighting the broader implications of systemic immunosuppression in the cancer context.Finally,we propose avenues for future research aimed at further elucidating the factors and molecular mechanisms associated with CD8^(+)T cell exhaustion,thereby underscoring the critical need for strategies aimed at reversing this state to improve outcomes in cancer immunotherapy.
