Epigenomic imbalance drives abnormal transcriptional processes,promoting the onset and progression of cancer.Although defective gene regulation generally affects carcinogenesis and tumor suppression networks,tumor imm...Epigenomic imbalance drives abnormal transcriptional processes,promoting the onset and progression of cancer.Although defective gene regulation generally affects carcinogenesis and tumor suppression networks,tumor immunogenicity and immune cells involved in antitumor responses may also be affected by epigenomic changes,which may have significant implications for the development and application of epigenetic therapy,cancer immunotherapy,and their combinations.Herein,we focus on the impact of epigenetic regulation on tumor immune cell function and the role of key abnormal epigenetic processes,DNA methylation,histone post-translational modification,and chromatin structure in tumor immunogenicity,and introduce these epigenetic research methods.We emphasize the value of small-molecule inhibitors of epigenetic modulators in enhancing antitumor immune responses and discuss the challenges of developing treatment plans that combine epigenetic therapy and immuno-therapy through the complex interaction between cancer epigenetics and cancer immunology.展开更多
Programmed cell death ligand-1(PD-L1)is a T cell inhibitory immune checkpoint molecule that interacts with programmed cell death-1(PD-1)to promote immune escape of tumor cells.Compared with antibody therapies,small mo...Programmed cell death ligand-1(PD-L1)is a T cell inhibitory immune checkpoint molecule that interacts with programmed cell death-1(PD-1)to promote immune escape of tumor cells.Compared with antibody therapies,small molecule drugs show better prospects due to their advantages such as higher bioavailability,better tissue penetration,and reduced risk of immunogenicity.Here,we found that the small molecule demethylzeylasteral(Dem)can significantly downregulate the expression of PD-L1 in colorectal cancer cells and enhance the killing effect of T cells on tumor cells.Mechanistically,Dem binds to the deubiquitinating enzyme USP22 and promotes its degradation,resulting in increased ubiquitination and degradation of PD-L1 through the proteasome pathway.In addition,Dem increased the activity of cytotoxic T cells and reduced the number of myeloid-derived suppressor cells(MDSCs)and regulatory T cells(Tregs)in tumor-infiltrating lymphocytes(TILs),thereby activating the tumor immune microenvironment and inhibiting the growth of subcutaneous MC38 tumors in C57BL/6 mice.Moreover,we also found that the combination of Dem and CTLA4 antibodies can further improve the efficacy of antitumor therapy.Our study reveals the mechanism by which Dem promotes PD-L1 degradation and suggests that the combination of Dem and CTLA4 antibodies may improve the efficacy of immunotherapy.展开更多
The preferable antigen delivery profile accompanied by sufficient adjuvants favors vaccine efficiency.Mitochondria,which feature prokaryotic characteristics and contain various damage-associated molecular patterns(DAM...The preferable antigen delivery profile accompanied by sufficient adjuvants favors vaccine efficiency.Mitochondria,which feature prokaryotic characteristics and contain various damage-associated molecular patterns(DAMPs),are easily taken up by phagocytes and simultaneously activate innate immunity.In the current study,we established a mitochondria engineering platform for generating antigen-enriched mitochondria as cancer vaccine.Ovalbumin(OVA)and tyrosinase-related protein 2(TRP2)were used as model antigens to synthesize fusion proteins with mitochondria-localized signal peptides.The lentiviral infection system was then employed to produce mitochondrial vaccines containing either OVA or TRP2.Engineered OVA-and TRP2-containing mitochondria(OVA-MITO and TRP2-MITO)were extracted and evaluated as potential cancer vaccines.Impressively,the engineered mitochondria vaccine demonstrated efficient antitumor effects when used as both prophylactic and therapeutic vaccines in murine tumor models.Mechanistically,OVA-MITO and TRP2-MITO potently recruited and activated dendritic cells(DCs)and induced a tumor-specific cell-mediated immunity.Moreover,DC activation by mitochondria vaccine critically involves TLR2 pathway and its lipid agonist,namely,cardiolipin derived from the mitochondrial membrane.The results demonstrated that engineered mitochondria are natively well-orchestrated carriers full of immune stimulants for antigen delivery,which could preferably target local dendritic cells and exert strong adaptive cellular immunity.This proof-of-concept study established a universal platform for vaccine construction with engineered mitochondria bearing alterable antigens for cancers as well as other diseases.展开更多
Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10(PTEN)gene in cancer cells may be associated with immunosuppressive tumor microenvironment(TME)and poor respon...Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10(PTEN)gene in cancer cells may be associated with immunosuppressive tumor microenvironment(TME)and poor response to immune checkpoint blockade(ICB)therapy.Therefore,efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy.Here,we screened an adeno-associated virus(AAV)capsid for efficient PTEN gene delivery into B16F10 tumor cells.We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death(ICD)and increasing immune cell infiltration.Moreover,we developed an anti-PD-1 loaded phospholipid-based phase separation gel(PPSG),which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo.In order to effectively inhibit the recurrence of melanoma,we further applied a triple therapy based on AAV6-PTEN,PPSG^(@anti-PD-1)and CpG,and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory,which completely rejected tumor recurrence.We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.展开更多
Exosomes （EXO） derived from dendritic cells （DC） and tumor cells have been used to stimulate antitumor immune responses in animal models and in clinical trials. However, there has been no side-by-side comparison o...Exosomes （EXO） derived from dendritic cells （DC） and tumor cells have been used to stimulate antitumor immune responses in animal models and in clinical trials. However, there has been no side-by-side comparison of the stimulatory efficiency of the antitumor immune responses induced by these two commonly used EXO vaccines. In this study, we selected to study the phenotype characteristics of EXO derived from a transfected EG7 tumor cells expressing ovalbumin （OVA） and OVA-pulsed DC by flow cytometry. We compared the stimulatory effect in induction of OVA-specific immune responses between these two types of EXO. We found that OVA protein-pulsed DCOVA-derived EXO （EXODC） can more efficiently stimulate naive OVA-specific CD8^＋ T cell proliferation and differentiation into cytotoxic T lymphocytes in vivo, and induce more efficient antitumor immunity than EG7 tumor cell-derived EXO （EXOEG7）. In addition, we elucidated the important role of the host DC in EXO vaccines that the stimulatory effect of EXO is delivered to T cell responses by the host DC. Therefore, DC-derived EXO may represent a more effective EXO-based vaccine in induction of antitumor immunity. Cellular ＆ Molecular Immunology. 2006;3（3）：205-211.展开更多
T cells secrete bioactive exosomes(EXO),but the potential immunoregulatory effect of T-cell EXO is largely unknown.In this study,we generated activated ovalbumin(OVA)-specific CD4^(+) T cells in vitro via coculture of...T cells secrete bioactive exosomes(EXO),but the potential immunoregulatory effect of T-cell EXO is largely unknown.In this study,we generated activated ovalbumin(OVA)-specific CD4^(+) T cells in vitro via coculture of OVA-pulsed dendritic cells(DC_(OVA))with naive CD4^(+) T cells derived from OVA-specific T-cell receptor(TCR)transgenic OTII mice.CD4^(+) T-cell EXO were then purified from the CD4^(+) T-cell culture supernatants by differential ultracentrifugation.CD4^(+) T-cell EXO exhibited the‘saucer’shape that is characteristic of EXO with a diameter between 50 and 100 nm,as assessed by electron microscopy,and contained the EXO-associated proteins LAMP-1,TCR and lymphocyte function associated antigen-1(LFA-1),as determined by western blot.Flow cytometric analysis showed that CD4^(+) T-cell EXO expressed CD4^(+) T-cell markers(CD4,TCR,LFA-1,CD25 and Fas ligand),but to a lesser extent than CD4^(+) T cells.We demonstrated that DC_(OVA) took up CD4^(+) T-cell EXO via peptide/major histocompatibility complex(pMHC)II/TCR and CD54/LFA-1 interactions.OVA-specific CD4^(+) T-cell EXO from OTII mice,but not ConA-stimulated polyclonal CD4^(+) T-cell EXO from wild-type C57BL/6 mice inhibited DC_(OVA)-stimulated in vitro CD4^(+) T-cell proliferation and in vivo CD81 cytotoxic T lymphocyte(CTL)responses and antitumor immunity against OVA-expressing B16 melanoma BL6-10OVA cells.In addition,EXO derived from a T-cell hybridoma cell line,MF72.2D9,expressing an OVA-specific CD4^(+) TCR,had a similar inhibitory effect as OTII CD4^(+) T-cell EXO on CTL-mediated antitumor immunity.Taken together,our data indicate that antigen-specific T-cell EXO may serve as a new type of immunosuppressive reagent for use in transplant rejection and treatment of autoimmune diseases.展开更多
The bile acid-responsive G-protein-coupled receptor TGR5 is expressed in monocytes and macrophages,and plays a critical role in regulating inflammatory response.Our previous work has shown its role in promoting the pr...The bile acid-responsive G-protein-coupled receptor TGR5 is expressed in monocytes and macrophages,and plays a critical role in regulating inflammatory response.Our previous work has shown its role in promoting the progression of non-small cell lung cancer(NSCLC),yet the mechanism remains unclear.Here,using Tgr5-knockout mice,we show that TGR5 is required for M2 polarization of tumorassociated macrophages(TAMs)and suppresses antitumor immunity in NSCLC via involving TAMsmediated CD8+T cell suppression.Mechanistically,we demonstrate that TGR5 promotes TAMs into protumorigenic M2-like phenotypes via activating c AMP-STAT3/STAT6 signaling.Induction of c AMP production restores M2-like phenotypes in TGR5-deficient macrophages.In NSCLC tissues from human patients,the expression of TGR5 is associated with the infiltration of TAMs.The co-expression of TGR5 and high TAMs infiltration are associated with the prognosis and overall survival of NSCLC patients.Together,this study provides molecular mechanisms for the protumor function of TGR5 in NSCLC,highlighting its potential as a target for TAMs-centric immunotherapy in NSCLC.展开更多
Chronic inflammation promotes tumor development,progression,and metastatic dissemination and causes treatment resistance.The accumulation of genetic alterations and loss of normal cellular regulatory processes are not...Chronic inflammation promotes tumor development,progression,and metastatic dissemination and causes treatment resistance.The accumulation of genetic alterations and loss of normal cellular regulatory processes are not only associated with cancer growth and progression but also result in the expression of tumor-specific and tumor-associated antigens that may activate antitumor immunity.This antagonism between inflammation and immunity and the ability of cancer cells to avoid immune detection affect the course of cancer development and treatment outcomes.While inflammation,particularly acute inflammation,supports T-cell priming,activation,and infiltration into infected tissues,chronic inflammation is mostly immunosuppressive.However,the main mechanisms that dictate the outcome of the inflammation-immunity interplay are not well understood.Recent data suggest that inflammation triggers epigenetic alterations in cancer cells and components of the tumor microenvironment.These alterations can affect and modulate numerous aspects of cancer development,including tumor growth,the metabolic state,metastatic spread,immune escape,and immunosuppressive or immunosupportive leukocyte generation.In this review,we discuss the role of inflammation in initiating epigenetic alterations in immune cells,cancer-associated fibroblasts,and cancer cells and suggest how and when epigenetic interventions can be combined with immunotherapies to improve therapeutic outcomes.展开更多
Stimulator of interferon genes(STING)is an adaptor protein that is critical for effective innate antiviral and antitumor immunity.The activity of STING is heavily regulated by protein ubiquitination,which is fine-tune...Stimulator of interferon genes(STING)is an adaptor protein that is critical for effective innate antiviral and antitumor immunity.The activity of STING is heavily regulated by protein ubiquitination,which is fine-tuned by both E3 ubiquitin ligases and deubiquitinases.Here,we report that the deubiquitinase OTUD5 interacts with STING,cleaves its K48-linked polyubiquitin chains,and promotes its stability.Consistently,knockout of OTUD5 resulted in faster turnover of STING and subsequently impaired type I IFN signaling following cytosolic DNA stimulation.More importantly,Lyz2-Cre Otud5^(fl/Y) mice and CD11-Cre Otud5^(fl/Y) mice showed more susceptibility to herpes simplex virus type 1(HSV-1)infection and faster development of melanomas than their corresponding control littermates,indicating that OTUD5 is indispensable for STING-mediated antiviral and antitumor immunity.Our data suggest that OTUD5 is a novel checkpoint in the cGAS-STING cytosolic DNA sensing pathway.展开更多
Dendritic cells （DCs） are the most potent antigen-presenting cells （APCs） for the initiation of antigen （Ag）-specific immune responses. In most studies, mature DCs are generated from bone marrow cells or periphe...Dendritic cells （DCs） are the most potent antigen-presenting cells （APCs） for the initiation of antigen （Ag）-specific immune responses. In most studies, mature DCs are generated from bone marrow cells or peripheral monocytes; in either case, the harvested cells are then cultured in medium containing recombinant GM-CSF, IL-4 and TNF-α for 7-10 days and stimulated with lipopolysaccharide （LPS）. However, this approach is time-consuming and expensive. There is another less cost approach of using immobilized DC cell lines, which can easily grow in the medium. A disadvantage with the immobilized DC cell lines, however, is that they are immature DCs and lack expression of MHC class Ⅱ and costimulatory CD40 and CD80 molecules. This, therefore, limits their capacity for inducing efficient antitumor immunity. In the current study, we investigated the possible efficacy of various stimuli （IL-1β, IFN-γ, TNF-α CpG and LPS） in converting the immature dendritic cell line DC2.4 to mature DCs. Our findings were quite interesting since we demonstrated for the first time that IFN-γ was able to stimulate the maturation of DC2.4 cells. The IFN-γ-activated ovalbumin （OVA）-pulsed DC2.4 cells have capacity to upregulate MHC class Ⅱ, CD40, CD80 and CCR7, and to more efficiently stimulate in vitro and in vivo OVA-specific CD8^＋ T cell responses and antitumor immunity. Therefore, IFN-γ-activated immortal DC2.4 ceils may prove to be useful in the study of DC biology and antitumor immunity.展开更多
The continuing challenges that limit effectiveness of tumor therapeutic vaccines were high heterogeneity of tumor immunogenicity, low bioactivity of antigens, as well as insufficient lymph nodes(LNs) drainage of antig...The continuing challenges that limit effectiveness of tumor therapeutic vaccines were high heterogeneity of tumor immunogenicity, low bioactivity of antigens, as well as insufficient lymph nodes(LNs) drainage of antigens and adjuvants. Transportation of in situ neoantigens and adjuvants to LNs may be an effective approach to solve the abovementioned problems. Therefore, an FA-TSL/AuNCs/SV nanoplatform was constructed by integrating simvastatin(SV) adjuvant loaded Au nanocages(AuNCs)as cores(AuNCs/SV) and folic acid modified thermal-sensitive liposomes(FA-TSL) as shells to enhance de novo antitumor immunity. After accumulation in tumor guided by FA, AuNCs mediated photothermal therapy(PTT) induced the release of tumor-derived protein antigens(TDPAs) and the shedding of FATSL. Exposed AuNCs/SV soon captured TDPAs to form in situ recombinant vaccine(AuNCs/SV/TDPAs). Subsequently, AuNCs/SV/TDPAs could efficiently transport to draining LNs owing to the hyperthermia induced vasodilation effect and small particle size, achieving co-delivery of antigens and adjuvant for initiation of specific T cell response. In melanoma bearing mice, FA-TSL/AuNCs/SV and laser irradiation effectively ablated primary tumor, against metastatic tumors and induced immunological memory. This approach served a hyperthermia enhanced platform drainage to enable robust personalized cancer vaccination.展开更多
CFTR,a chloride channel and ion channel regulator studied mostly in epithelial cells,has been reported to participate in immune regulation and likely affect the risk of cancer development.However,little is known about...CFTR,a chloride channel and ion channel regulator studied mostly in epithelial cells,has been reported to participate in immune regulation and likely affect the risk of cancer development.However,little is known about the effects of CFTR on the differentiation and function ofγδT cells.In this study,we observed that CFTR was functionally expressed on the cell surface ofγδT cells.Genetic deletion and pharmacological inhibition of CFTR both increased IFN-γrelease by peripheralγδT cells and potentiated the cytolytic activity of these cells against tumor cells both in vitro and in vivo.Interestingly,the molecular mechanisms underlying the regulation ofγδT cell IFN-γproduction by CFTR were either TCR dependent or related to Ca^(2+)influx.CFTR was recruited to TCR immunological synapses and attenuated Lck-P38 MAPK-c-Jun signaling.In addition,CFTR was found to modulate TCR-induced Ca^(2+)influx and membrane potential(Vm)-induced Ca^(2+)influx and subsequently regulate the calcineurin-NFATc1 signaling pathway inγδT cells.Thus,CFTR serves as a negative regulator of IFN-γproduction inγδT cells and the function of these cells in antitumor immunity.Our investigation suggests that modification of the CFTR activity ofγδT cells may be a potential immunotherapeutic strategy for cancer.展开更多
Aberrant expression of Myc is one of the most common oncogenic events in human cancers.Scores of Myc inhibitors are currently under development for treating Myc-driven cancers.In addition to directly targeting tumor c...Aberrant expression of Myc is one of the most common oncogenic events in human cancers.Scores of Myc inhibitors are currently under development for treating Myc-driven cancers.In addition to directly targeting tumor cells,Myc inhibition has been shown to modulate the tumor microenvironment to promote tumor regression.However,the effect of Myc inhibition on immune cells in the tumor microenvironment remains poorly understood.Here,we show that the adaptive immune system plays a vital role in the antitumor effect of pharmacologic inhibition of Myc.Combining genetic and pharmacologic approaches,we found that Myc inhibition enhanced CD8 T cell function by suppressing the homeostasis of regulatory T(Treg)cells and the differentiation of resting Treg(rTreg)cells to activated Treg(aTreg)cells in tumors.Importantly,we demonstrated that different Myc expression levels confer differential sensitivity of T cell subsets to pharmacologic inhibition of Myc.Although ablation of the Myc gene has been shown to suppress CD8 T cell function,Treg cells,which express much less Myc protein than CD8 T cells,are more sensitive to Myc inhibitors.The differential sensitivity of CD8 T and Treg cells to Myc inhibitors resulted in enhanced CD8 T cell function upon Myc inhibition.Our findings revealed that Myc inhibitors can induce an antitumor immune response during tumor progression.展开更多
This study aimed to investigate the role of long non-coding RNA maternally expressed gene 3(lncRNA MEG3)in chemosensitivity of osteosarcoma(OS),and to reveal the possible underlying mechanisms.In this study,we found t...This study aimed to investigate the role of long non-coding RNA maternally expressed gene 3(lncRNA MEG3)in chemosensitivity of osteosarcoma(OS),and to reveal the possible underlying mechanisms.In this study,we found that the expression of lncRNA MEG3 was significantly lower in OS tissues and cell lines.Furthermore,lncRNA MEG3 overexpression enhanced chemosensitivity of OS by inhibiting cell proliferation,migration,autophagy,and promoting antitumor immunity.LncRNA MEG3 functioned as miR-21-5 sponge to regulate p53 expression in OS.Mechanically,lncRNA MEG3 promoted OS chemosensitivity by regulating antitumor immunity via miR-21-5p/p53 pathway and autophagy.Collectively,this study provided the evidence that lncRNA MEG3 might be a promising therapeutic target for OS chemoresistance.展开更多
To determine whether squamous cell carcin-oma antigen recognized by human T cell 3(SART3)gene can induce antitumor immunity against tumor cells which express the gene,we constructed mouse tumor cells expressing human ...To determine whether squamous cell carcin-oma antigen recognized by human T cell 3(SART3)gene can induce antitumor immunity against tumor cells which express the gene,we constructed mouse tumor cells expressing human SART3(LM8-SART3)and carried out experiments in vitro/vivo.After subcutaneous injection with SART3 gene vaccine,cytotoxic T lymphocyte(CTL)activity in vitro was measured using Cell Counting Kit-8.As for the in vivo part,C3H mice were divided into several groups.One group was challenged with tumor cells after immunity.Another group was treated with the vaccine after tumor implantation.It was found that human SART3 DNA vaccine can elicit a specific CTL reaction from the mouse splenocytes.After vaccination,tumor occurrence and tumor growth speed was reduced.The vaccine also shows activity in tumor treatment.We con-clude that the human SART3 DNA vaccine can induce antitumor ability against tumor cells expressing human SART3(LM8-SART3)in vitro/vivo which may provide new possibilities in antitumor therapy.展开更多
Immunotherapy is revolutionizing the clinical management of cancer patients by modulating T cells and natural killer cells.Dendritic cells(DCs)have the capacity to orchestrate the expansion and function of these effec...Immunotherapy is revolutionizing the clinical management of cancer patients by modulating T cells and natural killer cells.Dendritic cells(DCs)have the capacity to orchestrate the expansion and function of these effector cells both in lymphoid and non-lymphoid tissues of cancer patients.Distinct subtypes of DCs have various capacities to prime and activate different T cell responses.Here,we review conventional type 1 dendritic cells(cDC1s)and their crucial role in protective anti-tumor immunity.Targeting cDC1s as a cancer vaccine against the development of hepatocellular carcinoma will be discussed.展开更多
The adaptive arm of the immune system is crucial for appropriate antitumor immune responses.It is generally accepted that clusters of differentiation 4^(+)(CD4^(+))T cells,which mediate T helper(Th)1 immunity(type 1 i...The adaptive arm of the immune system is crucial for appropriate antitumor immune responses.It is generally accepted that clusters of differentiation 4^(+)(CD4^(+))T cells,which mediate T helper(Th)1 immunity(type 1 immunity),are the primary Th cell subtype associated with tumor elimination.In this review,we discuss evidence showing that antitumor immunity and better prognosis can be associated with distinct Th cell subtypes in experimental mouse models and humans,with a focus on Th2 cells.The aim of this review is to provide an overview and understanding of the mechanisms associated with different tumor outcomes in the face of immune responses by focusing on the(1)site of tumor development,(2)tumor properties(i.e.,tumor metabolism and cytokine receptor expression),and(3)type of immune response that the tumor initially escaped.Therefore,we discuss how low-tolerance organs,such as lungs and brains,might benefit from a less tissue-destructive immune response mediated by Th2 cells.In addition,Th2 cells antitumor effects can be independent of CD8^(+)T cells,which would circumvent some of the immune escape mechanisms that tumor cells possess,like low expression of major histocompatibility-I(MHC-I).Finally,this review aims to stimulate further studies on the role of Th2 cells in antitumor immunity and briefly discusses emerging treatment options.展开更多
A novel approach for a dentritic cells (DCs) based tumor vaccine was developed for the formation of hybrid engineered J558 after fusion with DCs. To make the hybrid tumor vaccine generate more efficient specific CT...A novel approach for a dentritic cells (DCs) based tumor vaccine was developed for the formation of hybrid engineered J558 after fusion with DCs. To make the hybrid tumor vaccine generate more efficient specific CTL cytotoxicity against wild type tumor cells, we genetically engineered tumor cells with mIL 12 gene prior to the cell fusion. mIL 12 was detected at 870±60 pg/(10 5 cells/ml) in the culture supernatants and the fusion ratio was about 30 % by the co focal microscopic analysis. Vaccination of mice with DCs fused with engineered J558 induced more efficient tumor specific CTL cytotoxicity against wild type tumor cells in vitro and with efficient antitumor immunity in vivo . These results suggest that this approach of using DCs fused with engineered tumor cells could be applied in clinical settings of DCs based cancer vaccines.展开更多
Vaccinia melanoma oncolysate (VMO) prepared by infecting B16F10 melanoma cells with recombinant vaccinia virus encoding murine GMCSF gene was tested for its therapeutic effect on the preestablished melanoma. C57BL/6 m...Vaccinia melanoma oncolysate (VMO) prepared by infecting B16F10 melanoma cells with recombinant vaccinia virus encoding murine GMCSF gene was tested for its therapeutic effect on the preestablished melanoma. C57BL/6 mice were inoculated s.c. with 1×105 B16F10 melanoma cells and received s.c. administration with VMO prepared with GMCSF gene encoded vaccinia virus(GMCSFVMO), VMO prepared with thymidine kinase genedeficient vaccinia virus(TKVMO), B16F10 melanoma oncolysate(BMO), or PBS 3 days after tumor inoculation. The same treatment was bolstered one week later. The results demonstrated that GMCSFVMO treatment significantly inhibited the growth of subcutaneous tumor and prolonged the survival period of tumorbearing mice. Further study elucidated that cytotoxicity of PBL and splenocytes towards B16F10 increased obviously after treatment with GMCSFVMO, but NK activity remained unchanged. These results suggest that the tumor oncolysate vaccine prepared with GMCSF geneencoded vaccinia virus might exert potent therapeutic effect on the preestablished tumor through the efficient induction of specific antitumor immune response of the host.展开更多
To analyze the antitumor potential and mechanism of action of simultaneous Newcastle disease virus （NDV） hemagglutinin-neuraminidase（HN） and human interleukin 18（hIL-18） gene transfer in C57BL/6 mice with H22 he...To analyze the antitumor potential and mechanism of action of simultaneous Newcastle disease virus （NDV） hemagglutinin-neuraminidase（HN） and human interleukin 18（hIL-18） gene transfer in C57BL/6 mice with H22 hepatoma,the mouse model with H22 hepatoma was established in C57BL/6 mice, and the antitumor effects of the combined application of NDV HN and hIL-18 were evaluated in vivo. The results show that the growth of established tumors in mice immunized with adenovirus（Ad）-HN in conjunction with Ad-hIL-18 was significantly inhibited compared with that in mice immunized with Ad-HN, Ad-hIL-18 alone, or the empty vector（Ad-mock）. Furthermore, the immunization of mice with Ad-HN in conjunction with Ad-hIL-18 elicited strong natural killer activity and H22 tumor-specific cytotoxic T lymphocyte（CTL） responses in vivo. In addition, T cells from the lymph nodes of mice immunized with Ad-hIL-18 or Ad-HN＋Ad-hIL-18 secreted high levels of the Th1 cytokine IL-2 and interferon-γ （IFN-γ）, indicating that the regression of tumor cells is related to a Th1-type dominant immune response. These results demonstrate that vaccination with NDV HN together with hIL-18 may be a novel and powerful strategy for cancer immunotherapy.展开更多
基金supported by the Startup Foundation for Junior Faculty,Nankai University(Grant No.:63191439)the National Natural Science Foundation of China(Grant Nos.:32100418,3210040345)+1 种基金The Health Commission Foundation of China(Grant No.:2018ZX10712001-017)the Chongqing Medical College Natural Fund(Grant Nos.:ygz2019302 and ygz2019305).
文摘Epigenomic imbalance drives abnormal transcriptional processes,promoting the onset and progression of cancer.Although defective gene regulation generally affects carcinogenesis and tumor suppression networks,tumor immunogenicity and immune cells involved in antitumor responses may also be affected by epigenomic changes,which may have significant implications for the development and application of epigenetic therapy,cancer immunotherapy,and their combinations.Herein,we focus on the impact of epigenetic regulation on tumor immune cell function and the role of key abnormal epigenetic processes,DNA methylation,histone post-translational modification,and chromatin structure in tumor immunogenicity,and introduce these epigenetic research methods.We emphasize the value of small-molecule inhibitors of epigenetic modulators in enhancing antitumor immune responses and discuss the challenges of developing treatment plans that combine epigenetic therapy and immuno-therapy through the complex interaction between cancer epigenetics and cancer immunology.
基金funded by the National Key Research and Development Program of China(2022YFC3502000)National Natural Science Foundation of China(Nos.82141203,82374086,and 82104459)+3 种基金Shanghai Municipal Science and Technology Major Project(ZD2021CY001,China)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTDD-202004,China)Science and Technology Commission of Shanghai Municipality(20YF1458700,China)Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine(2023YZZ02,China)。
文摘Programmed cell death ligand-1(PD-L1)is a T cell inhibitory immune checkpoint molecule that interacts with programmed cell death-1(PD-1)to promote immune escape of tumor cells.Compared with antibody therapies,small molecule drugs show better prospects due to their advantages such as higher bioavailability,better tissue penetration,and reduced risk of immunogenicity.Here,we found that the small molecule demethylzeylasteral(Dem)can significantly downregulate the expression of PD-L1 in colorectal cancer cells and enhance the killing effect of T cells on tumor cells.Mechanistically,Dem binds to the deubiquitinating enzyme USP22 and promotes its degradation,resulting in increased ubiquitination and degradation of PD-L1 through the proteasome pathway.In addition,Dem increased the activity of cytotoxic T cells and reduced the number of myeloid-derived suppressor cells(MDSCs)and regulatory T cells(Tregs)in tumor-infiltrating lymphocytes(TILs),thereby activating the tumor immune microenvironment and inhibiting the growth of subcutaneous MC38 tumors in C57BL/6 mice.Moreover,we also found that the combination of Dem and CTLA4 antibodies can further improve the efficacy of antitumor therapy.Our study reveals the mechanism by which Dem promotes PD-L1 degradation and suggests that the combination of Dem and CTLA4 antibodies may improve the efficacy of immunotherapy.
基金supported by the National Science Foundation for Excellent Young Scholars(32122052)National Natural Science Foundation Regional Innovation and Development(No.U19A2003)+1 种基金West China Hospital Postdoctoral Research and Development Fund(2023HXBH068)Guizhou Provincial Science and Technology Projects-ZK[2021]General 455.
文摘The preferable antigen delivery profile accompanied by sufficient adjuvants favors vaccine efficiency.Mitochondria,which feature prokaryotic characteristics and contain various damage-associated molecular patterns(DAMPs),are easily taken up by phagocytes and simultaneously activate innate immunity.In the current study,we established a mitochondria engineering platform for generating antigen-enriched mitochondria as cancer vaccine.Ovalbumin(OVA)and tyrosinase-related protein 2(TRP2)were used as model antigens to synthesize fusion proteins with mitochondria-localized signal peptides.The lentiviral infection system was then employed to produce mitochondrial vaccines containing either OVA or TRP2.Engineered OVA-and TRP2-containing mitochondria(OVA-MITO and TRP2-MITO)were extracted and evaluated as potential cancer vaccines.Impressively,the engineered mitochondria vaccine demonstrated efficient antitumor effects when used as both prophylactic and therapeutic vaccines in murine tumor models.Mechanistically,OVA-MITO and TRP2-MITO potently recruited and activated dendritic cells(DCs)and induced a tumor-specific cell-mediated immunity.Moreover,DC activation by mitochondria vaccine critically involves TLR2 pathway and its lipid agonist,namely,cardiolipin derived from the mitochondrial membrane.The results demonstrated that engineered mitochondria are natively well-orchestrated carriers full of immune stimulants for antigen delivery,which could preferably target local dendritic cells and exert strong adaptive cellular immunity.This proof-of-concept study established a universal platform for vaccine construction with engineered mitochondria bearing alterable antigens for cancers as well as other diseases.
基金This study was supported by National Natural Science Foundation of China(Grant Nos.81925036,China)the Key Research and Development Program of Science and Technology Department of Sichuan Province(Grant No.2020YFS0570,China)111 project(Grant No.B18035,China).
文摘Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10(PTEN)gene in cancer cells may be associated with immunosuppressive tumor microenvironment(TME)and poor response to immune checkpoint blockade(ICB)therapy.Therefore,efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy.Here,we screened an adeno-associated virus(AAV)capsid for efficient PTEN gene delivery into B16F10 tumor cells.We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death(ICD)and increasing immune cell infiltration.Moreover,we developed an anti-PD-1 loaded phospholipid-based phase separation gel(PPSG),which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo.In order to effectively inhibit the recurrence of melanoma,we further applied a triple therapy based on AAV6-PTEN,PPSG^(@anti-PD-1)and CpG,and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory,which completely rejected tumor recurrence.We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.
文摘Exosomes （EXO） derived from dendritic cells （DC） and tumor cells have been used to stimulate antitumor immune responses in animal models and in clinical trials. However, there has been no side-by-side comparison of the stimulatory efficiency of the antitumor immune responses induced by these two commonly used EXO vaccines. In this study, we selected to study the phenotype characteristics of EXO derived from a transfected EG7 tumor cells expressing ovalbumin （OVA） and OVA-pulsed DC by flow cytometry. We compared the stimulatory effect in induction of OVA-specific immune responses between these two types of EXO. We found that OVA protein-pulsed DCOVA-derived EXO （EXODC） can more efficiently stimulate naive OVA-specific CD8^＋ T cell proliferation and differentiation into cytotoxic T lymphocytes in vivo, and induce more efficient antitumor immunity than EG7 tumor cell-derived EXO （EXOEG7）. In addition, we elucidated the important role of the host DC in EXO vaccines that the stimulatory effect of EXO is delivered to T cell responses by the host DC. Therefore, DC-derived EXO may represent a more effective EXO-based vaccine in induction of antitumor immunity. Cellular ＆ Molecular Immunology. 2006;3（3）：205-211.
基金This study was supported by research grants from the Canadian Institutes of Health Research(MOP 79415 and 89713).
文摘T cells secrete bioactive exosomes(EXO),but the potential immunoregulatory effect of T-cell EXO is largely unknown.In this study,we generated activated ovalbumin(OVA)-specific CD4^(+) T cells in vitro via coculture of OVA-pulsed dendritic cells(DC_(OVA))with naive CD4^(+) T cells derived from OVA-specific T-cell receptor(TCR)transgenic OTII mice.CD4^(+) T-cell EXO were then purified from the CD4^(+) T-cell culture supernatants by differential ultracentrifugation.CD4^(+) T-cell EXO exhibited the‘saucer’shape that is characteristic of EXO with a diameter between 50 and 100 nm,as assessed by electron microscopy,and contained the EXO-associated proteins LAMP-1,TCR and lymphocyte function associated antigen-1(LFA-1),as determined by western blot.Flow cytometric analysis showed that CD4^(+) T-cell EXO expressed CD4^(+) T-cell markers(CD4,TCR,LFA-1,CD25 and Fas ligand),but to a lesser extent than CD4^(+) T cells.We demonstrated that DC_(OVA) took up CD4^(+) T-cell EXO via peptide/major histocompatibility complex(pMHC)II/TCR and CD54/LFA-1 interactions.OVA-specific CD4^(+) T-cell EXO from OTII mice,but not ConA-stimulated polyclonal CD4^(+) T-cell EXO from wild-type C57BL/6 mice inhibited DC_(OVA)-stimulated in vitro CD4^(+) T-cell proliferation and in vivo CD81 cytotoxic T lymphocyte(CTL)responses and antitumor immunity against OVA-expressing B16 melanoma BL6-10OVA cells.In addition,EXO derived from a T-cell hybridoma cell line,MF72.2D9,expressing an OVA-specific CD4^(+) TCR,had a similar inhibitory effect as OTII CD4^(+) T-cell EXO on CTL-mediated antitumor immunity.Taken together,our data indicate that antigen-specific T-cell EXO may serve as a new type of immunosuppressive reagent for use in transplant rejection and treatment of autoimmune diseases.
基金supported by the National Natural Science Foundation of China(81874314 and 81903633)“Yangfan”project of Shanghai Science and Technology Commission(19YF1428700,China)。
文摘The bile acid-responsive G-protein-coupled receptor TGR5 is expressed in monocytes and macrophages,and plays a critical role in regulating inflammatory response.Our previous work has shown its role in promoting the progression of non-small cell lung cancer(NSCLC),yet the mechanism remains unclear.Here,using Tgr5-knockout mice,we show that TGR5 is required for M2 polarization of tumorassociated macrophages(TAMs)and suppresses antitumor immunity in NSCLC via involving TAMsmediated CD8+T cell suppression.Mechanistically,we demonstrate that TGR5 promotes TAMs into protumorigenic M2-like phenotypes via activating c AMP-STAT3/STAT6 signaling.Induction of c AMP production restores M2-like phenotypes in TGR5-deficient macrophages.In NSCLC tissues from human patients,the expression of TGR5 is associated with the infiltration of TAMs.The co-expression of TGR5 and high TAMs infiltration are associated with the prognosis and overall survival of NSCLC patients.Together,this study provides molecular mechanisms for the protumor function of TGR5 in NSCLC,highlighting its potential as a target for TAMs-centric immunotherapy in NSCLC.
基金This work was supported by grants from the NIH(U01AA027681 to SS and MK,and R01 AI043477,P01 CA128814,and R01 CA211794 to MK)the Tower Cancer Research Foundation(to MK).
文摘Chronic inflammation promotes tumor development,progression,and metastatic dissemination and causes treatment resistance.The accumulation of genetic alterations and loss of normal cellular regulatory processes are not only associated with cancer growth and progression but also result in the expression of tumor-specific and tumor-associated antigens that may activate antitumor immunity.This antagonism between inflammation and immunity and the ability of cancer cells to avoid immune detection affect the course of cancer development and treatment outcomes.While inflammation,particularly acute inflammation,supports T-cell priming,activation,and infiltration into infected tissues,chronic inflammation is mostly immunosuppressive.However,the main mechanisms that dictate the outcome of the inflammation-immunity interplay are not well understood.Recent data suggest that inflammation triggers epigenetic alterations in cancer cells and components of the tumor microenvironment.These alterations can affect and modulate numerous aspects of cancer development,including tumor growth,the metabolic state,metastatic spread,immune escape,and immunosuppressive or immunosupportive leukocyte generation.In this review,we discuss the role of inflammation in initiating epigenetic alterations in immune cells,cancer-associated fibroblasts,and cancer cells and suggest how and when epigenetic interventions can be combined with immunotherapies to improve therapeutic outcomes.
基金This work was supported by grants from the National Natural Science Foundation of China(31730026,81930039,and 81525012).
文摘Stimulator of interferon genes(STING)is an adaptor protein that is critical for effective innate antiviral and antitumor immunity.The activity of STING is heavily regulated by protein ubiquitination,which is fine-tuned by both E3 ubiquitin ligases and deubiquitinases.Here,we report that the deubiquitinase OTUD5 interacts with STING,cleaves its K48-linked polyubiquitin chains,and promotes its stability.Consistently,knockout of OTUD5 resulted in faster turnover of STING and subsequently impaired type I IFN signaling following cytosolic DNA stimulation.More importantly,Lyz2-Cre Otud5^(fl/Y) mice and CD11-Cre Otud5^(fl/Y) mice showed more susceptibility to herpes simplex virus type 1(HSV-1)infection and faster development of melanomas than their corresponding control littermates,indicating that OTUD5 is indispensable for STING-mediated antiviral and antitumor immunity.Our data suggest that OTUD5 is a novel checkpoint in the cGAS-STING cytosolic DNA sensing pathway.
文摘Dendritic cells （DCs） are the most potent antigen-presenting cells （APCs） for the initiation of antigen （Ag）-specific immune responses. In most studies, mature DCs are generated from bone marrow cells or peripheral monocytes; in either case, the harvested cells are then cultured in medium containing recombinant GM-CSF, IL-4 and TNF-α for 7-10 days and stimulated with lipopolysaccharide （LPS）. However, this approach is time-consuming and expensive. There is another less cost approach of using immobilized DC cell lines, which can easily grow in the medium. A disadvantage with the immobilized DC cell lines, however, is that they are immature DCs and lack expression of MHC class Ⅱ and costimulatory CD40 and CD80 molecules. This, therefore, limits their capacity for inducing efficient antitumor immunity. In the current study, we investigated the possible efficacy of various stimuli （IL-1β, IFN-γ, TNF-α CpG and LPS） in converting the immature dendritic cell line DC2.4 to mature DCs. Our findings were quite interesting since we demonstrated for the first time that IFN-γ was able to stimulate the maturation of DC2.4 cells. The IFN-γ-activated ovalbumin （OVA）-pulsed DC2.4 cells have capacity to upregulate MHC class Ⅱ, CD40, CD80 and CCR7, and to more efficiently stimulate in vitro and in vivo OVA-specific CD8^＋ T cell responses and antitumor immunity. Therefore, IFN-γ-activated immortal DC2.4 ceils may prove to be useful in the study of DC biology and antitumor immunity.
基金financially supported by the National Natural Science Foundation of China (Grant Nos.U1804183,81901878 and 81874304)China Postdoctoral Science Foundation (2019M662553,China)Key Scientific Research Project (Education Department of Henan Province,20HASTIT049,China)。
文摘The continuing challenges that limit effectiveness of tumor therapeutic vaccines were high heterogeneity of tumor immunogenicity, low bioactivity of antigens, as well as insufficient lymph nodes(LNs) drainage of antigens and adjuvants. Transportation of in situ neoantigens and adjuvants to LNs may be an effective approach to solve the abovementioned problems. Therefore, an FA-TSL/AuNCs/SV nanoplatform was constructed by integrating simvastatin(SV) adjuvant loaded Au nanocages(AuNCs)as cores(AuNCs/SV) and folic acid modified thermal-sensitive liposomes(FA-TSL) as shells to enhance de novo antitumor immunity. After accumulation in tumor guided by FA, AuNCs mediated photothermal therapy(PTT) induced the release of tumor-derived protein antigens(TDPAs) and the shedding of FATSL. Exposed AuNCs/SV soon captured TDPAs to form in situ recombinant vaccine(AuNCs/SV/TDPAs). Subsequently, AuNCs/SV/TDPAs could efficiently transport to draining LNs owing to the hyperthermia induced vasodilation effect and small particle size, achieving co-delivery of antigens and adjuvant for initiation of specific T cell response. In melanoma bearing mice, FA-TSL/AuNCs/SV and laser irradiation effectively ablated primary tumor, against metastatic tumors and induced immunological memory. This approach served a hyperthermia enhanced platform drainage to enable robust personalized cancer vaccination.
基金This work was supported by grants from the National Natural Science Foundation of China(31420103901 to Z.Y.,31830021 to Z.Y.,31970830 to J.H.,81702876 to X.L.,31500734 to Y.D.,and 31700753 to G.C.)grants from the Guangzhou Municipal Science and Technology Bureau(201904010090 to J.H.and 201906010085 to X.L.)a grant from the Health Commission of Guangdong Province(A2019520 to J.H.).
文摘CFTR,a chloride channel and ion channel regulator studied mostly in epithelial cells,has been reported to participate in immune regulation and likely affect the risk of cancer development.However,little is known about the effects of CFTR on the differentiation and function ofγδT cells.In this study,we observed that CFTR was functionally expressed on the cell surface ofγδT cells.Genetic deletion and pharmacological inhibition of CFTR both increased IFN-γrelease by peripheralγδT cells and potentiated the cytolytic activity of these cells against tumor cells both in vitro and in vivo.Interestingly,the molecular mechanisms underlying the regulation ofγδT cell IFN-γproduction by CFTR were either TCR dependent or related to Ca^(2+)influx.CFTR was recruited to TCR immunological synapses and attenuated Lck-P38 MAPK-c-Jun signaling.In addition,CFTR was found to modulate TCR-induced Ca^(2+)influx and membrane potential(Vm)-induced Ca^(2+)influx and subsequently regulate the calcineurin-NFATc1 signaling pathway inγδT cells.Thus,CFTR serves as a negative regulator of IFN-γproduction inγδT cells and the function of these cells in antitumor immunity.Our investigation suggests that modification of the CFTR activity ofγδT cells may be a potential immunotherapeutic strategy for cancer.
基金This study was supported by the National Natural Science Foundation of China(31770953,81830047,81961138008 to CX,32070877 to W-HL,and 31570883 to NX)1000 Young Talents Program of China(NX)the Fundamental Research Funds for the Central Universities of China-Xiamen University(20720170064 to CX).
文摘Aberrant expression of Myc is one of the most common oncogenic events in human cancers.Scores of Myc inhibitors are currently under development for treating Myc-driven cancers.In addition to directly targeting tumor cells,Myc inhibition has been shown to modulate the tumor microenvironment to promote tumor regression.However,the effect of Myc inhibition on immune cells in the tumor microenvironment remains poorly understood.Here,we show that the adaptive immune system plays a vital role in the antitumor effect of pharmacologic inhibition of Myc.Combining genetic and pharmacologic approaches,we found that Myc inhibition enhanced CD8 T cell function by suppressing the homeostasis of regulatory T(Treg)cells and the differentiation of resting Treg(rTreg)cells to activated Treg(aTreg)cells in tumors.Importantly,we demonstrated that different Myc expression levels confer differential sensitivity of T cell subsets to pharmacologic inhibition of Myc.Although ablation of the Myc gene has been shown to suppress CD8 T cell function,Treg cells,which express much less Myc protein than CD8 T cells,are more sensitive to Myc inhibitors.The differential sensitivity of CD8 T and Treg cells to Myc inhibitors resulted in enhanced CD8 T cell function upon Myc inhibition.Our findings revealed that Myc inhibitors can induce an antitumor immune response during tumor progression.
基金supported by The National Natural Science Foundation of China(No.82072979).
文摘This study aimed to investigate the role of long non-coding RNA maternally expressed gene 3(lncRNA MEG3)in chemosensitivity of osteosarcoma(OS),and to reveal the possible underlying mechanisms.In this study,we found that the expression of lncRNA MEG3 was significantly lower in OS tissues and cell lines.Furthermore,lncRNA MEG3 overexpression enhanced chemosensitivity of OS by inhibiting cell proliferation,migration,autophagy,and promoting antitumor immunity.LncRNA MEG3 functioned as miR-21-5 sponge to regulate p53 expression in OS.Mechanically,lncRNA MEG3 promoted OS chemosensitivity by regulating antitumor immunity via miR-21-5p/p53 pathway and autophagy.Collectively,this study provided the evidence that lncRNA MEG3 might be a promising therapeutic target for OS chemoresistance.
基金This study was supported by the Natural Science Foundation Project of the Health Department of Hubei Province,China.(No.NX200509)。
文摘To determine whether squamous cell carcin-oma antigen recognized by human T cell 3(SART3)gene can induce antitumor immunity against tumor cells which express the gene,we constructed mouse tumor cells expressing human SART3(LM8-SART3)and carried out experiments in vitro/vivo.After subcutaneous injection with SART3 gene vaccine,cytotoxic T lymphocyte(CTL)activity in vitro was measured using Cell Counting Kit-8.As for the in vivo part,C3H mice were divided into several groups.One group was challenged with tumor cells after immunity.Another group was treated with the vaccine after tumor implantation.It was found that human SART3 DNA vaccine can elicit a specific CTL reaction from the mouse splenocytes.After vaccination,tumor occurrence and tumor growth speed was reduced.The vaccine also shows activity in tumor treatment.We con-clude that the human SART3 DNA vaccine can induce antitumor ability against tumor cells expressing human SART3(LM8-SART3)in vitro/vivo which may provide new possibilities in antitumor therapy.
基金supported by the Natural Science Foundation of China(No.81571620)the Chinese Academy of Medical Sciences Innovative Medicine(No.2016-I2M-1-007).
文摘Immunotherapy is revolutionizing the clinical management of cancer patients by modulating T cells and natural killer cells.Dendritic cells(DCs)have the capacity to orchestrate the expansion and function of these effector cells both in lymphoid and non-lymphoid tissues of cancer patients.Distinct subtypes of DCs have various capacities to prime and activate different T cell responses.Here,we review conventional type 1 dendritic cells(cDC1s)and their crucial role in protective anti-tumor immunity.Targeting cDC1s as a cancer vaccine against the development of hepatocellular carcinoma will be discussed.
基金This work was supported by Coordination for the Improvement of Higher Education Personnel(CAPES),Carlos Chagas Filho Foundation for Supporting Research in the State of Rio de Janeiro(grant number FAPERJ E−26/200.628/2022)National Counsel of Technological and Scientific Development(CNPq)Brazil.
文摘The adaptive arm of the immune system is crucial for appropriate antitumor immune responses.It is generally accepted that clusters of differentiation 4^(+)(CD4^(+))T cells,which mediate T helper(Th)1 immunity(type 1 immunity),are the primary Th cell subtype associated with tumor elimination.In this review,we discuss evidence showing that antitumor immunity and better prognosis can be associated with distinct Th cell subtypes in experimental mouse models and humans,with a focus on Th2 cells.The aim of this review is to provide an overview and understanding of the mechanisms associated with different tumor outcomes in the face of immune responses by focusing on the(1)site of tumor development,(2)tumor properties(i.e.,tumor metabolism and cytokine receptor expression),and(3)type of immune response that the tumor initially escaped.Therefore,we discuss how low-tolerance organs,such as lungs and brains,might benefit from a less tissue-destructive immune response mediated by Th2 cells.In addition,Th2 cells antitumor effects can be independent of CD8^(+)T cells,which would circumvent some of the immune escape mechanisms that tumor cells possess,like low expression of major histocompatibility-I(MHC-I).Finally,this review aims to stimulate further studies on the role of Th2 cells in antitumor immunity and briefly discusses emerging treatment options.
文摘A novel approach for a dentritic cells (DCs) based tumor vaccine was developed for the formation of hybrid engineered J558 after fusion with DCs. To make the hybrid tumor vaccine generate more efficient specific CTL cytotoxicity against wild type tumor cells, we genetically engineered tumor cells with mIL 12 gene prior to the cell fusion. mIL 12 was detected at 870±60 pg/(10 5 cells/ml) in the culture supernatants and the fusion ratio was about 30 % by the co focal microscopic analysis. Vaccination of mice with DCs fused with engineered J558 induced more efficient tumor specific CTL cytotoxicity against wild type tumor cells in vitro and with efficient antitumor immunity in vivo . These results suggest that this approach of using DCs fused with engineered tumor cells could be applied in clinical settings of DCs based cancer vaccines.
文摘Vaccinia melanoma oncolysate (VMO) prepared by infecting B16F10 melanoma cells with recombinant vaccinia virus encoding murine GMCSF gene was tested for its therapeutic effect on the preestablished melanoma. C57BL/6 mice were inoculated s.c. with 1×105 B16F10 melanoma cells and received s.c. administration with VMO prepared with GMCSF gene encoded vaccinia virus(GMCSFVMO), VMO prepared with thymidine kinase genedeficient vaccinia virus(TKVMO), B16F10 melanoma oncolysate(BMO), or PBS 3 days after tumor inoculation. The same treatment was bolstered one week later. The results demonstrated that GMCSFVMO treatment significantly inhibited the growth of subcutaneous tumor and prolonged the survival period of tumorbearing mice. Further study elucidated that cytotoxicity of PBL and splenocytes towards B16F10 increased obviously after treatment with GMCSFVMO, but NK activity remained unchanged. These results suggest that the tumor oncolysate vaccine prepared with GMCSF geneencoded vaccinia virus might exert potent therapeutic effect on the preestablished tumor through the efficient induction of specific antitumor immune response of the host.
基金Supported by the Genetically Modified Organisms Breeding Major Projects, China(No.2009ZX08006-002B)the Key Technologies Research and Development Program of Jilin Province, China(No.10ZDGG007)the Postdoctoral Science Foundation Funded Project of China(No.20100481057)
文摘To analyze the antitumor potential and mechanism of action of simultaneous Newcastle disease virus （NDV） hemagglutinin-neuraminidase（HN） and human interleukin 18（hIL-18） gene transfer in C57BL/6 mice with H22 hepatoma,the mouse model with H22 hepatoma was established in C57BL/6 mice, and the antitumor effects of the combined application of NDV HN and hIL-18 were evaluated in vivo. The results show that the growth of established tumors in mice immunized with adenovirus（Ad）-HN in conjunction with Ad-hIL-18 was significantly inhibited compared with that in mice immunized with Ad-HN, Ad-hIL-18 alone, or the empty vector（Ad-mock）. Furthermore, the immunization of mice with Ad-HN in conjunction with Ad-hIL-18 elicited strong natural killer activity and H22 tumor-specific cytotoxic T lymphocyte（CTL） responses in vivo. In addition, T cells from the lymph nodes of mice immunized with Ad-hIL-18 or Ad-HN＋Ad-hIL-18 secreted high levels of the Th1 cytokine IL-2 and interferon-γ （IFN-γ）, indicating that the regression of tumor cells is related to a Th1-type dominant immune response. These results demonstrate that vaccination with NDV HN together with hIL-18 may be a novel and powerful strategy for cancer immunotherapy.
