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
(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
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
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
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
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
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
Tumor immunotherapy has emerged as a transformative approach following conventional treatments such as surgery,radiotherapy,and chemotherapy.The discovery and application of immune checkpoints,particularly through inh...Tumor immunotherapy has emerged as a transformative approach following conventional treatments such as surgery,radiotherapy,and chemotherapy.The discovery and application of immune checkpoints,particularly through inhibitors targeting PD-1 and CTLA-4,have led to remarkable clinical successes in cancers including melanoma and non-small cell lung cancer(NSCLC).However,not all patients respond to immune checkpoint inhibitors(ICIs),and treatment is often accompanied by immune-related adverse events,highlighting the need for predictive biomarkers.Assessing immune checkpoint expression prior to therapy is essential,yet current methods face limitations:immunohistochemistry(IHC)is invasive and hampered by tumor heterogeneity,while next-generation sequencing(NGS),circulating tumor cell(CTC)assays,and microsatellite instability(MSI)testing are constrained by cost and sample accessibility.Positron emission tomography(PET),a non-invasive functional imaging technique,offers a promising alternative by enabling real-time,whole-body quantification of target expression using radiolabeled probes.Recently,PET probes targeting PD-1,PD-L1,and CTLA-4 have been developed,facilitating patient stratification,treatment monitoring,and personalized immunotherapy.This review systematically examines methods for detecting tumor immune targets-from traditional pathology to advanced functional imaging-evaluating their principles,applications,and limitations,with the aim of guiding future research and clinical practice in precision immuno-oncology.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
BACKGROUND Chemotherapy with an immune checkpoint inhibitor is one of the standard regimens for treating advanced gastric cancer(AGC).Ascites and peritoneal dissemination are common complications and poor prognostic f...BACKGROUND Chemotherapy with an immune checkpoint inhibitor is one of the standard regimens for treating advanced gastric cancer(AGC).Ascites and peritoneal dissemination are common complications and poor prognostic factors of AGC;however,reports regarding its efficacy and safety in patients with AGC and massive ascites are limited.AIM To evaluate the safety and efficacy of nivolumab combined with chemotherapy in patients with AGC and ascites.METHODS We retrospectively collected clinical data from 124 patients with AGC who received chemotherapy plus nivolumab as first-line treatment from July 2017 to December 2024.Based on computed tomography scans,massive or moderate ascites were classified as high ascites burden(HAB),whereas mild or no ascites were classified as low ascites burden.RESULTS Ascites was detected in 47 patients(38%);26(21%)were classified into the HAB group.Patients in the HAB group exhibited a significantly poorer performance status,a higher prevalence of diffuse-type histology,and lower programmed cell death ligand 1(PD-L1)expression.Combination therapy with FOLFOX and neutropenia was significantly more common in the HAB group.Progression-free survival(PFS)(4.4 months vs 9.3 months,P=0.0012)and overall survival(OS)(7.3 months vs 21.2 months,P<0.0001)were significantly poorer in the HAB group.However,an improvement in ascites was observed in 61.5%of patients in the HAB group.PD-L1 expression did not correlate with either PFS or OS in the HAB group.CONCLUSION Nivolumab plus chemotherapy demonstrated modest efficacy and acceptable toxicity in patients with AGC and HAB.展开更多
Infection with SARS-COV-2 is the cause of COVID-19 and has generated an unprecedented health crisis worldwide.While most of the patients experience mild symptoms,around 20%develop severe disease,characterized by pneum...Infection with SARS-COV-2 is the cause of COVID-19 and has generated an unprecedented health crisis worldwide.While most of the patients experience mild symptoms,around 20%develop severe disease,characterized by pneumonia and in the worst cases by acute respiratory distress syndrome(ARDS).展开更多
Tumor-promoting inflammation and the avoidance of immune destruction are hallmarks of cancer.While innate immune cells,such as neutrophils,monocytes,and macrophages,are critical mediators for sterile and nonsterile in...Tumor-promoting inflammation and the avoidance of immune destruction are hallmarks of cancer.While innate immune cells,such as neutrophils,monocytes,and macrophages,are critical mediators for sterile and nonsterile inflammation,persistent inflammation,such as that which occurs in cancer,is known to disturb normal myelopoiesis.This disturbance leads to the generation of immunosuppressive myeloid cells,such as myeloid-derived suppressor cells(MDSCs)and tumor-associated macrophages(TAMs).Due to their potent suppressive activities against effector lymphocytes and their abundance in the tumor microenvironment,immunosuppressive myeloid cells act as a major barrier to cancer immunotherapy.Indeed,various therapeutic approaches directed toward immunosuppressive myeloid cells are actively being tested in preclinical and clinical studies.These include antiinflammatory agents,therapeutic blockade of the mobilization and survival of myeloid cells,and immunostimulatory adjuvants.More recently,immune checkpoint molecules expressed on tumor-infiltrating myeloid cells have emerged as potential therapeutic targets to redirect these cells to eliminate tumor cells.In this review,we discuss the complex crosstalk between cancer-related inflammation and immunosuppressive myeloid cells and possible therapeutic strategies to harness antitumor immune responses.展开更多
Immunotherapy has been recently considered as a promising alternative for cancer treatment.Indeed,targeting of immune checkpoint(ICP)strategies have shown significant success in human malignancies.However,despite rema...Immunotherapy has been recently considered as a promising alternative for cancer treatment.Indeed,targeting of immune checkpoint(ICP)strategies have shown significant success in human malignancies.However,despite remarkable success of cancer immunotherapy in pancreatic cancer(PCa),many of the developed immunotherapy methods show poor therapeutic outcomes in PCa with no or few effective treatment options thus far.In this process,immunosuppression in the tumor microenvironment(TME)is found to be the main obstacle to the effectiveness of antitumor immune response induced by an immunotherapy method.In this paper,the latest findings on the ICPs,which mediate immunosuppression in the TME have been reviewed.In addition,different approaches for targeting ICPs in the TME of PCa have been discussed.This review has also synopsized the cutting-edge advances in the latest studies to clinical applications of ICP-targeted therapy in PCa.展开更多
Checkpoint blockade-based immunotherapy offers new options and powerful weapons for the treatment of cancer,but its efficacy varies greatly among different types of cancer and across individual patients.Thus,the devel...Checkpoint blockade-based immunotherapy offers new options and powerful weapons for the treatment of cancer,but its efficacy varies greatly among different types of cancer and across individual patients.Thus,the development of the right tools that can be used to identify patients who could benefit from this therapy is of utmost importance in order to maximize the therapeutic benefit,minimize risk of toxicities,and guide combination approaches.Multiple predictors have emerged that are based on checkpoint receptor ligand expression,tumor mutational burden,neoantigen and microsatellite instability,tumor-infiltrating immune cells,and peripheral blood biomarkers.In this review,we discuss the current state and progress of predictors as aids in checkpoint blockadebased immunotherapy in cancer.展开更多
Natural killer(NK)cells are unique innate immune cells that mediate antiviral and anti-tumor responses.Thus,they might hold great potential for cancer immunotherapy.NK cell adoptive immunotherapy in humans has shown m...Natural killer(NK)cells are unique innate immune cells that mediate antiviral and anti-tumor responses.Thus,they might hold great potential for cancer immunotherapy.NK cell adoptive immunotherapy in humans has shown modest efficacy.In particular,it has failed to demonstrate therapeutic efficiency in the treatment of solid tumors,possibly due in part to the immunosuppressive tumor microenvironment(TME),which reduces NK cell immunotherapy’s efficiencies.It is known that immune checkpoints play a prominent role in creating an immunosuppressive TME,leading to NK cell exhaustion and tumor immune escape.Therefore,NK cells must be reversed from their dysfunctional status and increased in their effector roles in order to improve the efficiency of cancer immunotherapy.Blockade of immune checkpoints can not only rescue NK cells from exhaustion but also augment their robust anti-tumor activity.In this review,we discussed immune checkpoint blockade strategies with a focus on chimeric antigen receptor(CAR)-NK cells to redirect NK cells to cancer cells in the treatment of solid tumors.展开更多
Studies on immune checkpoint inhibitors targeting B7-CD28 family pathways in esophageal squamous cell carcinoma(ESCC)have shown promising results.However,a comprehensive understanding of B7-CD28 family members in ESCC...Studies on immune checkpoint inhibitors targeting B7-CD28 family pathways in esophageal squamous cell carcinoma(ESCC)have shown promising results.However,a comprehensive understanding of B7-CD28 family members in ESCC is still limited.This study aimed to construct a novel B7-CD28 family-based prognosis system to predict survival in patients with ESCC.We collected 179 cases from our previously published microarray data and 86 cases with qPCR data.Specifically,119 microarray data(GSE53624)were used as a training set,whereas the remaining 60 microarray data(GSE53622),all 179 microarray data(GSE53625)and an independent cohort with 86 qPCR data were used for validation.The underlying mechanism and immune landscape of the system were also explored using bioinformatics and immunofluorescence.We examined 13 well-defined B7-CD28 family members and identified 2 genes(ICSOLG and HHLA2)with the greatest prognostic value.A system based on the combination HHLA2 and ICOSLG(B7-CD28 signature)was constructed to distinguish patients as high-or low-risk of an unfavorable outcome,which was further confirmed as an independent prognostic factor.As expected,the signature was well validated in the entire cohort and in the independent cohort,as well as in different clinical subgroups.The signature was found to be closely related to immune-specific biological processes and pathways.Additionally,high-risk group samples demonstrated high infiltration of Tregs and fibroblasts and distinctive immune checkpoint panels.Collectively,we built the first,practical B7-CD28 signature for ESCC that could independently identify high-risk patients.Such information may help inform immunotherapy-based treatment decisions for patients with ESCC.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
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.
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.
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.
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.
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.
文摘Tumor immunotherapy has emerged as a transformative approach following conventional treatments such as surgery,radiotherapy,and chemotherapy.The discovery and application of immune checkpoints,particularly through inhibitors targeting PD-1 and CTLA-4,have led to remarkable clinical successes in cancers including melanoma and non-small cell lung cancer(NSCLC).However,not all patients respond to immune checkpoint inhibitors(ICIs),and treatment is often accompanied by immune-related adverse events,highlighting the need for predictive biomarkers.Assessing immune checkpoint expression prior to therapy is essential,yet current methods face limitations:immunohistochemistry(IHC)is invasive and hampered by tumor heterogeneity,while next-generation sequencing(NGS),circulating tumor cell(CTC)assays,and microsatellite instability(MSI)testing are constrained by cost and sample accessibility.Positron emission tomography(PET),a non-invasive functional imaging technique,offers a promising alternative by enabling real-time,whole-body quantification of target expression using radiolabeled probes.Recently,PET probes targeting PD-1,PD-L1,and CTLA-4 have been developed,facilitating patient stratification,treatment monitoring,and personalized immunotherapy.This review systematically examines methods for detecting tumor immune targets-from traditional pathology to advanced functional imaging-evaluating their principles,applications,and limitations,with the aim of guiding future research and clinical practice in precision immuno-oncology.
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.
文摘BACKGROUND Chemotherapy with an immune checkpoint inhibitor is one of the standard regimens for treating advanced gastric cancer(AGC).Ascites and peritoneal dissemination are common complications and poor prognostic factors of AGC;however,reports regarding its efficacy and safety in patients with AGC and massive ascites are limited.AIM To evaluate the safety and efficacy of nivolumab combined with chemotherapy in patients with AGC and ascites.METHODS We retrospectively collected clinical data from 124 patients with AGC who received chemotherapy plus nivolumab as first-line treatment from July 2017 to December 2024.Based on computed tomography scans,massive or moderate ascites were classified as high ascites burden(HAB),whereas mild or no ascites were classified as low ascites burden.RESULTS Ascites was detected in 47 patients(38%);26(21%)were classified into the HAB group.Patients in the HAB group exhibited a significantly poorer performance status,a higher prevalence of diffuse-type histology,and lower programmed cell death ligand 1(PD-L1)expression.Combination therapy with FOLFOX and neutropenia was significantly more common in the HAB group.Progression-free survival(PFS)(4.4 months vs 9.3 months,P=0.0012)and overall survival(OS)(7.3 months vs 21.2 months,P<0.0001)were significantly poorer in the HAB group.However,an improvement in ascites was observed in 61.5%of patients in the HAB group.PD-L1 expression did not correlate with either PFS or OS in the HAB group.CONCLUSION Nivolumab plus chemotherapy demonstrated modest efficacy and acceptable toxicity in patients with AGC and HAB.
文摘Infection with SARS-COV-2 is the cause of COVID-19 and has generated an unprecedented health crisis worldwide.While most of the patients experience mild symptoms,around 20%develop severe disease,characterized by pneumonia and in the worst cases by acute respiratory distress syndrome(ARDS).
基金K.N.was supported by a Naito Foundation and a NHMRC Project Grant(1174363)M.J.S.was supported by a National Health and Medical Research Council(NH&MRC)Senior Principal Research Fellowship(1078671)+1 种基金Program Grant(1132519)K.N.and M.J.S were recipients of a Leukaemia Foundation of Australia SERP grant.
文摘Tumor-promoting inflammation and the avoidance of immune destruction are hallmarks of cancer.While innate immune cells,such as neutrophils,monocytes,and macrophages,are critical mediators for sterile and nonsterile inflammation,persistent inflammation,such as that which occurs in cancer,is known to disturb normal myelopoiesis.This disturbance leads to the generation of immunosuppressive myeloid cells,such as myeloid-derived suppressor cells(MDSCs)and tumor-associated macrophages(TAMs).Due to their potent suppressive activities against effector lymphocytes and their abundance in the tumor microenvironment,immunosuppressive myeloid cells act as a major barrier to cancer immunotherapy.Indeed,various therapeutic approaches directed toward immunosuppressive myeloid cells are actively being tested in preclinical and clinical studies.These include antiinflammatory agents,therapeutic blockade of the mobilization and survival of myeloid cells,and immunostimulatory adjuvants.More recently,immune checkpoint molecules expressed on tumor-infiltrating myeloid cells have emerged as potential therapeutic targets to redirect these cells to eliminate tumor cells.In this review,we discuss the complex crosstalk between cancer-related inflammation and immunosuppressive myeloid cells and possible therapeutic strategies to harness antitumor immune responses.
文摘Immunotherapy has been recently considered as a promising alternative for cancer treatment.Indeed,targeting of immune checkpoint(ICP)strategies have shown significant success in human malignancies.However,despite remarkable success of cancer immunotherapy in pancreatic cancer(PCa),many of the developed immunotherapy methods show poor therapeutic outcomes in PCa with no or few effective treatment options thus far.In this process,immunosuppression in the tumor microenvironment(TME)is found to be the main obstacle to the effectiveness of antitumor immune response induced by an immunotherapy method.In this paper,the latest findings on the ICPs,which mediate immunosuppression in the TME have been reviewed.In addition,different approaches for targeting ICPs in the TME of PCa have been discussed.This review has also synopsized the cutting-edge advances in the latest studies to clinical applications of ICP-targeted therapy in PCa.
基金the grants from the National Natural Science Foundation of China(81672797)the Science and Technology Planning Project of Beijing City(Z151100003915076)the National Key Research and Development Program of China(2016YFC1303501 and 2016YFC1303504).
文摘Checkpoint blockade-based immunotherapy offers new options and powerful weapons for the treatment of cancer,but its efficacy varies greatly among different types of cancer and across individual patients.Thus,the development of the right tools that can be used to identify patients who could benefit from this therapy is of utmost importance in order to maximize the therapeutic benefit,minimize risk of toxicities,and guide combination approaches.Multiple predictors have emerged that are based on checkpoint receptor ligand expression,tumor mutational burden,neoantigen and microsatellite instability,tumor-infiltrating immune cells,and peripheral blood biomarkers.In this review,we discuss the current state and progress of predictors as aids in checkpoint blockadebased immunotherapy in cancer.
基金This work was supported by Isfahan University of Medical Sciences,Isfahan,Iran(grant No.140170).
文摘Natural killer(NK)cells are unique innate immune cells that mediate antiviral and anti-tumor responses.Thus,they might hold great potential for cancer immunotherapy.NK cell adoptive immunotherapy in humans has shown modest efficacy.In particular,it has failed to demonstrate therapeutic efficiency in the treatment of solid tumors,possibly due in part to the immunosuppressive tumor microenvironment(TME),which reduces NK cell immunotherapy’s efficiencies.It is known that immune checkpoints play a prominent role in creating an immunosuppressive TME,leading to NK cell exhaustion and tumor immune escape.Therefore,NK cells must be reversed from their dysfunctional status and increased in their effector roles in order to improve the efficiency of cancer immunotherapy.Blockade of immune checkpoints can not only rescue NK cells from exhaustion but also augment their robust anti-tumor activity.In this review,we discussed immune checkpoint blockade strategies with a focus on chimeric antigen receptor(CAR)-NK cells to redirect NK cells to cancer cells in the treatment of solid tumors.
基金This work was supported by the CAMS Innovation Fund for Medical Sciences(No.2017-I2M-1-005,2016-I2M-1-001)the National Key R&D Program of China(No.2016YFC1303201)+2 种基金the National Natural Science Foundation of China(No.81802299,81502514)the Fundamental Research Funds for the Central Universities(No.3332018070)the National Key Basic Research Development Plan(No.2018YFC1312105).
文摘Studies on immune checkpoint inhibitors targeting B7-CD28 family pathways in esophageal squamous cell carcinoma(ESCC)have shown promising results.However,a comprehensive understanding of B7-CD28 family members in ESCC is still limited.This study aimed to construct a novel B7-CD28 family-based prognosis system to predict survival in patients with ESCC.We collected 179 cases from our previously published microarray data and 86 cases with qPCR data.Specifically,119 microarray data(GSE53624)were used as a training set,whereas the remaining 60 microarray data(GSE53622),all 179 microarray data(GSE53625)and an independent cohort with 86 qPCR data were used for validation.The underlying mechanism and immune landscape of the system were also explored using bioinformatics and immunofluorescence.We examined 13 well-defined B7-CD28 family members and identified 2 genes(ICSOLG and HHLA2)with the greatest prognostic value.A system based on the combination HHLA2 and ICOSLG(B7-CD28 signature)was constructed to distinguish patients as high-or low-risk of an unfavorable outcome,which was further confirmed as an independent prognostic factor.As expected,the signature was well validated in the entire cohort and in the independent cohort,as well as in different clinical subgroups.The signature was found to be closely related to immune-specific biological processes and pathways.Additionally,high-risk group samples demonstrated high infiltration of Tregs and fibroblasts and distinctive immune checkpoint panels.Collectively,we built the first,practical B7-CD28 signature for ESCC that could independently identify high-risk patients.Such information may help inform immunotherapy-based treatment decisions for patients with ESCC.
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.
