Objective: To study the synergic effects of IL-12 and B7-1 transfectant on antitumor immunity in vivo. Methods: The retrovirus vector encoding mIL-12 and mB7-1 gene was tranfected into EL-4 thymic lymphoma cells respe...Objective: To study the synergic effects of IL-12 and B7-1 transfectant on antitumor immunity in vivo. Methods: The retrovirus vector encoding mIL-12 and mB7-1 gene was tranfected into EL-4 thymic lymphoma cells respectively.The cells were used as tumor vaccine and the therapeutic effect was observed. Results: In contrast to the miceimmunized with EL-4/Wt or EL-4/Neo groups, thetumorigenicity of EL-4/IL-12 transfectant was decreased(P<0.001). The EL-4/IL-12 and EL-4/B7-1 cells irradiatedwith 60Co showed significant systematic protective effectsagainst the rechallenge of EL-4/Wt. 60Co irradiatedEL-4/IL-12 cells delayed the occurrence of tumor andprolonged the survival period of tumor bearing mice.Combination of the vaccines of EL-4/IL-12 and EL-4/B7-1 resulted in the enhanced therapeutic effect compared witheach single transfectant group (P<0.001). Conclusion: The results showed that IL-12 transduced cells could enhancethe antitumor immunity of host as cancer vaccine.Combination of the EL-4/IL-12 and EL-4/B7-1 transfectant could improve immunity of host and is a prospect cancervaccine.展开更多
BACKGROUND Nucleus accumbens-1(NAC-1)is highly expressed in a variety of tumors,including colon cancer,and is closely associated with tumor recurrence,metastasis,and invasion.AIM To determine whether and how NAC-1 aff...BACKGROUND Nucleus accumbens-1(NAC-1)is highly expressed in a variety of tumors,including colon cancer,and is closely associated with tumor recurrence,metastasis,and invasion.AIM To determine whether and how NAC-1 affects antitumor immunity in colon cancer.METHODS NAC-1-siRNA was transfected into RKO colon cancer cells to knock down NAC expression;tumor cells with or without knockdown of NAC-1 were treated with CD8+T cells to test their cytocidal effect.The level of the immune checkpoint programmed death receptor-1 ligand(PD-L1)in colon cancer cells with or without knockdown of NAC-1 was analyzed using Quantitative real-time polymerase chain reaction and Western blotting.A double luciferase reporter assay was used to examine the effects of NAC-1 on the transcription of PD-L1.Mice bearing MC-38-OVA colon cancer cells expressing NAC-shRNA or controlshRNA were treated with OT-I mouse CD8+T cells to determine the tumor response to immunotherapy.Immune cells in the tumor tissues were analyzed using flow cytometry.NAC-1,PD-L1 and CD8+T cells in colon cancer specimens from patients were examined using immunohistochemistry staining.RESULTS Knockdown of NAC-1 expression in colon cancer cells significantly enhanced the cytocidal effect of CD8+T cells in cell culture experiments.The sensitizing effect of NAC-1 knockdown on the antitumor action of cytotoxic CD8+T cells was recapitulated in a colon cancer xenograft animal model.Furthermore,knockdown of NAC-1 in colon cancer cells decreased the expression of PD-L1 at both the mRNA and protein levels,and this effect could be rescued by transfection of an RNAi-resistant NAC-1 expression plasmid.In a reporter gene assay,transient expression of NAC-1 in colon cancer cells increased the promoter activity of PD-L1,indicating that NAC-1 regulates PD-L1 expression at the transcriptional level.In addition,depletion of tumoral NAC-1 increased the number of CD8+T cells but decreased the number of suppressive myeloid-derived suppressor cells and regulatory T cells.CONCLUSION Tumor expression of NAC-1 is a negative determinant of immunotherapy.展开更多
To compare the difference in tumor immunity and autoimmunity elicited by adenovirus （Ad） encoding human or murine tyrosinase-related protein 2 （AdhTRP2 or AdmTRP2）, and to find the most effective way to induce i...To compare the difference in tumor immunity and autoimmunity elicited by adenovirus （Ad） encoding human or murine tyrosinase-related protein 2 （AdhTRP2 or AdmTRP2）, and to find the most effective way to induce immunity by AdhTRP2 or AdmTRP2, C57BL/6 mice were immunized with AdhTRP2 or AdmTRP2 intramuscularly at different doses of 10^5, 10^6, 10^7 and 10^8 separately （ 10 mice for each dose）. Two weeks after the immunization, in vivo CTL assay and intracellular staining （ICS） of IFN-γ were carried out to analyze the dose-effect relationship. Tumor growth and vitiligo （as an sign of autoimmunity） were observed until 3 months after challenge with 10^5 B 16F10 tumor cells. The results showed that Ad encoding AdmTrp2 induced weak tumor immune response. Similar immunization with AdhTrp-2 elicited stronger protective immunity. CTL activity and IFN-γ-produced CD8＋T cells were directly proportional to dose of AdhTrp2 or AdmTrp2. Moreover, AdhTrp2 group showed tumor rejection in 100% of challenged mice till the end of 3rd month while 60% of mice immunized with AdmTrp2 were protected against tumor. In the whole process of this experiment, no vitiligo was observed in mice immunized either with AdhTrp2 or AdmTrp2. It is concluded that anti-melanoma responses induced by genetic vaccination expressing xenoantigens breaks immune tolerance effectively and is able to elicit strong antigen-specific cytotoxic T cell response without vitiligo.展开更多
Traditional Chinese medicine has been used to treat more than 70%of cancer patients in China.Traditional Chinese medicine treatment includes the application of traditional Chinese medicine monomers,extracts,classical ...Traditional Chinese medicine has been used to treat more than 70%of cancer patients in China.Traditional Chinese medicine treatment includes the application of traditional Chinese medicine monomers,extracts,classical Chinese medicine compounds,self-made compounds,acupuncture,etc.Mechanisms of the anti-tumor effects of traditional Chinese medicine are related to their immune-regulatory roles.Some traditional Chinese medicines improve the sensitivity of chemotherapeutic drugs,enhance tumor-suppressive effects,and decrease adverse reactions.In 2021,research papers from China accounted for about two-thirds of all the papers on traditional Chinese medicine and anti-tumor immunity.China continues to lead the world in the field of anti-tumor immunity of traditional Chinese medicine,and the efficient and productive academic cooperation between China and other countries has promoted the rapid development of this field.In this review,we summarize the research progress of traditional Chinese medicine in the field of tumor immunity in 2021 to provide new insights into mechanisms underlying the anti-tumor effects of traditional Chinese medicine.展开更多
Objective: Abnormal metabolism is the underlying reason for breast cancer progression. Decreased lactate dehydrogenase B(LDHB) has been detected in breast cancer but the function of LDHB remains unknown.Methods: Weste...Objective: Abnormal metabolism is the underlying reason for breast cancer progression. Decreased lactate dehydrogenase B(LDHB) has been detected in breast cancer but the function of LDHB remains unknown.Methods: Western blot was used to analyze LDHB expression in breast cancer cells. The impact of LDHB on tumor cell migration and invasion was determined using Transwell assays, wound healing assays, and a mouse lung metastasis model. Subcutaneous tumor formation, a natural killer(NK) cell cytotoxicity assay, and flow cytometry evaluated NK cell activation. Immunofluorescence and quantitative real-time PCR detected NK cell activation markers. Kaplan-Meier analysis evaluated the effect of immune cell infiltration on prognosis. Single-sample gene set enrichment analysis determined NK cell activation scores. A support vector machine predicted the role of LDHB in NK cell activation.Results: In this study we showed that LDHB inhibits the breast cancer cell metastasis and orchestrates metabolic reprogramming within tumor cells. Our results revealed that LDHB-mediated lactic acid clearance in breast cancer cells triggers NK cell activation within the tumor microenvironment. Our findings, which were confirmed in a murine model, demonstrated that LDHB in tumor cells promotes NK cell activation and ultimately results in the eradication of malignant cells. Clinically, our study further validated that LDHB affects immune cell infiltration and function. Specifically, its expression has been linked to enhanced NK cell-mediated cytotoxicity and improved patient survival. Furthermore, we identified LDHB expression in tumors as an important predictor of NK cell activation, with strong predictive ability in some cancers.Conclusions: Our results suggest that LDHB is a promising target for activating the tumor immune microenvironment in breast cancer, where LDHB-associated lactic acid clearance leads to increased NK cell activity. This study highlights the critical role of LDHB in regulating immune responses and its potential as a therapeutic target for breast cancer.展开更多
As a highly invasive malignancy,esophageal cancer(EC)is a global health issue,and was the eighth most prevalent cancer and the sixth leading cause of cancerrelated death worldwide in 2020.Due to its highly immunogenic...As a highly invasive malignancy,esophageal cancer(EC)is a global health issue,and was the eighth most prevalent cancer and the sixth leading cause of cancerrelated death worldwide in 2020.Due to its highly immunogenic nature,emerging immunotherapy approaches,such as immune checkpoint blockade,have demonstrated promising efficacy in treating EC;however,certain limitations and challenges still exist.In addition,tumors may exhibit primary or acquired resistance to immunotherapy in the tumor immune microenvironment(TIME);thus,understanding the TIME is urgent and crucial,especially given the importance of an immunosuppressive microenvironment in tumor progression.The aim of this review was to better elucidate the mechanisms of the suppressive TIME,including cell infiltration,immune cell subsets,cytokines and signaling pathways in the tumor microenvironment of EC patients,as well as the downregulated expression of major histocompatibility complex molecules in tumor cells,to obtain a better understanding of the differences in EC patient responses to immunotherapeutic strategies and accurately predict the efficacy of immunotherapies.Therefore,personalized treatments could be developed to maximize the advantages of immunotherapy.展开更多
Objective:Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents,with a poor prognosis.Anchorage-dependent cell death(anoikis)has been proven to be indispensable in ...Objective:Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents,with a poor prognosis.Anchorage-dependent cell death(anoikis)has been proven to be indispensable in tumor metastasis,regulating the migration and adhesion of tumor cells at the primary site.However,as a type of programmed cell death,anoikis is rarely studied in osteosarcoma,especially in the tumor immune microenvironment.This study aims to clarify prognostic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma.Methods:Anoikis-related genes(ANRGs)were obtained from GeneCards.Clinical information and ANRGs expression profiles of osteosarcoma patients were sourced from the therapeutically applicable research to generate effective therapies and Gene Expression Omnibus(GEO)databases.ANRGs highly associated with tumor immune microenvironment were identified by the estimate package and the weighted gene coexpression network analysis(WGCNA)algorithm.Machine learning algorithms were performed to construct long-term survival predictive strategy,each sample was divided into high-risk and low-risk subgroups,which was further verified in the GEO cohort.Finally,based on single-cell RNA-seq from the GEO database,analysis was done on the function of signature genes in the osteosarcoma tumor microenvironment.Results:A total of 51 hub ANRGs closely associated with the tumor microenvironment were identified,from which 3 genes(MERTK,BNIP3,S100A8)were selected to construct the prognostic model.Significant differences in immune cell activation and immune-related signaling pathways were observed between the high-risk and low-risk groups based on tumor microenvironment analysis(all P<0.05).Additionally,characteristic genes within the osteosarcoma microenvironment were identified in regulation of intercellular crosstalk through the GAS6-MERTK signaling pathway.Conclusion:The prognostic model based on ANRGs and tumor microenvironment demonstrate good predictive power and provide more personalized treatment options for patients with osteosarcoma.展开更多
Objective:Lung squamous cell carcinoma(LUSC)is associated with a low survival rate.Evidence suggests that bone morphogenetic proteins(BMPs)and their receptors(BMPRs)play crucial roles in tumorigenesis and progression....Objective:Lung squamous cell carcinoma(LUSC)is associated with a low survival rate.Evidence suggests that bone morphogenetic proteins(BMPs)and their receptors(BMPRs)play crucial roles in tumorigenesis and progression.However,a comprehensive analysis of their role in LUSC is lacking.Our study aimed to explore the relationship between BMPs/BMPRs expression levels and the tumorigenesis and prognosis of LUSC.Methods:The“R/Limma”package was utilized to analyze the differential expression characteristics of BMPs/BMPRs in LUSC,using data from TCGA,GTEx,and GEO databases.Concurrently,the“survminer”packages were employed to investigate their prognostic value and correlation with clinical features in LUSC.The core gene associated with LUSC progression was further explored through weighted gene correlation network analysis(WGCNA).LASSO analysis was conducted to construct a prognostic risk model for LUSC.Clinical specimens were examined by immunohistochemical analysis to confirm the diagnostic value in LUSC.Furthermore,based on the tumor immune estimation resource database and tumor-immune system interaction database,the role of the core gene in the tumor microenvironment of LUSC was explored.Results:GDF10 had a significant correlation only with the pathological T stage of LUSC,and the protein expression level of GDF10 decreased with the tumorigenesis of LUSC.A prognostic risk model was constructed with GDF10 as the core gene and 5 hub genes(HRASLS,HIST1H2BH,FLRT3,CHEK2,and ALPL)for LUSC.GDF10 showed a significant positive correlation with immune cell infiltration and immune checkpoint expression.Conclusion:GDF10 might serve as a diagnostic biomarker reflecting the tumorigenesis of LUSC and regulating the tumor immune microenvironment to guide more effective treatment for LUSC.展开更多
The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant...The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking.To address this gap,we conducted a study aiming to investigate this association and identify relevant biomarkers.We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment,biological activity,and the immune microenvironment.Additionally,we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies(GWASs)involving both East Asian(7062 cases and 195745 controls)and European(24476 cases and 23073 controls)populations.We employed mediation analysis to infer the causal pathway,and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells.Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1(FEN1)gene were significantly enriched in colorectal tumor tissues,compared with normal tissues.Moreover,a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer(odds ratio=0.94,95%confidence interval:0.90–0.97,P_(meta)=4.70×10^(-9)).Importantly,we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors,and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication.In conclusion,this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity,expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.展开更多
Objective:CD8+T cells are the key effector cells in the anti-tumor immune response.The mechanism underlying the infiltration of CD8+T cells in esophageal squamous cell carcinoma(ESCC)has not been clearly elucidated.Me...Objective:CD8+T cells are the key effector cells in the anti-tumor immune response.The mechanism underlying the infiltration of CD8+T cells in esophageal squamous cell carcinoma(ESCC)has not been clearly elucidated.Methods:Fresh ESCC tissues were collected and grouped according to the infiltration density of CD8+T cells.After the transcriptome sequencing on these samples and the combined analyses with The Cancer Genome Atlas(TCGA)ESCC data,a secreted protein DEFB1 was selected to explore its potential role in the infiltration of CD8+T cells.Bioinformatics analyses,histological verification and in vitro experiments were then performed.Results:DEFB1 was highly expressed in ESCC,and the high expression of DEFB1 was an independent risk factor for overall survival.Since the up-regulation or down-regulation of DEFB1 did not affect the proliferation,migration and apoptosis of ESCC cells,we speculated that the oncogenic effect of DEFB1 was achieved by regulating microenvironmental characteristics.Bioinformatics analyses suggested that DEFB1 might play a major role in the inflammatory response and anti-tumor immune response,and correlate to the infiltration of immature dendritic cell(imDC)in ESCC.Histological analyses further confirmed that there were less CD8+T cells infiltrated,less CD83+mature DC(mDC)infiltrated and more CD1a+imDC infiltrated in those ESCC samples with high expression of DEFB1.After the treatment with recombinant DEFB1 protein,the maturation of DC was hindered significantly,followed by the impairment of the killing effects of T cells in both 2D and 3D culture in vitro.Conclusions:Tumor-derived DEFB1 can inhibit the maturation of DC and weaken the function of CD8+T cells,accounting for the immune tolerance in ESCC.The role of DEFB1 in ESCC deserves further exploration.展开更多
Dear Editor,Physical exercise has been shown to be associated with reduced cancer incidence and cancer-associated mortality[1,2],but the underlying mechanisms are obscure.Immunometabolic regulation has emerged as one ...Dear Editor,Physical exercise has been shown to be associated with reduced cancer incidence and cancer-associated mortality[1,2],but the underlying mechanisms are obscure.Immunometabolic regulation has emerged as one of the most prominent mechanisms explaining the effects of exercise on cancer[1,2].Physical exercise primarily lowers blood cholesterol and triglycerides,and protects against cardiovascular diseases[3].However,whether physical exercise can modulate cholesterol metabolism in tumor cells is currently unknown.展开更多
DNA damage occurs across tumorigenesis and tumor development.Tumor intrinsic DNA damage can not only increase the risk of mutations responsible for tumor generation but also initiate a cellular stress response to orch...DNA damage occurs across tumorigenesis and tumor development.Tumor intrinsic DNA damage can not only increase the risk of mutations responsible for tumor generation but also initiate a cellular stress response to orchestrate the tumor immune microenvironment(TIME)and dominate tumor progression.Accumulating evidence documents that multiple signaling pathways,including cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)and ataxia telangiectasia-mutated protein/ataxia telangiectasia and Rad3-related protein(ATM/ATR),are activated downstream of DNA damage and they are associated with the secretion of diverse cytokines.These cytokines possess multifaced functions in the anti-tumor immune response.Thus,it is necessary to deeply interpret the complex TIME reshaped by damaged DNA and tumor-derived cytokines,critical for the development of effective tumor therapies.This manuscript comprehensively reviews the relationship between the DNA damage response and related cytokines in tumors and depicts the dual immunoregulatory roles of these cytokines.We also summarize clinical trials targeting signaling pathways and cytokines associated with DNA damage and provide future perspectives on emerging technologies.展开更多
Among various immunoregulatory molecules,the B7 family of immune-checkpoint receptors consists of highly valuable targets for cancer immunotherapy.Antibodies targeting two B7 family co-inhibitory receptors,CTLA-4 and ...Among various immunoregulatory molecules,the B7 family of immune-checkpoint receptors consists of highly valuable targets for cancer immunotherapy.Antibodies targeting two B7 family co-inhibitory receptors,CTLA-4 and PD-1,have elicited long-term clinical outcomes in previously refractory cancer types and are considered a breakthrough in cancer therapy.Despite the success,the relatively low response rate(20–30%)warrants efforts to identify and overcome additional immune-suppressive pathways.Among the expanding list of T cell inhibitory regulators,V domain immunoglobulin suppressor of T cell activation(VISTA)is a unique B7 family checkpoint that regulates a broad spectrum of immune responses.Here,we summarize recent advances that highlight the structure,expression,and multi-faceted immunomodulatory mechanisms of VISTA in the context of autoimmunity,inflammation,and anti-tumor immunity.展开更多
Nicotinamide phosphoribosyl transferase(NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and inflammation.However,therapeutic benefit of NAMPT enzymatic ...Nicotinamide phosphoribosyl transferase(NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and inflammation.However,therapeutic benefit of NAMPT enzymatic inhibitors appears very limited,likely due to the failure to intervene nonenzymatic functions of NAMPT.Herein,we show that NAMPT dampens antitumor immunity by promoting the expansion of tumor infiltrating myeloid derived suppressive cells(MDSCs) via a mechanism independent of its enzymatic activity.Using proteolysis-targeting chimera(PROTAC) technology,PROTAC A7 is identified as a potent and selective degrader of NAMPT,which degrades intracellular NAMPT(iNAMPT) via the ubiquitin-proteasome system,and in turn decreases the secretion of extracellular NAMPT(eNAMPT),the major player of the non-enzymatic activity of NAMPT.In vivo,PROTAC A7 efficiently degrades NAMPT,inhibits tumor infiltrating MDSCs,and boosts antitumor efficacy.Of note,the anticancer activity of PROTAC A7 is superior to NAMPT enzymatic inhibitors that fail to achieve the same impact on MDSCs.Together,our findings uncover the new role of enzymatically-independent function of NAMPT in remodeling the immunosuppressive tumor microenvironment,and reports the first NAMPT PROTAC A7 that is able to block the pro-tumor function of both iNAMPT and eNAMPT,pointing out a new direction for the development of NAMPT-targeted therapies.展开更多
Background Genetic modification of dendritic cells （DCs） has been used as an effective approach to enhance anti-tumor immunity. RNA interference （RNAi）, which can cause the degradation of any RNA in a sequence-spe...Background Genetic modification of dendritic cells （DCs） has been used as an effective approach to enhance anti-tumor immunity. RNA interference （RNAi）, which can cause the degradation of any RNA in a sequence-specific manner, is a post-transcriptional gene silencing mechanism. In this study, small-interfering RNA （siRNA） specific for the li gene was transfected into DCs, and the anti-tumor immunity of li-silenced DCs was assessed. Methods The silencing effect of siRNA was evaluated by Western blotting and real-time PCR analyses. In vitro cytotoxic activity of T cells was evaluated using a Cytotox 96 non-radioactive cytotoxicity assay kit. The time to tumor onset and the tumor volumes were used as reliable indices to assess the anti-tumor immunity in vivo. To further examine the mechanisms underlying the anti-tumor immunity, flow cytometry analysis was used. Results The li expression of DCs was significantly reduced after li siRNA transfection. Significant in vitro anti-tumor ability was exhibited when DCs were co-transfected with li siRNA plus endogenous tumor antigen （P 〈0.05）. Furthermore tumor growth was greatly inhibited when mice were immunized with DCs transfected with li siRNA plus tumor antigen prior to or subsequent to tumor implantation. Flow cytometry analysis in vitro and in vivo indicated that both CD4^= and CD8^＋ T cells were significantly activated in the li siRNA group （P 〈0.05）. Conclusion Silencing of the li gene of DCs may offer a potential approach to enhance DC-based anti-tumor immunity.展开更多
Interleukin(IL)-4 is a crucial cytokine in tumor immunology.In the initial murine experiments,IL-4 exhibited potent anti-tumor ability.Tumors genetically modified to produce IL-4 were rejected,while parental tumors gr...Interleukin(IL)-4 is a crucial cytokine in tumor immunology.In the initial murine experiments,IL-4 exhibited potent anti-tumor ability.Tumors genetically modified to produce IL-4 were rejected,while parental tumors grew progressively.Mice rejected IL-4-producing tumors got long-lasting anti-tumor immunity.The comparative study showed that IL-4 induced the most effective immune response among several cytokines in both prophylactic and therapeutic models.All of these indicate IL-4 has strong potential as a tumor therapy agent.However,contrary evidence indeed exists,and is becoming more and more abundant which shows IL-4 is a tumor-promoting molecule.IL-4 amounts are usually elevated in human cancer patients.IL-4 knockout mice are more resistant to tumor challenge than IL-4 competent mice.Furthermore,tumor cells of various histological origins often express increased levels of IL-4 receptor in comparison to their normal counterparts.By carefully examining presently available data,we found the effects of IL-4 in tumor immunity are closely related to its sources,expressing time and dose,as well as the molecular and cellular environments.In this mini-review,we concentrate on illustrating the paradoxical roles and underlying mechanisms of IL-4 in tumor immunity and try to understand how one molecule has opposite effects.展开更多
A dendritic cell(DC)vaccine strategy has been developed as a new cancer immunotherapy,but the goal of complete tumor eradication has not yet been achieved.We have previously shown that baculoviruses potently infect DC...A dendritic cell(DC)vaccine strategy has been developed as a new cancer immunotherapy,but the goal of complete tumor eradication has not yet been achieved.We have previously shown that baculoviruses potently infect DCs and induce antitumor immunity against hepatomas in a mouse model.Baculovirus-infected,bone marrow-derived DCs(BMDCs)display increased surface expression of costimulatory molecules,such as CD80,CD86 and major histocompatibility complex(MHC)classes I and II,and secrete interferons and other proinflammatory cytokines.In this study,we evaluated the induction of antitumor immunity in mice by baculovirus-infected BMDCs against lung cancer and melanoma.After treatment with baculovirus-infected BMDCs,murine lung tumors caused by Lewis lung carcinoma(LLC)cells were significantly reduced in size,and the survival of the mice was improved.In addition,experiments using a melanoma mouse model showed that baculovirus-infected BMDCs inhibited tumor growth and improved survival compared with controls.Serum alanine aminotransferase(ALT),aspartate aminotransferase(AST)and creatinine levels remained normal in baculovirus-infected BMDC-treated mice.Our findings show that baculovirus-infected DCs induce antitumor immunity and pave the way for the use of this technique as an effective tool for DC immunotherapy against malignancies.展开更多
B and T-lymphocyte attenuator(BTLA)plays an immunosuppressive role by inhibiting T-and B-cell functions.BTLA is associated with a variety of diseases,especially cancer immunity.However,the function of BTLA in various ...B and T-lymphocyte attenuator(BTLA)plays an immunosuppressive role by inhibiting T-and B-cell functions.BTLA is associated with a variety of diseases,especially cancer immunity.However,the function of BTLA in various cancers and its clinical prognostic value have still not been comprehensively analyzed.This study aimed to identify the relationship between BTLA and cancer from the perspectives of differences in BTLA expression,its clinical value,immune infiltration,and the correlation with immune-related genes in various cancers.Data regarding mRNA expression,miRNA expression,lncRNA expression,and clinical data of patients of 33 existing cancers were collected from the TCGA database.Target miRNA of BTLA and the lncRNA that interacts with the target miRNA were obtained from the StarBase database.Based on bioinformatics analysis methods,the relationship between various types of cancers and BTLA was thoroughly investigated,and a competing endogenous RNA network of BTLA,target miRNA,and interacting lncRNA was constructed.The Kaplan-Meier(KM)prognostic analysis of BTLA and target miRNA(has-miR-137)in various types of cancers was completed using the KM plotter.BTLA expression varied in different cancers,with statistical significance in nine cancer types.KM plotter to analyze the overall survival(OS)and regression-free survival prognosis of cancer patients revealed that the BTLA expression was statistically different in the OS of 11 types of cancers out of 21 types of cancers;the OS of 8 type of cancers was also statistically different.Correlation analysis of tumor immune genes revealed a positive correlation of BTLA expression with immunosuppressive gene(CTLA4 and PDCD1)expression.Gene Set Enrichment Analysis showed that BTLA and its co-expressed genes mainly act through biological processes and pathways,including immune response regulation,cell surface receptor signaling pathway,antigen binding,antigen receptor-mediated signaling pathway,and leukocyte migration.BTLA has the potential as a prognostic marker for CLL,COAD,NSCLC,and OV and a diagnostic marker for CLL,COAD,and KIRC.BTLA has a close and complex relationship with the occurrence and development of tumors,and cancer immunotherapy for BTLA is worthy of further analysis.展开更多
Immunotherapy has efficiently revolutionized the treatment of human neoplastic diseases.However,the overall responsive rate of current immunotherapy is still unsatisfactory,benefiting only a small proportion of patien...Immunotherapy has efficiently revolutionized the treatment of human neoplastic diseases.However,the overall responsive rate of current immunotherapy is still unsatisfactory,benefiting only a small proportion of patients.Therefore,significant attention has been paid to the modulation of tumor microenvironment(TME)for the enhancement of immunotherapy.Interestingly,recent studies have shown that cyclic GMP-AMP synthasestimulator of interferon gene(cGAS-STING)was initially found as an innate immune sensor to recognize cytoplasmic DNA(such as bacterial,viral,micronuclei,and mitochondrial).It is a promising signaling pathway to activate antitumor immune responses via type I interferon production.Notably,Mn^(2+)was found to be a critical molecule to sensitize the activation of the cGAS-STING pathway for better immunotherapy.This activation led to the development of Mn^(2+)-based strategies for tumor immunotherapy via the activation of the cGAS-STING pathway.In this critical review,we aimed to summarize the recent progress of this field,focusing on the following three aspects.First,we briefly introduced the signaling pathway of cGAS-STING activation,and its regulation effect on the antitumor immunity cycle has been discussed.Along with this,several agonists of the cGAS-STING pathway were introduced with their potential as immunotherapeutic drugs.Then,the basic biological functions of Mn^(2+)have been illustrated,focusing on its critical roles in the cGAS-STING pathway activation.Next,we systematically reviewed the Mn^(2+)-based strategies for tumor immunotherapy,which can be classified by the methods based on Mn^(2+)alone or Mn^(2+)combined with other therapeutic modalities.We finally speculated the future perspectives of the field and provided rational suggestions to develop better Mn^(2+)-based therapeutics.展开更多
Objective: The interplay between chemokine C-X-C motif ligand 12(CXCL12) and its specific receptors is known to trigger various signaling pathways, contributing to tumor proliferation and metastasis. Consequently,targ...Objective: The interplay between chemokine C-X-C motif ligand 12(CXCL12) and its specific receptors is known to trigger various signaling pathways, contributing to tumor proliferation and metastasis. Consequently,targeting this signaling axis has emerged as a potential strategy in cancer therapy. However, the precise role of CXCL12 in clinical therapy, especially in immunotherapy for bladder cancer(BCa), remains poorly elucidated.Methods: We gathered multiple omics data from public databases to unveil the clinical relevance and tumor immune landscape associated with CXCL12 in BCa patients. Univariate and multivariate Cox regression analyses were employed to assess the independent prognostic significance of CXCL12 expression and formulate a nomogram. The expression of CXCL12 in BCa cell lines and clinical tissue samples was validated using enzymelinked immunosorbent assays(ELISA) and immunohistochemistry(IHC).Results: While transcriptional expression of CXCL12 exhibited a decrease in nearly all tumor tissues, CXCL12 methylation expression was notably increased in BCa tissues. Single-cell RNA analysis highlighted tissue stem cells and endothelial cells as the primary sources expressing CXCL12. Abnormal CXCL12 expression, based on transcriptional and methylation levels, correlated with various clinical characteristics in BCa patients. Functional analysis indicated enrichment of CXCL12 and its co-expression genes in immune regulation and cell adhesion. The immune landscape analysis unveiled a significant association between CXCL12 expression and M2 macrophages(CD163~+ cells) in BCa tissues. Notably, CXCL12 expression emerged as a potential predictor of immunotherapy response and chemotherapy drug sensitivity in BCa patients.Conclusions: Taken together, these findings suggest aberrant production of CXCL12 in BCa tissues,potentially influencing the treatment responses of affected individuals.展开更多
基金supported by a grant from the National"95"Key Project of China(No.96-906A-01-20).
文摘Objective: To study the synergic effects of IL-12 and B7-1 transfectant on antitumor immunity in vivo. Methods: The retrovirus vector encoding mIL-12 and mB7-1 gene was tranfected into EL-4 thymic lymphoma cells respectively.The cells were used as tumor vaccine and the therapeutic effect was observed. Results: In contrast to the miceimmunized with EL-4/Wt or EL-4/Neo groups, thetumorigenicity of EL-4/IL-12 transfectant was decreased(P<0.001). The EL-4/IL-12 and EL-4/B7-1 cells irradiatedwith 60Co showed significant systematic protective effectsagainst the rechallenge of EL-4/Wt. 60Co irradiatedEL-4/IL-12 cells delayed the occurrence of tumor andprolonged the survival period of tumor bearing mice.Combination of the vaccines of EL-4/IL-12 and EL-4/B7-1 resulted in the enhanced therapeutic effect compared witheach single transfectant group (P<0.001). Conclusion: The results showed that IL-12 transduced cells could enhancethe antitumor immunity of host as cancer vaccine.Combination of the EL-4/IL-12 and EL-4/B7-1 transfectant could improve immunity of host and is a prospect cancervaccine.
基金the Changsha Municipal Natural Science Foundation,No.kq2014258.
文摘BACKGROUND Nucleus accumbens-1(NAC-1)is highly expressed in a variety of tumors,including colon cancer,and is closely associated with tumor recurrence,metastasis,and invasion.AIM To determine whether and how NAC-1 affects antitumor immunity in colon cancer.METHODS NAC-1-siRNA was transfected into RKO colon cancer cells to knock down NAC expression;tumor cells with or without knockdown of NAC-1 were treated with CD8+T cells to test their cytocidal effect.The level of the immune checkpoint programmed death receptor-1 ligand(PD-L1)in colon cancer cells with or without knockdown of NAC-1 was analyzed using Quantitative real-time polymerase chain reaction and Western blotting.A double luciferase reporter assay was used to examine the effects of NAC-1 on the transcription of PD-L1.Mice bearing MC-38-OVA colon cancer cells expressing NAC-shRNA or controlshRNA were treated with OT-I mouse CD8+T cells to determine the tumor response to immunotherapy.Immune cells in the tumor tissues were analyzed using flow cytometry.NAC-1,PD-L1 and CD8+T cells in colon cancer specimens from patients were examined using immunohistochemistry staining.RESULTS Knockdown of NAC-1 expression in colon cancer cells significantly enhanced the cytocidal effect of CD8+T cells in cell culture experiments.The sensitizing effect of NAC-1 knockdown on the antitumor action of cytotoxic CD8+T cells was recapitulated in a colon cancer xenograft animal model.Furthermore,knockdown of NAC-1 in colon cancer cells decreased the expression of PD-L1 at both the mRNA and protein levels,and this effect could be rescued by transfection of an RNAi-resistant NAC-1 expression plasmid.In a reporter gene assay,transient expression of NAC-1 in colon cancer cells increased the promoter activity of PD-L1,indicating that NAC-1 regulates PD-L1 expression at the transcriptional level.In addition,depletion of tumoral NAC-1 increased the number of CD8+T cells but decreased the number of suppressive myeloid-derived suppressor cells and regulatory T cells.CONCLUSION Tumor expression of NAC-1 is a negative determinant of immunotherapy.
基金a grant of National R&D Program for Chinese Scholars Returning from Oversea (No. 20071108)
文摘To compare the difference in tumor immunity and autoimmunity elicited by adenovirus （Ad） encoding human or murine tyrosinase-related protein 2 （AdhTRP2 or AdmTRP2）, and to find the most effective way to induce immunity by AdhTRP2 or AdmTRP2, C57BL/6 mice were immunized with AdhTRP2 or AdmTRP2 intramuscularly at different doses of 10^5, 10^6, 10^7 and 10^8 separately （ 10 mice for each dose）. Two weeks after the immunization, in vivo CTL assay and intracellular staining （ICS） of IFN-γ were carried out to analyze the dose-effect relationship. Tumor growth and vitiligo （as an sign of autoimmunity） were observed until 3 months after challenge with 10^5 B 16F10 tumor cells. The results showed that Ad encoding AdmTrp2 induced weak tumor immune response. Similar immunization with AdhTrp-2 elicited stronger protective immunity. CTL activity and IFN-γ-produced CD8＋T cells were directly proportional to dose of AdhTrp2 or AdmTrp2. Moreover, AdhTrp2 group showed tumor rejection in 100% of challenged mice till the end of 3rd month while 60% of mice immunized with AdmTrp2 were protected against tumor. In the whole process of this experiment, no vitiligo was observed in mice immunized either with AdhTrp2 or AdmTrp2. It is concluded that anti-melanoma responses induced by genetic vaccination expressing xenoantigens breaks immune tolerance effectively and is able to elicit strong antigen-specific cytotoxic T cell response without vitiligo.
基金the Fundamental Research Funds for the Central Universities(2632022ZD10).
文摘Traditional Chinese medicine has been used to treat more than 70%of cancer patients in China.Traditional Chinese medicine treatment includes the application of traditional Chinese medicine monomers,extracts,classical Chinese medicine compounds,self-made compounds,acupuncture,etc.Mechanisms of the anti-tumor effects of traditional Chinese medicine are related to their immune-regulatory roles.Some traditional Chinese medicines improve the sensitivity of chemotherapeutic drugs,enhance tumor-suppressive effects,and decrease adverse reactions.In 2021,research papers from China accounted for about two-thirds of all the papers on traditional Chinese medicine and anti-tumor immunity.China continues to lead the world in the field of anti-tumor immunity of traditional Chinese medicine,and the efficient and productive academic cooperation between China and other countries has promoted the rapid development of this field.In this review,we summarize the research progress of traditional Chinese medicine in the field of tumor immunity in 2021 to provide new insights into mechanisms underlying the anti-tumor effects of traditional Chinese medicine.
基金supported by the Shenzhen Science and Technology Program (Grant no. JCYJ20230807090459001)the Joint Research Fund of the National Science Fund of China Science and Technology Development Fund of Macao SAR (No. 32161160303 for NSFC and No. 0010/2021/AFJ for FDCT)the Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University (Grant no. ZNJC202330)。
文摘Objective: Abnormal metabolism is the underlying reason for breast cancer progression. Decreased lactate dehydrogenase B(LDHB) has been detected in breast cancer but the function of LDHB remains unknown.Methods: Western blot was used to analyze LDHB expression in breast cancer cells. The impact of LDHB on tumor cell migration and invasion was determined using Transwell assays, wound healing assays, and a mouse lung metastasis model. Subcutaneous tumor formation, a natural killer(NK) cell cytotoxicity assay, and flow cytometry evaluated NK cell activation. Immunofluorescence and quantitative real-time PCR detected NK cell activation markers. Kaplan-Meier analysis evaluated the effect of immune cell infiltration on prognosis. Single-sample gene set enrichment analysis determined NK cell activation scores. A support vector machine predicted the role of LDHB in NK cell activation.Results: In this study we showed that LDHB inhibits the breast cancer cell metastasis and orchestrates metabolic reprogramming within tumor cells. Our results revealed that LDHB-mediated lactic acid clearance in breast cancer cells triggers NK cell activation within the tumor microenvironment. Our findings, which were confirmed in a murine model, demonstrated that LDHB in tumor cells promotes NK cell activation and ultimately results in the eradication of malignant cells. Clinically, our study further validated that LDHB affects immune cell infiltration and function. Specifically, its expression has been linked to enhanced NK cell-mediated cytotoxicity and improved patient survival. Furthermore, we identified LDHB expression in tumors as an important predictor of NK cell activation, with strong predictive ability in some cancers.Conclusions: Our results suggest that LDHB is a promising target for activating the tumor immune microenvironment in breast cancer, where LDHB-associated lactic acid clearance leads to increased NK cell activity. This study highlights the critical role of LDHB in regulating immune responses and its potential as a therapeutic target for breast cancer.
基金Supported by Xi’an Municipal Health Commission of China,No.2022qn07 and No.2023ms11.
文摘As a highly invasive malignancy,esophageal cancer(EC)is a global health issue,and was the eighth most prevalent cancer and the sixth leading cause of cancerrelated death worldwide in 2020.Due to its highly immunogenic nature,emerging immunotherapy approaches,such as immune checkpoint blockade,have demonstrated promising efficacy in treating EC;however,certain limitations and challenges still exist.In addition,tumors may exhibit primary or acquired resistance to immunotherapy in the tumor immune microenvironment(TIME);thus,understanding the TIME is urgent and crucial,especially given the importance of an immunosuppressive microenvironment in tumor progression.The aim of this review was to better elucidate the mechanisms of the suppressive TIME,including cell infiltration,immune cell subsets,cytokines and signaling pathways in the tumor microenvironment of EC patients,as well as the downregulated expression of major histocompatibility complex molecules in tumor cells,to obtain a better understanding of the differences in EC patient responses to immunotherapeutic strategies and accurately predict the efficacy of immunotherapies.Therefore,personalized treatments could be developed to maximize the advantages of immunotherapy.
基金This work was supported by the National Natural Science Foundation(82172594 and 82373046)the Hunan Graduate Research Innovation Project(CX20230318),China.
文摘Objective:Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents,with a poor prognosis.Anchorage-dependent cell death(anoikis)has been proven to be indispensable in tumor metastasis,regulating the migration and adhesion of tumor cells at the primary site.However,as a type of programmed cell death,anoikis is rarely studied in osteosarcoma,especially in the tumor immune microenvironment.This study aims to clarify prognostic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma.Methods:Anoikis-related genes(ANRGs)were obtained from GeneCards.Clinical information and ANRGs expression profiles of osteosarcoma patients were sourced from the therapeutically applicable research to generate effective therapies and Gene Expression Omnibus(GEO)databases.ANRGs highly associated with tumor immune microenvironment were identified by the estimate package and the weighted gene coexpression network analysis(WGCNA)algorithm.Machine learning algorithms were performed to construct long-term survival predictive strategy,each sample was divided into high-risk and low-risk subgroups,which was further verified in the GEO cohort.Finally,based on single-cell RNA-seq from the GEO database,analysis was done on the function of signature genes in the osteosarcoma tumor microenvironment.Results:A total of 51 hub ANRGs closely associated with the tumor microenvironment were identified,from which 3 genes(MERTK,BNIP3,S100A8)were selected to construct the prognostic model.Significant differences in immune cell activation and immune-related signaling pathways were observed between the high-risk and low-risk groups based on tumor microenvironment analysis(all P<0.05).Additionally,characteristic genes within the osteosarcoma microenvironment were identified in regulation of intercellular crosstalk through the GAS6-MERTK signaling pathway.Conclusion:The prognostic model based on ANRGs and tumor microenvironment demonstrate good predictive power and provide more personalized treatment options for patients with osteosarcoma.
文摘Objective:Lung squamous cell carcinoma(LUSC)is associated with a low survival rate.Evidence suggests that bone morphogenetic proteins(BMPs)and their receptors(BMPRs)play crucial roles in tumorigenesis and progression.However,a comprehensive analysis of their role in LUSC is lacking.Our study aimed to explore the relationship between BMPs/BMPRs expression levels and the tumorigenesis and prognosis of LUSC.Methods:The“R/Limma”package was utilized to analyze the differential expression characteristics of BMPs/BMPRs in LUSC,using data from TCGA,GTEx,and GEO databases.Concurrently,the“survminer”packages were employed to investigate their prognostic value and correlation with clinical features in LUSC.The core gene associated with LUSC progression was further explored through weighted gene correlation network analysis(WGCNA).LASSO analysis was conducted to construct a prognostic risk model for LUSC.Clinical specimens were examined by immunohistochemical analysis to confirm the diagnostic value in LUSC.Furthermore,based on the tumor immune estimation resource database and tumor-immune system interaction database,the role of the core gene in the tumor microenvironment of LUSC was explored.Results:GDF10 had a significant correlation only with the pathological T stage of LUSC,and the protein expression level of GDF10 decreased with the tumorigenesis of LUSC.A prognostic risk model was constructed with GDF10 as the core gene and 5 hub genes(HRASLS,HIST1H2BH,FLRT3,CHEK2,and ALPL)for LUSC.GDF10 showed a significant positive correlation with immune cell infiltration and immune checkpoint expression.Conclusion:GDF10 might serve as a diagnostic biomarker reflecting the tumorigenesis of LUSC and regulating the tumor immune microenvironment to guide more effective treatment for LUSC.
基金supported by the National Natural Science Foundation of China(Grant No.82173601)Yili&Jiangsu Joint Institute of Health(Grant No.yl2021ms02).
文摘The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking.To address this gap,we conducted a study aiming to investigate this association and identify relevant biomarkers.We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment,biological activity,and the immune microenvironment.Additionally,we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies(GWASs)involving both East Asian(7062 cases and 195745 controls)and European(24476 cases and 23073 controls)populations.We employed mediation analysis to infer the causal pathway,and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells.Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1(FEN1)gene were significantly enriched in colorectal tumor tissues,compared with normal tissues.Moreover,a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer(odds ratio=0.94,95%confidence interval:0.90–0.97,P_(meta)=4.70×10^(-9)).Importantly,we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors,and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication.In conclusion,this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity,expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.
基金supported by the National Natural Science Foundation of China(No.81972681,82103677)Tianjin Education Commission Research Plan Project(No.2021KJ201)+1 种基金Shenzhen High-level Hospital Construction Fund(No.G2022139)Tianjin Key Medical Discipline(Specialty)Construction Project(No.TJYXZDXK-009A).
文摘Objective:CD8+T cells are the key effector cells in the anti-tumor immune response.The mechanism underlying the infiltration of CD8+T cells in esophageal squamous cell carcinoma(ESCC)has not been clearly elucidated.Methods:Fresh ESCC tissues were collected and grouped according to the infiltration density of CD8+T cells.After the transcriptome sequencing on these samples and the combined analyses with The Cancer Genome Atlas(TCGA)ESCC data,a secreted protein DEFB1 was selected to explore its potential role in the infiltration of CD8+T cells.Bioinformatics analyses,histological verification and in vitro experiments were then performed.Results:DEFB1 was highly expressed in ESCC,and the high expression of DEFB1 was an independent risk factor for overall survival.Since the up-regulation or down-regulation of DEFB1 did not affect the proliferation,migration and apoptosis of ESCC cells,we speculated that the oncogenic effect of DEFB1 was achieved by regulating microenvironmental characteristics.Bioinformatics analyses suggested that DEFB1 might play a major role in the inflammatory response and anti-tumor immune response,and correlate to the infiltration of immature dendritic cell(imDC)in ESCC.Histological analyses further confirmed that there were less CD8+T cells infiltrated,less CD83+mature DC(mDC)infiltrated and more CD1a+imDC infiltrated in those ESCC samples with high expression of DEFB1.After the treatment with recombinant DEFB1 protein,the maturation of DC was hindered significantly,followed by the impairment of the killing effects of T cells in both 2D and 3D culture in vitro.Conclusions:Tumor-derived DEFB1 can inhibit the maturation of DC and weaken the function of CD8+T cells,accounting for the immune tolerance in ESCC.The role of DEFB1 in ESCC deserves further exploration.
基金This work was supported by the National Natural Science Foundation of China(82172511)the Natural Science Foundation of Jiangsu Province(BK20210068)+4 种基金the Sanming Project of Medicine in Shenzhen(SZSM201612078)the Health Shanghai Initiative Special Fund[Medical-Sports Integration(JKSHZX-2022-02)]the Top Talent Support Program for Young-and Middle-aged People of Wuxi Municipal Health Commission(HB2020003)the Mega-project of Wuxi Commission of Health(Z202216)the High-end Medical Expert Team of the 2019 Taihu Talent Plan(2019-THRCTD-1)
文摘Dear Editor,Physical exercise has been shown to be associated with reduced cancer incidence and cancer-associated mortality[1,2],but the underlying mechanisms are obscure.Immunometabolic regulation has emerged as one of the most prominent mechanisms explaining the effects of exercise on cancer[1,2].Physical exercise primarily lowers blood cholesterol and triglycerides,and protects against cardiovascular diseases[3].However,whether physical exercise can modulate cholesterol metabolism in tumor cells is currently unknown.
文摘DNA damage occurs across tumorigenesis and tumor development.Tumor intrinsic DNA damage can not only increase the risk of mutations responsible for tumor generation but also initiate a cellular stress response to orchestrate the tumor immune microenvironment(TIME)and dominate tumor progression.Accumulating evidence documents that multiple signaling pathways,including cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)and ataxia telangiectasia-mutated protein/ataxia telangiectasia and Rad3-related protein(ATM/ATR),are activated downstream of DNA damage and they are associated with the secretion of diverse cytokines.These cytokines possess multifaced functions in the anti-tumor immune response.Thus,it is necessary to deeply interpret the complex TIME reshaped by damaged DNA and tumor-derived cytokines,critical for the development of effective tumor therapies.This manuscript comprehensively reviews the relationship between the DNA damage response and related cytokines in tumors and depicts the dual immunoregulatory roles of these cytokines.We also summarize clinical trials targeting signaling pathways and cytokines associated with DNA damage and provide future perspectives on emerging technologies.
基金supported by research funding from NCI R01 CA164225(LW),Advancing A Healthier Wisconsin Research and Education Program(AHW REP)fund(LW)the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Cancer Research Program under Award No.W81XWH-14-1-0587(LW),Cancer Research Institute CLIP Grant(LW),pilot grant 504057 from the Melanoma Research Alliance(LW),Worldwide Cancer Research grant 16-1161(LW and SM),NIH R01 AI102893(SM),NCI R01 CA179363(SM),the Nicholas Family Foundation(SM),and the Gardetto Family endowment(SM).
文摘Among various immunoregulatory molecules,the B7 family of immune-checkpoint receptors consists of highly valuable targets for cancer immunotherapy.Antibodies targeting two B7 family co-inhibitory receptors,CTLA-4 and PD-1,have elicited long-term clinical outcomes in previously refractory cancer types and are considered a breakthrough in cancer therapy.Despite the success,the relatively low response rate(20–30%)warrants efforts to identify and overcome additional immune-suppressive pathways.Among the expanding list of T cell inhibitory regulators,V domain immunoglobulin suppressor of T cell activation(VISTA)is a unique B7 family checkpoint that regulates a broad spectrum of immune responses.Here,we summarize recent advances that highlight the structure,expression,and multi-faceted immunomodulatory mechanisms of VISTA in the context of autoimmunity,inflammation,and anti-tumor immunity.
基金supported by the National Natural Science Foundation of China (grant 82030105 to Chunquan Sheng91957126 to Min Huang)the National Key Research and Development Program of China (grant 2020YFA0509100 to Chunquan Sheng)。
文摘Nicotinamide phosphoribosyl transferase(NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and inflammation.However,therapeutic benefit of NAMPT enzymatic inhibitors appears very limited,likely due to the failure to intervene nonenzymatic functions of NAMPT.Herein,we show that NAMPT dampens antitumor immunity by promoting the expansion of tumor infiltrating myeloid derived suppressive cells(MDSCs) via a mechanism independent of its enzymatic activity.Using proteolysis-targeting chimera(PROTAC) technology,PROTAC A7 is identified as a potent and selective degrader of NAMPT,which degrades intracellular NAMPT(iNAMPT) via the ubiquitin-proteasome system,and in turn decreases the secretion of extracellular NAMPT(eNAMPT),the major player of the non-enzymatic activity of NAMPT.In vivo,PROTAC A7 efficiently degrades NAMPT,inhibits tumor infiltrating MDSCs,and boosts antitumor efficacy.Of note,the anticancer activity of PROTAC A7 is superior to NAMPT enzymatic inhibitors that fail to achieve the same impact on MDSCs.Together,our findings uncover the new role of enzymatically-independent function of NAMPT in remodeling the immunosuppressive tumor microenvironment,and reports the first NAMPT PROTAC A7 that is able to block the pro-tumor function of both iNAMPT and eNAMPT,pointing out a new direction for the development of NAMPT-targeted therapies.
基金This research was supported by grants from the National Natural Science Foundation of China （No. 30570828 and No. 30471961）.Acknowledgements： The authors deeply appreciate technical assistance from Q. Li and D. Q. Zhang valuble discussion with R. F Ge and help from the experimental Animal Facility technicians for animal care. We thank the International Science Editing for help in editing our manuscript.
文摘Background Genetic modification of dendritic cells （DCs） has been used as an effective approach to enhance anti-tumor immunity. RNA interference （RNAi）, which can cause the degradation of any RNA in a sequence-specific manner, is a post-transcriptional gene silencing mechanism. In this study, small-interfering RNA （siRNA） specific for the li gene was transfected into DCs, and the anti-tumor immunity of li-silenced DCs was assessed. Methods The silencing effect of siRNA was evaluated by Western blotting and real-time PCR analyses. In vitro cytotoxic activity of T cells was evaluated using a Cytotox 96 non-radioactive cytotoxicity assay kit. The time to tumor onset and the tumor volumes were used as reliable indices to assess the anti-tumor immunity in vivo. To further examine the mechanisms underlying the anti-tumor immunity, flow cytometry analysis was used. Results The li expression of DCs was significantly reduced after li siRNA transfection. Significant in vitro anti-tumor ability was exhibited when DCs were co-transfected with li siRNA plus endogenous tumor antigen （P 〈0.05）. Furthermore tumor growth was greatly inhibited when mice were immunized with DCs transfected with li siRNA plus tumor antigen prior to or subsequent to tumor implantation. Flow cytometry analysis in vitro and in vivo indicated that both CD4^= and CD8^＋ T cells were significantly activated in the li siRNA group （P 〈0.05）. Conclusion Silencing of the li gene of DCs may offer a potential approach to enhance DC-based anti-tumor immunity.
基金This work was supported by Chinese Academy of Sciences(KSCX2-YW-R-42)National Natural Science Foundation of China(30771972 and 30700287)+1 种基金Ministry of Science and Technology of China(2006CB504304,2006CB910901,and 2009CB918900)Ministry of Education,Culture,Sports,Science and Technology(MEXT)of Japan.
文摘Interleukin(IL)-4 is a crucial cytokine in tumor immunology.In the initial murine experiments,IL-4 exhibited potent anti-tumor ability.Tumors genetically modified to produce IL-4 were rejected,while parental tumors grew progressively.Mice rejected IL-4-producing tumors got long-lasting anti-tumor immunity.The comparative study showed that IL-4 induced the most effective immune response among several cytokines in both prophylactic and therapeutic models.All of these indicate IL-4 has strong potential as a tumor therapy agent.However,contrary evidence indeed exists,and is becoming more and more abundant which shows IL-4 is a tumor-promoting molecule.IL-4 amounts are usually elevated in human cancer patients.IL-4 knockout mice are more resistant to tumor challenge than IL-4 competent mice.Furthermore,tumor cells of various histological origins often express increased levels of IL-4 receptor in comparison to their normal counterparts.By carefully examining presently available data,we found the effects of IL-4 in tumor immunity are closely related to its sources,expressing time and dose,as well as the molecular and cellular environments.In this mini-review,we concentrate on illustrating the paradoxical roles and underlying mechanisms of IL-4 in tumor immunity and try to understand how one molecule has opposite effects.
基金a Grant-in-Aid for High Technology Research(No.09309011)from the Ministry of Education,Science,Sports,and Culture,Japanand by a Grant-in-Aid for AIDS research from the Ministry of Health,Labor and Welfare,Japan.
文摘A dendritic cell(DC)vaccine strategy has been developed as a new cancer immunotherapy,but the goal of complete tumor eradication has not yet been achieved.We have previously shown that baculoviruses potently infect DCs and induce antitumor immunity against hepatomas in a mouse model.Baculovirus-infected,bone marrow-derived DCs(BMDCs)display increased surface expression of costimulatory molecules,such as CD80,CD86 and major histocompatibility complex(MHC)classes I and II,and secrete interferons and other proinflammatory cytokines.In this study,we evaluated the induction of antitumor immunity in mice by baculovirus-infected BMDCs against lung cancer and melanoma.After treatment with baculovirus-infected BMDCs,murine lung tumors caused by Lewis lung carcinoma(LLC)cells were significantly reduced in size,and the survival of the mice was improved.In addition,experiments using a melanoma mouse model showed that baculovirus-infected BMDCs inhibited tumor growth and improved survival compared with controls.Serum alanine aminotransferase(ALT),aspartate aminotransferase(AST)and creatinine levels remained normal in baculovirus-infected BMDC-treated mice.Our findings show that baculovirus-infected DCs induce antitumor immunity and pave the way for the use of this technique as an effective tool for DC immunotherapy against malignancies.
基金funded by the Central to guide local scientific and Technological Development(ZYYDDFFZZJ-1)Natural Science Foundation of Gansu Province,China(No.18JR3RA052)+2 种基金Lanzhou Talent Innovation and Entrepreneurship Project Task Contract(No.2016-RC-56)Gansu Da Vinci Robot High-End Diagnosis and Treatment Team Construction Project,and Gansu Provincial Youth Science and Technology Fund Program(20JR10RA415)National Key Research and Development Program(No.2018YFC1311500).
文摘B and T-lymphocyte attenuator(BTLA)plays an immunosuppressive role by inhibiting T-and B-cell functions.BTLA is associated with a variety of diseases,especially cancer immunity.However,the function of BTLA in various cancers and its clinical prognostic value have still not been comprehensively analyzed.This study aimed to identify the relationship between BTLA and cancer from the perspectives of differences in BTLA expression,its clinical value,immune infiltration,and the correlation with immune-related genes in various cancers.Data regarding mRNA expression,miRNA expression,lncRNA expression,and clinical data of patients of 33 existing cancers were collected from the TCGA database.Target miRNA of BTLA and the lncRNA that interacts with the target miRNA were obtained from the StarBase database.Based on bioinformatics analysis methods,the relationship between various types of cancers and BTLA was thoroughly investigated,and a competing endogenous RNA network of BTLA,target miRNA,and interacting lncRNA was constructed.The Kaplan-Meier(KM)prognostic analysis of BTLA and target miRNA(has-miR-137)in various types of cancers was completed using the KM plotter.BTLA expression varied in different cancers,with statistical significance in nine cancer types.KM plotter to analyze the overall survival(OS)and regression-free survival prognosis of cancer patients revealed that the BTLA expression was statistically different in the OS of 11 types of cancers out of 21 types of cancers;the OS of 8 type of cancers was also statistically different.Correlation analysis of tumor immune genes revealed a positive correlation of BTLA expression with immunosuppressive gene(CTLA4 and PDCD1)expression.Gene Set Enrichment Analysis showed that BTLA and its co-expressed genes mainly act through biological processes and pathways,including immune response regulation,cell surface receptor signaling pathway,antigen binding,antigen receptor-mediated signaling pathway,and leukocyte migration.BTLA has the potential as a prognostic marker for CLL,COAD,NSCLC,and OV and a diagnostic marker for CLL,COAD,and KIRC.BTLA has a close and complex relationship with the occurrence and development of tumors,and cancer immunotherapy for BTLA is worthy of further analysis.
基金National Natural Science Foundation of China(No.U1903125,82073799)Natural Science Foundation of Hunan province in China(No.2021JJ20084)the Science and Technology Innovation Program of Hunan Province(No.2021RC3020)。
文摘Immunotherapy has efficiently revolutionized the treatment of human neoplastic diseases.However,the overall responsive rate of current immunotherapy is still unsatisfactory,benefiting only a small proportion of patients.Therefore,significant attention has been paid to the modulation of tumor microenvironment(TME)for the enhancement of immunotherapy.Interestingly,recent studies have shown that cyclic GMP-AMP synthasestimulator of interferon gene(cGAS-STING)was initially found as an innate immune sensor to recognize cytoplasmic DNA(such as bacterial,viral,micronuclei,and mitochondrial).It is a promising signaling pathway to activate antitumor immune responses via type I interferon production.Notably,Mn^(2+)was found to be a critical molecule to sensitize the activation of the cGAS-STING pathway for better immunotherapy.This activation led to the development of Mn^(2+)-based strategies for tumor immunotherapy via the activation of the cGAS-STING pathway.In this critical review,we aimed to summarize the recent progress of this field,focusing on the following three aspects.First,we briefly introduced the signaling pathway of cGAS-STING activation,and its regulation effect on the antitumor immunity cycle has been discussed.Along with this,several agonists of the cGAS-STING pathway were introduced with their potential as immunotherapeutic drugs.Then,the basic biological functions of Mn^(2+)have been illustrated,focusing on its critical roles in the cGAS-STING pathway activation.Next,we systematically reviewed the Mn^(2+)-based strategies for tumor immunotherapy,which can be classified by the methods based on Mn^(2+)alone or Mn^(2+)combined with other therapeutic modalities.We finally speculated the future perspectives of the field and provided rational suggestions to develop better Mn^(2+)-based therapeutics.
基金supported by the Research fund of Anhui Institute of Translational Medicine (No. 2021zhyx-C62)。
文摘Objective: The interplay between chemokine C-X-C motif ligand 12(CXCL12) and its specific receptors is known to trigger various signaling pathways, contributing to tumor proliferation and metastasis. Consequently,targeting this signaling axis has emerged as a potential strategy in cancer therapy. However, the precise role of CXCL12 in clinical therapy, especially in immunotherapy for bladder cancer(BCa), remains poorly elucidated.Methods: We gathered multiple omics data from public databases to unveil the clinical relevance and tumor immune landscape associated with CXCL12 in BCa patients. Univariate and multivariate Cox regression analyses were employed to assess the independent prognostic significance of CXCL12 expression and formulate a nomogram. The expression of CXCL12 in BCa cell lines and clinical tissue samples was validated using enzymelinked immunosorbent assays(ELISA) and immunohistochemistry(IHC).Results: While transcriptional expression of CXCL12 exhibited a decrease in nearly all tumor tissues, CXCL12 methylation expression was notably increased in BCa tissues. Single-cell RNA analysis highlighted tissue stem cells and endothelial cells as the primary sources expressing CXCL12. Abnormal CXCL12 expression, based on transcriptional and methylation levels, correlated with various clinical characteristics in BCa patients. Functional analysis indicated enrichment of CXCL12 and its co-expression genes in immune regulation and cell adhesion. The immune landscape analysis unveiled a significant association between CXCL12 expression and M2 macrophages(CD163~+ cells) in BCa tissues. Notably, CXCL12 expression emerged as a potential predictor of immunotherapy response and chemotherapy drug sensitivity in BCa patients.Conclusions: Taken together, these findings suggest aberrant production of CXCL12 in BCa tissues,potentially influencing the treatment responses of affected individuals.
