Exo-atmospheric vehicles are constrained by limited maneuverability,which leads to the contradiction between evasive maneuver and precision strike.To address the problem of Integrated Evasion and Impact(IEI)decision u...Exo-atmospheric vehicles are constrained by limited maneuverability,which leads to the contradiction between evasive maneuver and precision strike.To address the problem of Integrated Evasion and Impact(IEI)decision under multi-constraint conditions,a hierarchical intelligent decision-making method based on Deep Reinforcement Learning(DRL)was proposed.First,an intelligent decision-making framework of“DRL evasion decision”+“impact prediction guidance decision”was established:it takes the impact point deviation correction ability as the constraint and the maximum miss distance as the objective,and effectively solves the problem of poor decisionmaking effect caused by the large IEI decision space.Second,to solve the sparse reward problem faced by evasion decision-making,a hierarchical decision-making method consisting of maneuver timing decision and maneuver duration decision was proposed,and the corresponding Markov Decision Process(MDP)was designed.A detailed simulation experiment was designed to analyze the advantages and computational complexity of the proposed method.Simulation results show that the proposed model has good performance and low computational resource requirement.The minimum miss distance is 21.3 m under the condition of guaranteeing the impact point accuracy,and the single decision-making time is 4.086 ms on an STM32F407 single-chip microcomputer,which has engineering application value.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact mo...BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact molecular mechanisms leading to the progression of HCC are still unclear.Research has shown that the microRNA-142-3p level decreases in HCC,whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues.In this paper,we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity,and the association between them.AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients.METHODS In this study,we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues,and retrospectively analyzed the prognosis of HCC patients.Furthermore,explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments,which involved the following experimental methods:Immunohistochemical staining,western blot,quantitative real-time-polymerase chain reaction,flow cytometric analysis,tumor xenografts in nude mice,etc.The statistical methods involved in this study contained t-test,one-way analysis of variance,theχ^(2)test,the Kaplan-Meier approach and the log-rank test.RESULTS In this study,we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate.ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3′untranslated region.Furthermore,microRNA-142-3p promotes apoptosis and inhibits proliferation,invasion,and migration of HCC cell lines in vitro via ASH1L.For the exploration mechanism,we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1,which is potentially relevant to the immune system.CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC.Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.展开更多
Cold tumors,defined by insufficient immune cell infiltration and a highly immunosuppressive tumor microenvironment(TME),exhibit limited responsiveness to conventional immunotherapies.This reviewsystematically summariz...Cold tumors,defined by insufficient immune cell infiltration and a highly immunosuppressive tumor microenvironment(TME),exhibit limited responsiveness to conventional immunotherapies.This reviewsystematically summarizes the mechanisms of immune evasion and the therapeutic strategies for cold tumors as revealed by multiomics technologies.By integrating genomic,transcriptomic,proteomic,metabolomic,and spatialmulti-omics data,the review elucidates key immune evasionmechanisms,including activation of the WNT/β-catenin pathway,transforming growth factor-β(TGF-β)–mediated immunosuppression,metabolic reprogramming(e.g.,lactate accumulation),and aberrant expression of immune checkpoint molecules.Furthermore,this review proposes multi-dimensional therapeutic strategies,such as targeting immunosuppressive pathways(e.g.,programmed death-1(PD-1)/programmed death-ligand 1(PD-L1)inhibitors combined with TGF-βblockade),reshaping the TME through chemokine-based therapies,oncolytic viruses,and vascular normalization,and metabolic interventions(e.g.,inhibition of lactate dehydrogenase A(LDHA)or glutaminase(GLS)).In addition,personalized neoantigen vaccines and engineered cell therapies(e.g.,T cell receptor-engineered T(TCR-T)and natural killer(NK)cells)show promising potential.Emerging evidence also highlights the role of epigenetic regulation(e.g.,histone deacetylase(HDAC)inhibitors)and N6-Methyladenosine(m6A)RNA modifications in reversing immune evasion.Despite the promising insights offered by multi-omics integration in guiding precision immunotherapy,challenges remain in clinical translation,including data heterogeneity,target-specific toxicity,and limitations in preclinical models.Future efforts should focus on coupling dynamic multi-omics technologies with intelligent therapeutic design to convert cold tumors into immunologically active(“hot”)microenvironments,ultimately facilitating breakthroughs in personalized immunotherapy.展开更多
In practical combat scenarios,Hypersonic Glide Vehicles(HGV)face the challenge of evading Successive Pursuers from the Same Direction while satisfying the Homing Constraint(SPSDHC).To address this problem,this paper p...In practical combat scenarios,Hypersonic Glide Vehicles(HGV)face the challenge of evading Successive Pursuers from the Same Direction while satisfying the Homing Constraint(SPSDHC).To address this problem,this paper proposes a parameterized evasion guidance algorithm based on reinforcement learning.The three-player optimal evasion strategy is firstly analyzed and approximated by parametrization.The switching acceleration command of HGV optimal evasion strategy considering the upper limit of missile acceleration command is analyzed based on the optimal control theory.The terminal miss of HGV in the case of evading two missiles is analyzed,which means that the three-player optimal evasion strategy is a linear combination of two one-toone strategies.Then,a velocity control algorithm is proposed to increase the terminal miss by actively controlling the flight speed of the HGV based on the parametrized evasion strategy.The reinforcement learning method is used to implement the strategy in real time and a reward function is designed by deducing homing strategy for the HGV to approach the target,which ensures that the HGV satisfies the homing constraint.Experimental results demonstrate the feasibility and robustness of the proposed parameterized evasion strategy,which enables the HGV to generate maximum terminal miss and satisfy homing constraint when facing single or double missiles.展开更多
This paper presents a novel evasion guidance law for hypersonic morphing vehicles,focusing on determining the optimized wing's unfolded angle to promote maneuverability based on an intelligent algorithm.First,the ...This paper presents a novel evasion guidance law for hypersonic morphing vehicles,focusing on determining the optimized wing's unfolded angle to promote maneuverability based on an intelligent algorithm.First,the pursuit-evasion problem is modeled as a Markov decision process.And the agent's action consists of maneuver overload and the unfolded angle of wings,which is different from the conventional evasion guidance designed for fixed-shape vehicles.The reward function is formulated to ensure that the miss distances satisfy the prescribed bounds while minimizing energy consumption.Then,to maximize the expected cumulative reward,a residual learning method is proposed based on proximal policy optimization,which integrates the optimal evasion for linear cases as the baseline and trains to optimize the performance for nonlinear engagement with multiple pursuers.Therefore,offline training guarantees improvement of the constructed evasion guidance law over conventional ones.Ultimately,the guidance law for online implementation includes only analytical calculations.It maps from the confrontation state to the expected angle of attack and the unfolded angle while retaining high computational efficiency.Simulations show that the proposed evasion guidance law can utilize the change of unfolded angle to extend the maximum overload capability.And it surpasses conventional maneuver strategies by ensuring better evasion efficacy and higher energy efficiency.展开更多
BACKGROUND The incidence of primary liver cancer is increasing year by year.In 2022 alone,more than 900000 people were diagnosed with liver cancer worldwide,with hepatocellular carcinoma(HCC)accounting for 75%-85%of c...BACKGROUND The incidence of primary liver cancer is increasing year by year.In 2022 alone,more than 900000 people were diagnosed with liver cancer worldwide,with hepatocellular carcinoma(HCC)accounting for 75%-85%of cases.HCC is the most common primary liver cancer.China has the highest incidence and mortality rate of HCC in the world,and it is one of the malignant tumors that seriously threaten the health of Chinese people.The onset of liver cancer is occult,the early cases lack typical clinical symptoms,and most of the patients are already in the middle and late stage when diagnosed.Therefore,it is very important to find new markers for the early detection and diagnosis of liver cancer,improve the therapeutic effect,and improve the prognosis of patients.Protein tyrosine phosphatase non-receptor 2(PTPN2)has been shown to be associated with colorectal cancer,triple-negative breast cancer,non-small cell lung cancer,and prostate cancer,but its biological role and function in tumors remain to be further studied.AIM To combine the results of relevant data obtained from The Cancer Genome Atlas(TCGA)to provide the first in-depth analysis of the biological role of PTPN2 in HCC.METHODS The expression of PTPN2 in HCC was first analyzed based on the TCGA database,and the findings were then verified by immunohistochemical staining,quantitative real-time polymerase chain reaction(qRT-PCR),and immunoblotting.The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features.Finally,the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining.RESULTS The results of immunohistochemical staining,qRT-PCR,and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients.Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways,including cancer-related pathways,the Notch signaling pathway,and the MAPK signaling pathway.Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways,such as the epithelial mesenchymal transition process.A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group.CONCLUSION This study investigated PTPN2 from multiple biological perspectives,revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.展开更多
Mpox is an infectious and contagious zoonotic disease caused by the mpox virus(MPXV),which belongs to the genus Orthopoxvirus.Since 2022,MPXV has posed a significant threat to global public health.The emergence of thou...Mpox is an infectious and contagious zoonotic disease caused by the mpox virus(MPXV),which belongs to the genus Orthopoxvirus.Since 2022,MPXV has posed a significant threat to global public health.The emergence of thousands of cases across the Western Hemisphere prompted the World Health Organization to declare an emergency.The extensive coevolutionary history of poxviruses with humans has enabled these viruses to develop sophisticated mechanisms to counter the human immune system.Specifically,MPXV employs unique immune evasion strategies against a wide range of immunological elements,presenting a considerable challenge for treatment,especially following the discontinuation of routine smallpox vaccination among the general population.In this review,we start by discussing the entry of the mpox virus and the onset of early infection,followed by an introduction to the mechanisms by which the mpox virus can evade the innate and adaptive immune responses.Two caspase-1 inhibitory proteins and a PKR escape-related protein have been identified as phylogenomic hubs involved in modulating the immune environment during the MPXV infection.With respect to adaptive immunity,mpox viruses exhibit unique and exceptional T-cell inhibition capabilities,thereby comprehensively remodeling the host immune environment.The viral envelope also poses challenges for the neutralizing effects of antibodies and the complement system.The unique immune evasion mechanisms employed by MPXV make novel multi-epitope and nucleic acid-based vaccines highly promising research directions worth investigating.Finally,we briefly discuss the impact of MPXV infection on immunosuppressed patients and the current status of MPXV vaccine development.This review may provide valuable information for the development of new immunological treatments for mpox.展开更多
BACKGROUND For the first time,we investigated the oncological role of plexin domain-containing 1(PLXDC1),also known as tumor endothelial marker 7(TEM7),in hepatocellular carcinoma(HCC).AIM To investigate the oncologic...BACKGROUND For the first time,we investigated the oncological role of plexin domain-containing 1(PLXDC1),also known as tumor endothelial marker 7(TEM7),in hepatocellular carcinoma(HCC).AIM To investigate the oncological profile of PLXDC1 in HCC.METHODS Based on The Cancer Genome Atlas database,we analyzed the expression of PLXDC1 in HCC.Using immunohistochemistry,quantitative real-time polymerase chain reaction(qRT-PCR),and Western blotting,we validated our results.The prognostic value of PLXDC1 in HCC was analyzed by assessing its correlation with clinicopathological features,such as patient survival,methylation level,tumor immune microenvironment features,and immune cell surface checkpoint expression.Finally,to assess the immune evasion potential of PLXDC1 in HCC,we used the tumor immune dysfunction and exclusion(TIDE)website and immunohistochemical staining assays.RESULTS Based on immunohistochemistry,qRT-PCR,and Western blot assays,overexpression of PLXDC1 in HCC was associated with poor prognosis.Univariate and multivariate Cox analyses indicated that PLXDC1 might be an independent prognostic factor.In HCC patients with high methylation levels,the prognosis was worse than in patients with low methylation levels.Pathway enrichment analysis of HCC tissues indicated that genes upregulated in the high-PLXDC1 subgroup were enriched in mesenchymal and immune activation signaling,and TIDE assessment showed that the risk of immune evasion was significantly higher in the high-PLXDC1 subgroup compared to the low-PLXDC1 subgroup.The high-risk group had a significantly lower immune evasion rate as well as a poor prognosis,and PLXDC1-related risk scores were also associated with a poor prognosis.CONCLUSION As a result of this study analyzing PLXDC1 from multiple biological perspectives,it was revealed that it is a biomarker of poor prognosis for HCC patients,and that it plays a role in determining immune evasion status.展开更多
Background: Omicron JN.1 has become the dominant SARS-CoV-2 variant in recent months. JN.1 has the highest number of amino acid mutations in its receptor binding domain (RBD) and has acquired a hallmark L455S mutation...Background: Omicron JN.1 has become the dominant SARS-CoV-2 variant in recent months. JN.1 has the highest number of amino acid mutations in its receptor binding domain (RBD) and has acquired a hallmark L455S mutation. The immune evasion capability of JN.1 is a subject of scientific investigation. The US CDC used SGTF of TaqPath COVID-19 Combo Kit RT-qPCR as proxy indicator of JN.1 infections for evaluation of the effectiveness of updated monovalent XBB.1.5 COVID-19 vaccines against JN.1 and recommended that all persons aged ≥ 6 months should receive an updated COVID-19 vaccine dose. Objective: Recommend Sanger sequencing instead of proxy indicator to diagnose JN.1 infections to generate the data based on which guidelines are made to direct vaccination policies. Methods: The RNA in nasopharyngeal swab specimens from patients with clinical respiratory infection was subjected to nested RT-PCR, targeting a 398-base segment of the N-gene and a 445-base segment of the RBD of SARS-CoV-2 for amplification. The nested PCR amplicons were sequenced. The DNA sequences were analyzed for amino acid mutations. Results: The N-gene sequence showed R203K, G204R and Q229K, the 3 mutations associated with Omicron BA.2.86 (+JN.1). The RBD sequence showed 24 of the 26 known amino acid mutations, including the hallmark L455S mutation for JN.1 and the V483del for BA.2.86 lineage. Conclusions: Sanger sequencing of a 445-base segment of the SARS-CoV-2 RBD is useful for accurate determination of emerging variants. The CDC may consider using Sanger sequencing of the RBD to diagnose JN.1 infections for statistical analysis in making vaccination policies.展开更多
This paper investigates a new approach for a scenario in which an Attacker attempts to intercept a defended aerial Target. The problem is formulated as a game among three players, an Attacker, a Defender, and a Target...This paper investigates a new approach for a scenario in which an Attacker attempts to intercept a defended aerial Target. The problem is formulated as a game among three players, an Attacker, a Defender, and a Target, with bounded controls. In the considered pursuit–evasion problem, the Target uses an optimal evasion strategy and the Defender uses an optimal pursuit strategy.The proposed approach focuses on the miss distance as the outcome of the conflict. The infeasible region for the initial Zero-Effort-Miss（ZEM） distance between the Attacker and the Defender, for a scenario in which the Attacker evades the Defender, is analyzed, assuming that the Attacker uses a control effort chosen from the permitted control region. The sufficient conditions are investigated under which, for ideal players, the Attacker can pursue the Target while evading the Defender launched by the Target. The guidance provided on how the Attacker can accomplish the task is divided into two parts. During the final time between the Attacker and the Defender, the Attacker chooses the control effort that guarantees the miss distance, and then uses the optimal pursuit strategy to accomplish the task. The derived guidance law is verified by nonlinear simulation.展开更多
Spacecraft orbit evasion is an effective method to ensure space safety. In the spacecraft’s orbital plane, the space non-cooperate target with autonomous approaching to the spacecraft may have a dangerous rendezvous....Spacecraft orbit evasion is an effective method to ensure space safety. In the spacecraft’s orbital plane, the space non-cooperate target with autonomous approaching to the spacecraft may have a dangerous rendezvous. To deal with this problem, an optimal maneuvering strategy based on the relative navigation observability degree is proposed with angles-only measurements. A maneuver evasion relative navigation model in the spacecraft’s orbital plane is constructed and the observability measurement criteria with process noise and measurement noise are defined based on the posterior Cramer-Rao lower bound. Further, the optimal maneuver evasion strategy in spacecraft’s orbital plane based on the observability is proposed. The strategy provides a new idea for spacecraft to evade safety threats autonomously. Compared with the spacecraft evasion problem based on the absolute navigation, more accurate evasion results can be obtained. The simulation indicates that this optimal strategy can weaken the system’s observability and reduce the state estimation accuracy of the non-cooperative target, making it impossible for the non-cooperative target to accurately approach the spacecraft.展开更多
Natural killer(NK)cells can elicit an immune response against malignantly transformed cells without recognizing antigens,and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy...Natural killer(NK)cells can elicit an immune response against malignantly transformed cells without recognizing antigens,and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy.Although several studies have shown the promising antitumor effects of NK cells in immunotherapy,their function is often limited in the tumor microenvironment because tumor cells can easily escape NK cell-induced death.Thus,for efficient tumor immunotherapy,the mechanism by which tumor cells escape NK cell-induced cytotoxicity must be fully understood.Various novel molecules and checkpoint receptors that mediate the disruption of NK cells in the tumor microenvironment have been discovered.In this review,we analyze and detail the major activating and inhibitory receptors on the surface of NK cells to delineate the mechanism by which tumor cells suppress NKG2D ligand expression and increase tumor receptor and inhibitory receptor expression[NKG2A,programmed cell death1(PD-1),and T-cell immunoglobulin and immunoreceptor tyrosine inhibitory motif(TIGIT)]on the NK cell surface,and thus inhibit NK cell activity.We also reviewed the current status of treatments based on these surface molecules.By comparing the therapeutic effects related to the treatment status and bypass mechanisms,we attempt to identify optimal single or combined treatments to suggest new treatment strategies for tumor immunotherapy.展开更多
The host immune system functions as a guardian against tumor development. It has been demonstrated that cytotoxic T lymphocyte (CTL)-mediated cytotoxic pathways function to inhibit or delay human colorectal cancer dev...The host immune system functions as a guardian against tumor development. It has been demonstrated that cytotoxic T lymphocyte (CTL)-mediated cytotoxic pathways function to inhibit or delay human colorectal cancer development. However, the host anti-tumor immune responses also 'edit' the tumor and select for more aggressive variants, resulting in immune evasion and tumor escape. Fas is a death receptor that mediates one of the major cytotoxic effector mechanisms of the CTLs. Fas is highly expressed in normal human colon epithelial cells but is frequently silenced in colorectal carcinoma, especially in metastatic colorectal carcinoma, suggesting that loss of Fas expression and function may be an immune evasion and tumor escape mechanism. In addition, recent studies indicated that Fas also mediates cellular proliferation signaling pathways to promote tumor development. Therefore, the death receptor Fas may not only transduce death signals to suppress tumor development but also activate cellular proliferation and the migration process to promote tumor growth and progression. Thus, understanding the mechanisms by which the Fas receptor and its associated protein complex transduces the death and survival signals may identify molecular targets for the development of therapeutic strategy to enhance the Fas-mediated death signals to increase the efficacy of cancer immunotherapy.展开更多
Epstein-Barr virus(EBV) is an oncogenic virus that ubiquitously establishes life-long persistence in humans. To ensure its survival and maintain its B cell transformation function, EBV has developed powerful strategie...Epstein-Barr virus(EBV) is an oncogenic virus that ubiquitously establishes life-long persistence in humans. To ensure its survival and maintain its B cell transformation function, EBV has developed powerful strategies to evade host immune responses. Emerging evidence has shown that micro RNAs(mi RNAs) are powerful regulators of the maintenance of cellular homeostasis. In this review, we summarize current progress on how EBV utilizes mi RNAs for immune evasion. EBV encodes mi RNAs targeting both viral and host genes involved in the immune response. The mi RNAs are found in two gene clusters, and recent studies have demonstrated that lack of these clusters increases the CD4^+ and CD8^+ T cell response of infected cells. These reports strongly indicate that EBV mi RNAs are critical for immune evasion. In addition, EBV is able to dysregulate the expression of a variety of host mi RNAs, which influence multiple immune-related molecules and signaling pathways. The transport via exosomes of EBV-regulated mi RNAs and viral proteins contributes to the construction and modification of the inflammatory tumor microenvironment.During EBV immune evasion, viral proteins, immune cells, chemokines, pro-inflammatory cytokines, and pro-apoptosis molecules are involved. Our increasing knowledge of the role of mi RNAs in immune evasion will improve the understanding of EBV persistence and help to develop new treatments for EBV-associated cancers and other diseases.展开更多
The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development.Regardless,it is not uncommon that cancerous cells can intelligently acquire abilities to bypas...The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development.Regardless,it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses,thus allowing continuous tumor growth and development.Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer.Compared with other cancers,pancreatic cancer has a tumor microenvironment that can resist most treatment modalities,including emerging immunotherapy.Sadly,the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients,suggesting that pancreatic cancer has successfully evaded immunomodulation.In this review,we summarize the impact of genetic alteration and epigenetic modification(especially histone deacetylases,HDAC)on immune evasion in pancreatic cancer.HDAC overexpression significantly suppresses tumor suppressor genes,contributing to tumor growth and progression.We review the evidence on HDAC inhibitors in tumor eradication,improving T cells activation,restoring tumor immunogenicity,and modulating programmed death 1 interaction.We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer.展开更多
Gastric cancer(GC)is a malignancy with a high incidence and mortality.The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression.Accumulating evidence shows t...Gastric cancer(GC)is a malignancy with a high incidence and mortality.The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression.Accumulating evidence shows that GC cells can exert versatile mechanisms to remodel the tumor immune microenvironment and induce immune evasion.In this review,we systematically summarize the intricate crosstalk between GC cells and immune cells,including tumor-associated macrophages,neutrophils,myeloid-derived suppressor cells,natural killer cells,effector T cells,regulatory T cells,and B cells.We focus on how GC cells alter these immune cells to create an immunosuppressive microenvironment that protects GC cells from immune attack.We conclude by compiling the latest progression of immune checkpoint inhibitor-based immunotherapies,both alone and in combination with conventional therapies.Anti-cytotoxic Tlymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 therapy alone does not provide substantial clinical benefit for GC treatment.However,the combination of immune checkpoint inhibitors with chemotherapy or targeted therapy has promising survival advantages in refractory and advanced GC patients.This review provides a comprehensive understanding of the immune evasion mechanisms of GC,and highlights promising immunotherapeutic strategies.展开更多
Objective： It has been proposed that Fas ligand （FasL） may play an important role in immune escape of tumors and FLIP is an important mediator of Fas/FasL pathway. In this study, the expression of FLIP was determin...Objective： It has been proposed that Fas ligand （FasL） may play an important role in immune escape of tumors and FLIP is an important mediator of Fas/FasL pathway. In this study, the expression of FLIP was determined in human colon carcinoma cell lines and tissue to investigate the new mechanism of immune evasion of human colon carcinomas. Methods： RT-PCR and immunohistochemistry （IHC） were performed to investigate the expression of FLIP in human colon carcinoma cell lines SW480, LS174 and twenty human primary colon carcinoma specimens. Results： It was shown that SW480 cells, LS174 cells and primary colon carcinoma specimen constitutively expressed FLIP at the mRNA and protein level. The expression of FLIP was not found in the epithelial cells of normal colon mucosa. Conclusion： FLIP was expressed in human primary colon carcinoma specimens but not in the normal counterpart. It suggested that the expression of FLIP may occur during the malignant transformation from normal colon epithelial cells to colon carcinoma cells. Tumor cells might obtain the ability to resist the Fas-mediated apoptosis by expressing FLIP. The expression of FLIP might contribute to the formation of colon carcinomas.展开更多
The recently discovered SARS-CoV-2 variant Omicron(B.1.1.529) has rapidly become a global public health issue.The substantial mutations in the spike protein in this new variant have raised concerns about its ability t...The recently discovered SARS-CoV-2 variant Omicron(B.1.1.529) has rapidly become a global public health issue.The substantial mutations in the spike protein in this new variant have raised concerns about its ability to escape from pre-existing immunity established by natural infection or vaccination. In this review, we give a summary of current knowledge concerning the antibody evasion properties of Omicron and its subvariants(BA.2, BA.2.12.1,BA.4/5, and BA.2.75) from therapeutic monoclonal antibodies and the sera of SARS-CoV-2 vaccine recipients or convalescent patients. We also summarize whether vaccine-induced cellular immunity(memory B cell and T cell response) can recognize Omicron specifically. In brief, the Omicron variants demonstrated remarkable antibody evasion, with even more striking antibody escape seen in the Omicron BA.4 and BA.5 sub-lineages. Luckily, the third booster vaccine dose significantly increased the neutralizing antibodies titers, and the vaccine-induced cellular response remains conserved and provides second-line defense against the Omicron.展开更多
Objective: To explore the effects of IL-10 on acute leukemic immune evasion.Methods: Plasma concentrations of IL-10 were measured by ELISA in 56 first-visit acute leukemic patients.And expressions of IL-10 on leukemic...Objective: To explore the effects of IL-10 on acute leukemic immune evasion.Methods: Plasma concentrations of IL-10 were measured by ELISA in 56 first-visit acute leukemic patients.And expressions of IL-10 on leukemic cells in 30 patients were measured by indirect immunofluorescence technique. Results:Compared with those in control group,IL-10 concentrations increased significantly in first-visit acute leukemic patients.And there was a slight but not significant decrease of IL-10 in patients with acute lymphocytic leukemia(ALL) compared with those with acute non lymphocytic leukemic(ANLL).After intensive chemotherapy,there was a significant decrease of IL-10 in completely remitted(CR) patients,especially in those with ANLL,but there was still a significant increase compared with those in control group.The positive rate of cells giving out yellow-green bright fluorescence on membranes was 10%-80%;there were 18 patients expressing IL-10(18/30,60%) positively:among them 11 with ANLL(11/19,58%) and 7 with ALL(7/11,64%) respectively while that of peripheral mononucleate cells in control group was 13%.Compared with that in control group,there was a significant increase of positive rate in ANLL and ALL but with no significant difference between ANLL and ALL.Conclusion: Probably as one of important mechanisms of acute leukemic immune evasion,IL-10 secreted by leukemic cells,contributing to the immunosuppressive state at the tumor site,increase significantly in acute leukemic patients.展开更多
基金co-supported by the National Natural Science Foundation of China(No.62103432)the China Postdoctoral Science Foundation(No.284881)the Young Talent fund of University Association for Science and Technology in Shaanxi,China(No.20210108)。
文摘Exo-atmospheric vehicles are constrained by limited maneuverability,which leads to the contradiction between evasive maneuver and precision strike.To address the problem of Integrated Evasion and Impact(IEI)decision under multi-constraint conditions,a hierarchical intelligent decision-making method based on Deep Reinforcement Learning(DRL)was proposed.First,an intelligent decision-making framework of“DRL evasion decision”+“impact prediction guidance decision”was established:it takes the impact point deviation correction ability as the constraint and the maximum miss distance as the objective,and effectively solves the problem of poor decisionmaking effect caused by the large IEI decision space.Second,to solve the sparse reward problem faced by evasion decision-making,a hierarchical decision-making method consisting of maneuver timing decision and maneuver duration decision was proposed,and the corresponding Markov Decision Process(MDP)was designed.A detailed simulation experiment was designed to analyze the advantages and computational complexity of the proposed method.Simulation results show that the proposed model has good performance and low computational resource requirement.The minimum miss distance is 21.3 m under the condition of guaranteeing the impact point accuracy,and the single decision-making time is 4.086 ms on an STM32F407 single-chip microcomputer,which has engineering application value.
基金Supported by the Haihe Laboratory of Cell Ecosystem Innovation Fund,No.22HHXBJC00001the Key Discipline Special Project of Tianjin Municipal Health Commission,No.TJWJ2022XK016.
文摘BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact molecular mechanisms leading to the progression of HCC are still unclear.Research has shown that the microRNA-142-3p level decreases in HCC,whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues.In this paper,we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity,and the association between them.AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients.METHODS In this study,we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues,and retrospectively analyzed the prognosis of HCC patients.Furthermore,explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments,which involved the following experimental methods:Immunohistochemical staining,western blot,quantitative real-time-polymerase chain reaction,flow cytometric analysis,tumor xenografts in nude mice,etc.The statistical methods involved in this study contained t-test,one-way analysis of variance,theχ^(2)test,the Kaplan-Meier approach and the log-rank test.RESULTS In this study,we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate.ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3′untranslated region.Furthermore,microRNA-142-3p promotes apoptosis and inhibits proliferation,invasion,and migration of HCC cell lines in vitro via ASH1L.For the exploration mechanism,we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1,which is potentially relevant to the immune system.CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC.Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.
基金The 75th Batch of China Postdoctoral Science Foundation projects(No.2024M754279)Natural Science Foundation of Jiangsu Province(No.BK20240738)+2 种基金Basic Science(Natural Science)Research Project in Universities of Jiangsu Province(No.24KJB360004)Jiangsu Province Chinese Medicine Science and Technology Development Plan Youth Talent Project(No.QN202206)Nanjing University of ChineseMedicine Luo Linxiu Teacher Development Fund Project(No.LLX202310).
文摘Cold tumors,defined by insufficient immune cell infiltration and a highly immunosuppressive tumor microenvironment(TME),exhibit limited responsiveness to conventional immunotherapies.This reviewsystematically summarizes the mechanisms of immune evasion and the therapeutic strategies for cold tumors as revealed by multiomics technologies.By integrating genomic,transcriptomic,proteomic,metabolomic,and spatialmulti-omics data,the review elucidates key immune evasionmechanisms,including activation of the WNT/β-catenin pathway,transforming growth factor-β(TGF-β)–mediated immunosuppression,metabolic reprogramming(e.g.,lactate accumulation),and aberrant expression of immune checkpoint molecules.Furthermore,this review proposes multi-dimensional therapeutic strategies,such as targeting immunosuppressive pathways(e.g.,programmed death-1(PD-1)/programmed death-ligand 1(PD-L1)inhibitors combined with TGF-βblockade),reshaping the TME through chemokine-based therapies,oncolytic viruses,and vascular normalization,and metabolic interventions(e.g.,inhibition of lactate dehydrogenase A(LDHA)or glutaminase(GLS)).In addition,personalized neoantigen vaccines and engineered cell therapies(e.g.,T cell receptor-engineered T(TCR-T)and natural killer(NK)cells)show promising potential.Emerging evidence also highlights the role of epigenetic regulation(e.g.,histone deacetylase(HDAC)inhibitors)and N6-Methyladenosine(m6A)RNA modifications in reversing immune evasion.Despite the promising insights offered by multi-omics integration in guiding precision immunotherapy,challenges remain in clinical translation,including data heterogeneity,target-specific toxicity,and limitations in preclinical models.Future efforts should focus on coupling dynamic multi-omics technologies with intelligent therapeutic design to convert cold tumors into immunologically active(“hot”)microenvironments,ultimately facilitating breakthroughs in personalized immunotherapy.
基金supported by the National Natural Science Foundation of China(No.62103014)。
文摘In practical combat scenarios,Hypersonic Glide Vehicles(HGV)face the challenge of evading Successive Pursuers from the Same Direction while satisfying the Homing Constraint(SPSDHC).To address this problem,this paper proposes a parameterized evasion guidance algorithm based on reinforcement learning.The three-player optimal evasion strategy is firstly analyzed and approximated by parametrization.The switching acceleration command of HGV optimal evasion strategy considering the upper limit of missile acceleration command is analyzed based on the optimal control theory.The terminal miss of HGV in the case of evading two missiles is analyzed,which means that the three-player optimal evasion strategy is a linear combination of two one-toone strategies.Then,a velocity control algorithm is proposed to increase the terminal miss by actively controlling the flight speed of the HGV based on the parametrized evasion strategy.The reinforcement learning method is used to implement the strategy in real time and a reward function is designed by deducing homing strategy for the HGV to approach the target,which ensures that the HGV satisfies the homing constraint.Experimental results demonstrate the feasibility and robustness of the proposed parameterized evasion strategy,which enables the HGV to generate maximum terminal miss and satisfy homing constraint when facing single or double missiles.
基金This work was supported by the National Natural Science Foundation of China(No.52202438).
文摘This paper presents a novel evasion guidance law for hypersonic morphing vehicles,focusing on determining the optimized wing's unfolded angle to promote maneuverability based on an intelligent algorithm.First,the pursuit-evasion problem is modeled as a Markov decision process.And the agent's action consists of maneuver overload and the unfolded angle of wings,which is different from the conventional evasion guidance designed for fixed-shape vehicles.The reward function is formulated to ensure that the miss distances satisfy the prescribed bounds while minimizing energy consumption.Then,to maximize the expected cumulative reward,a residual learning method is proposed based on proximal policy optimization,which integrates the optimal evasion for linear cases as the baseline and trains to optimize the performance for nonlinear engagement with multiple pursuers.Therefore,offline training guarantees improvement of the constructed evasion guidance law over conventional ones.Ultimately,the guidance law for online implementation includes only analytical calculations.It maps from the confrontation state to the expected angle of attack and the unfolded angle while retaining high computational efficiency.Simulations show that the proposed evasion guidance law can utilize the change of unfolded angle to extend the maximum overload capability.And it surpasses conventional maneuver strategies by ensuring better evasion efficacy and higher energy efficiency.
文摘BACKGROUND The incidence of primary liver cancer is increasing year by year.In 2022 alone,more than 900000 people were diagnosed with liver cancer worldwide,with hepatocellular carcinoma(HCC)accounting for 75%-85%of cases.HCC is the most common primary liver cancer.China has the highest incidence and mortality rate of HCC in the world,and it is one of the malignant tumors that seriously threaten the health of Chinese people.The onset of liver cancer is occult,the early cases lack typical clinical symptoms,and most of the patients are already in the middle and late stage when diagnosed.Therefore,it is very important to find new markers for the early detection and diagnosis of liver cancer,improve the therapeutic effect,and improve the prognosis of patients.Protein tyrosine phosphatase non-receptor 2(PTPN2)has been shown to be associated with colorectal cancer,triple-negative breast cancer,non-small cell lung cancer,and prostate cancer,but its biological role and function in tumors remain to be further studied.AIM To combine the results of relevant data obtained from The Cancer Genome Atlas(TCGA)to provide the first in-depth analysis of the biological role of PTPN2 in HCC.METHODS The expression of PTPN2 in HCC was first analyzed based on the TCGA database,and the findings were then verified by immunohistochemical staining,quantitative real-time polymerase chain reaction(qRT-PCR),and immunoblotting.The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features.Finally,the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining.RESULTS The results of immunohistochemical staining,qRT-PCR,and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients.Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways,including cancer-related pathways,the Notch signaling pathway,and the MAPK signaling pathway.Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways,such as the epithelial mesenchymal transition process.A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group.CONCLUSION This study investigated PTPN2 from multiple biological perspectives,revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.
基金supported by the High-Level Public Health Specialized Talents Project of Beijing Municipal Health Commission(2022-2-018 to B.S.)Beijing Key Laboratory for HIV/AIDS Research(BZ0089).The funders had no role in study design,data collection and analysis,decision to publish,or preparation of the manuscript.
文摘Mpox is an infectious and contagious zoonotic disease caused by the mpox virus(MPXV),which belongs to the genus Orthopoxvirus.Since 2022,MPXV has posed a significant threat to global public health.The emergence of thousands of cases across the Western Hemisphere prompted the World Health Organization to declare an emergency.The extensive coevolutionary history of poxviruses with humans has enabled these viruses to develop sophisticated mechanisms to counter the human immune system.Specifically,MPXV employs unique immune evasion strategies against a wide range of immunological elements,presenting a considerable challenge for treatment,especially following the discontinuation of routine smallpox vaccination among the general population.In this review,we start by discussing the entry of the mpox virus and the onset of early infection,followed by an introduction to the mechanisms by which the mpox virus can evade the innate and adaptive immune responses.Two caspase-1 inhibitory proteins and a PKR escape-related protein have been identified as phylogenomic hubs involved in modulating the immune environment during the MPXV infection.With respect to adaptive immunity,mpox viruses exhibit unique and exceptional T-cell inhibition capabilities,thereby comprehensively remodeling the host immune environment.The viral envelope also poses challenges for the neutralizing effects of antibodies and the complement system.The unique immune evasion mechanisms employed by MPXV make novel multi-epitope and nucleic acid-based vaccines highly promising research directions worth investigating.Finally,we briefly discuss the impact of MPXV infection on immunosuppressed patients and the current status of MPXV vaccine development.This review may provide valuable information for the development of new immunological treatments for mpox.
基金Supported by the Anhui Provincial Health Scientific Research Project Provincial Financial Support Key Project,No.AHWJ2023A10110College Teaching Quality Engineering Project of Anhui Educational Committee,No.2021jyxm0954College Student Innovation Training Program of Bengbu Medical College,No.Byycxz22110.
文摘BACKGROUND For the first time,we investigated the oncological role of plexin domain-containing 1(PLXDC1),also known as tumor endothelial marker 7(TEM7),in hepatocellular carcinoma(HCC).AIM To investigate the oncological profile of PLXDC1 in HCC.METHODS Based on The Cancer Genome Atlas database,we analyzed the expression of PLXDC1 in HCC.Using immunohistochemistry,quantitative real-time polymerase chain reaction(qRT-PCR),and Western blotting,we validated our results.The prognostic value of PLXDC1 in HCC was analyzed by assessing its correlation with clinicopathological features,such as patient survival,methylation level,tumor immune microenvironment features,and immune cell surface checkpoint expression.Finally,to assess the immune evasion potential of PLXDC1 in HCC,we used the tumor immune dysfunction and exclusion(TIDE)website and immunohistochemical staining assays.RESULTS Based on immunohistochemistry,qRT-PCR,and Western blot assays,overexpression of PLXDC1 in HCC was associated with poor prognosis.Univariate and multivariate Cox analyses indicated that PLXDC1 might be an independent prognostic factor.In HCC patients with high methylation levels,the prognosis was worse than in patients with low methylation levels.Pathway enrichment analysis of HCC tissues indicated that genes upregulated in the high-PLXDC1 subgroup were enriched in mesenchymal and immune activation signaling,and TIDE assessment showed that the risk of immune evasion was significantly higher in the high-PLXDC1 subgroup compared to the low-PLXDC1 subgroup.The high-risk group had a significantly lower immune evasion rate as well as a poor prognosis,and PLXDC1-related risk scores were also associated with a poor prognosis.CONCLUSION As a result of this study analyzing PLXDC1 from multiple biological perspectives,it was revealed that it is a biomarker of poor prognosis for HCC patients,and that it plays a role in determining immune evasion status.
文摘Background: Omicron JN.1 has become the dominant SARS-CoV-2 variant in recent months. JN.1 has the highest number of amino acid mutations in its receptor binding domain (RBD) and has acquired a hallmark L455S mutation. The immune evasion capability of JN.1 is a subject of scientific investigation. The US CDC used SGTF of TaqPath COVID-19 Combo Kit RT-qPCR as proxy indicator of JN.1 infections for evaluation of the effectiveness of updated monovalent XBB.1.5 COVID-19 vaccines against JN.1 and recommended that all persons aged ≥ 6 months should receive an updated COVID-19 vaccine dose. Objective: Recommend Sanger sequencing instead of proxy indicator to diagnose JN.1 infections to generate the data based on which guidelines are made to direct vaccination policies. Methods: The RNA in nasopharyngeal swab specimens from patients with clinical respiratory infection was subjected to nested RT-PCR, targeting a 398-base segment of the N-gene and a 445-base segment of the RBD of SARS-CoV-2 for amplification. The nested PCR amplicons were sequenced. The DNA sequences were analyzed for amino acid mutations. Results: The N-gene sequence showed R203K, G204R and Q229K, the 3 mutations associated with Omicron BA.2.86 (+JN.1). The RBD sequence showed 24 of the 26 known amino acid mutations, including the hallmark L455S mutation for JN.1 and the V483del for BA.2.86 lineage. Conclusions: Sanger sequencing of a 445-base segment of the SARS-CoV-2 RBD is useful for accurate determination of emerging variants. The CDC may consider using Sanger sequencing of the RBD to diagnose JN.1 infections for statistical analysis in making vaccination policies.
基金supported by the National Natural Science Foundation of China (No. 11672093)Shanghai Aerospace Science and Technology Innovation Foundation of China (No. SAST2016039)
文摘This paper investigates a new approach for a scenario in which an Attacker attempts to intercept a defended aerial Target. The problem is formulated as a game among three players, an Attacker, a Defender, and a Target, with bounded controls. In the considered pursuit–evasion problem, the Target uses an optimal evasion strategy and the Defender uses an optimal pursuit strategy.The proposed approach focuses on the miss distance as the outcome of the conflict. The infeasible region for the initial Zero-Effort-Miss（ZEM） distance between the Attacker and the Defender, for a scenario in which the Attacker evades the Defender, is analyzed, assuming that the Attacker uses a control effort chosen from the permitted control region. The sufficient conditions are investigated under which, for ideal players, the Attacker can pursue the Target while evading the Defender launched by the Target. The guidance provided on how the Attacker can accomplish the task is divided into two parts. During the final time between the Attacker and the Defender, the Attacker chooses the control effort that guarantees the miss distance, and then uses the optimal pursuit strategy to accomplish the task. The derived guidance law is verified by nonlinear simulation.
基金supported by the National Key R&D Program of China (2020YFA0713502)the Special Fund Project for Guiding Local Scientific and Technological Development (2020ZYT003)+1 种基金the National Natural Science Foundation of China (U20B2055,61773021,61903086)the Natural Science Foundation of Hunan Province (2019JJ20018,2020JJ4280)。
文摘Spacecraft orbit evasion is an effective method to ensure space safety. In the spacecraft’s orbital plane, the space non-cooperate target with autonomous approaching to the spacecraft may have a dangerous rendezvous. To deal with this problem, an optimal maneuvering strategy based on the relative navigation observability degree is proposed with angles-only measurements. A maneuver evasion relative navigation model in the spacecraft’s orbital plane is constructed and the observability measurement criteria with process noise and measurement noise are defined based on the posterior Cramer-Rao lower bound. Further, the optimal maneuver evasion strategy in spacecraft’s orbital plane based on the observability is proposed. The strategy provides a new idea for spacecraft to evade safety threats autonomously. Compared with the spacecraft evasion problem based on the absolute navigation, more accurate evasion results can be obtained. The simulation indicates that this optimal strategy can weaken the system’s observability and reduce the state estimation accuracy of the non-cooperative target, making it impossible for the non-cooperative target to accurately approach the spacecraft.
文摘Natural killer(NK)cells can elicit an immune response against malignantly transformed cells without recognizing antigens,and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy.Although several studies have shown the promising antitumor effects of NK cells in immunotherapy,their function is often limited in the tumor microenvironment because tumor cells can easily escape NK cell-induced death.Thus,for efficient tumor immunotherapy,the mechanism by which tumor cells escape NK cell-induced cytotoxicity must be fully understood.Various novel molecules and checkpoint receptors that mediate the disruption of NK cells in the tumor microenvironment have been discovered.In this review,we analyze and detail the major activating and inhibitory receptors on the surface of NK cells to delineate the mechanism by which tumor cells suppress NKG2D ligand expression and increase tumor receptor and inhibitory receptor expression[NKG2A,programmed cell death1(PD-1),and T-cell immunoglobulin and immunoreceptor tyrosine inhibitory motif(TIGIT)]on the NK cell surface,and thus inhibit NK cell activity.We also reviewed the current status of treatments based on these surface molecules.By comparing the therapeutic effects related to the treatment status and bypass mechanisms,we attempt to identify optimal single or combined treatments to suggest new treatment strategies for tumor immunotherapy.
文摘The host immune system functions as a guardian against tumor development. It has been demonstrated that cytotoxic T lymphocyte (CTL)-mediated cytotoxic pathways function to inhibit or delay human colorectal cancer development. However, the host anti-tumor immune responses also 'edit' the tumor and select for more aggressive variants, resulting in immune evasion and tumor escape. Fas is a death receptor that mediates one of the major cytotoxic effector mechanisms of the CTLs. Fas is highly expressed in normal human colon epithelial cells but is frequently silenced in colorectal carcinoma, especially in metastatic colorectal carcinoma, suggesting that loss of Fas expression and function may be an immune evasion and tumor escape mechanism. In addition, recent studies indicated that Fas also mediates cellular proliferation signaling pathways to promote tumor development. Therefore, the death receptor Fas may not only transduce death signals to suppress tumor development but also activate cellular proliferation and the migration process to promote tumor growth and progression. Thus, understanding the mechanisms by which the Fas receptor and its associated protein complex transduces the death and survival signals may identify molecular targets for the development of therapeutic strategy to enhance the Fas-mediated death signals to increase the efficacy of cancer immunotherapy.
基金supported by the National Natural Science Foundations of China(81372139,31670171)the Hunan Provincial Natural Science Foundation of China(2015JJ2149)the Hunan Provincial Innovation Foundation for Postgraduates(CX2016B055)
文摘Epstein-Barr virus(EBV) is an oncogenic virus that ubiquitously establishes life-long persistence in humans. To ensure its survival and maintain its B cell transformation function, EBV has developed powerful strategies to evade host immune responses. Emerging evidence has shown that micro RNAs(mi RNAs) are powerful regulators of the maintenance of cellular homeostasis. In this review, we summarize current progress on how EBV utilizes mi RNAs for immune evasion. EBV encodes mi RNAs targeting both viral and host genes involved in the immune response. The mi RNAs are found in two gene clusters, and recent studies have demonstrated that lack of these clusters increases the CD4^+ and CD8^+ T cell response of infected cells. These reports strongly indicate that EBV mi RNAs are critical for immune evasion. In addition, EBV is able to dysregulate the expression of a variety of host mi RNAs, which influence multiple immune-related molecules and signaling pathways. The transport via exosomes of EBV-regulated mi RNAs and viral proteins contributes to the construction and modification of the inflammatory tumor microenvironment.During EBV immune evasion, viral proteins, immune cells, chemokines, pro-inflammatory cytokines, and pro-apoptosis molecules are involved. Our increasing knowledge of the role of mi RNAs in immune evasion will improve the understanding of EBV persistence and help to develop new treatments for EBV-associated cancers and other diseases.
基金Supported by International Medical University to Sim W,Lim WM,and Leong CO,No.BMS I/2020(10)Shanghai Municipal Science and Technology Commission to Mai CW,No.20WZ250460.
文摘The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development.Regardless,it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses,thus allowing continuous tumor growth and development.Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer.Compared with other cancers,pancreatic cancer has a tumor microenvironment that can resist most treatment modalities,including emerging immunotherapy.Sadly,the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients,suggesting that pancreatic cancer has successfully evaded immunomodulation.In this review,we summarize the impact of genetic alteration and epigenetic modification(especially histone deacetylases,HDAC)on immune evasion in pancreatic cancer.HDAC overexpression significantly suppresses tumor suppressor genes,contributing to tumor growth and progression.We review the evidence on HDAC inhibitors in tumor eradication,improving T cells activation,restoring tumor immunogenicity,and modulating programmed death 1 interaction.We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer.
基金The Natural Science Foundation of China,No.81672378,No.81201521,No.81873874 and No.81773089the Clinical Research Plan of SHDC,No.SHDC2020CR2021B。
文摘Gastric cancer(GC)is a malignancy with a high incidence and mortality.The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression.Accumulating evidence shows that GC cells can exert versatile mechanisms to remodel the tumor immune microenvironment and induce immune evasion.In this review,we systematically summarize the intricate crosstalk between GC cells and immune cells,including tumor-associated macrophages,neutrophils,myeloid-derived suppressor cells,natural killer cells,effector T cells,regulatory T cells,and B cells.We focus on how GC cells alter these immune cells to create an immunosuppressive microenvironment that protects GC cells from immune attack.We conclude by compiling the latest progression of immune checkpoint inhibitor-based immunotherapies,both alone and in combination with conventional therapies.Anti-cytotoxic Tlymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 therapy alone does not provide substantial clinical benefit for GC treatment.However,the combination of immune checkpoint inhibitors with chemotherapy or targeted therapy has promising survival advantages in refractory and advanced GC patients.This review provides a comprehensive understanding of the immune evasion mechanisms of GC,and highlights promising immunotherapeutic strategies.
文摘Objective： It has been proposed that Fas ligand （FasL） may play an important role in immune escape of tumors and FLIP is an important mediator of Fas/FasL pathway. In this study, the expression of FLIP was determined in human colon carcinoma cell lines and tissue to investigate the new mechanism of immune evasion of human colon carcinomas. Methods： RT-PCR and immunohistochemistry （IHC） were performed to investigate the expression of FLIP in human colon carcinoma cell lines SW480, LS174 and twenty human primary colon carcinoma specimens. Results： It was shown that SW480 cells, LS174 cells and primary colon carcinoma specimen constitutively expressed FLIP at the mRNA and protein level. The expression of FLIP was not found in the epithelial cells of normal colon mucosa. Conclusion： FLIP was expressed in human primary colon carcinoma specimens but not in the normal counterpart. It suggested that the expression of FLIP may occur during the malignant transformation from normal colon epithelial cells to colon carcinoma cells. Tumor cells might obtain the ability to resist the Fas-mediated apoptosis by expressing FLIP. The expression of FLIP might contribute to the formation of colon carcinomas.
基金supported by the National Science and Technology Major Project of China(92169121)the Applied Basic and Frontier Technology Research Project of Wuhan(2020020601012233)the Key Biosafety Science and Technology Program of Hubei Jiangxia Laboratory(JXBS001)
文摘The recently discovered SARS-CoV-2 variant Omicron(B.1.1.529) has rapidly become a global public health issue.The substantial mutations in the spike protein in this new variant have raised concerns about its ability to escape from pre-existing immunity established by natural infection or vaccination. In this review, we give a summary of current knowledge concerning the antibody evasion properties of Omicron and its subvariants(BA.2, BA.2.12.1,BA.4/5, and BA.2.75) from therapeutic monoclonal antibodies and the sera of SARS-CoV-2 vaccine recipients or convalescent patients. We also summarize whether vaccine-induced cellular immunity(memory B cell and T cell response) can recognize Omicron specifically. In brief, the Omicron variants demonstrated remarkable antibody evasion, with even more striking antibody escape seen in the Omicron BA.4 and BA.5 sub-lineages. Luckily, the third booster vaccine dose significantly increased the neutralizing antibodies titers, and the vaccine-induced cellular response remains conserved and provides second-line defense against the Omicron.
文摘Objective: To explore the effects of IL-10 on acute leukemic immune evasion.Methods: Plasma concentrations of IL-10 were measured by ELISA in 56 first-visit acute leukemic patients.And expressions of IL-10 on leukemic cells in 30 patients were measured by indirect immunofluorescence technique. Results:Compared with those in control group,IL-10 concentrations increased significantly in first-visit acute leukemic patients.And there was a slight but not significant decrease of IL-10 in patients with acute lymphocytic leukemia(ALL) compared with those with acute non lymphocytic leukemic(ANLL).After intensive chemotherapy,there was a significant decrease of IL-10 in completely remitted(CR) patients,especially in those with ANLL,but there was still a significant increase compared with those in control group.The positive rate of cells giving out yellow-green bright fluorescence on membranes was 10%-80%;there were 18 patients expressing IL-10(18/30,60%) positively:among them 11 with ANLL(11/19,58%) and 7 with ALL(7/11,64%) respectively while that of peripheral mononucleate cells in control group was 13%.Compared with that in control group,there was a significant increase of positive rate in ANLL and ALL but with no significant difference between ANLL and ALL.Conclusion: Probably as one of important mechanisms of acute leukemic immune evasion,IL-10 secreted by leukemic cells,contributing to the immunosuppressive state at the tumor site,increase significantly in acute leukemic patients.
