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
The ideal photodynamic therapy(PDT)should effectively remove the primary tumor,and produce a stronger immune memory effect to inhibit the tumor recurrence and tumor metastasis.However,limited by the hypoxic and immuno...The ideal photodynamic therapy(PDT)should effectively remove the primary tumor,and produce a stronger immune memory effect to inhibit the tumor recurrence and tumor metastasis.However,limited by the hypoxic and immunosuppressive microenvironment,the PDT efficiency is apparently low.Here,Chlorella(Chl.)is exploited to enhance local effect by producing oxygen to reverse hypoxia,and release adjuvants to reverse immunosuppressive microenvironment to enhance abscopal effect afterwards.Results from different animal models indicated that Chl.could enhance local effect and PDT related immune response.Ultimately,Chl.coupled PDT elicited anti-tumor effects toward established primary tumors(inhibition rate:90%)and abscopal tumors(75%),controlled the challenged tumors(100%)and alleviated metastatic tumors(90%).This Chl.coupled PDT strategy can also produce a stronger anti-tumor immune memory effect.Overall,this Chl.coupled PDT strategy generates enhanced local tumor killing,boosts PDT-induced immune responses and promotes anti-tumor immune memory effect,which may be a great progress for realizing systemic effect of PDT.展开更多
Background In 2015,herpes simplex virus 1(HSV-1)-derived talimogene laherparepvec(T-VEC)was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment.However...Background In 2015,herpes simplex virus 1(HSV-1)-derived talimogene laherparepvec(T-VEC)was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment.However,its antitumor application is limited to local treatment of melanoma,and there is a lack of understanding of the mechanisms underlying the regulation of HSV-1 replication in cancer cells and the associated antitumor immunity.We hypothesized that increasing the replication capacity of HSV-1 in tumor cells would enhance the antitumor effect of this virus.Methods We systematically identified IFN-stimulated genes induced by HSV-1 by performing functional screens and clarified the mechanism by which BACH1 acts against HSV-1.Then,we tested the effect of BACH1 deficiency on immunogenic cell death induced by HSV-1.Furthermore,we investigated the antitumor effect of BACH1 deficiency on HSV-1 in MCA205 and B16 murine tumor models.Results We identified eight IFN-stimulated genes(ISGs)controlling HSV-1 replication,among which BTB and CNC homology 1(BACH1)suppressed HSV-1 replication by inhibiting the transcription of ICP4,ICP27,and UL39.Loss of Bach1 function not only increased HSV-1 proliferation but also promoted HSV-1-induced cell apoptosis,HMGB1 secretion,and calreticulin exposure in tumor cells.More importantly,hemin,an FDA-approved drug known to downregulate BACH1,significantly enhanced HSV-1-mediated antitumor activity with increased T lymphocyte infiltration at the tumor site.Conclusions Our studies uncovered a novel antiviral activity of BACH1 and provided a new strategy for improving the clinical efficiency of the oncolytic virus HSV-1.展开更多
Background: To induce and collect tumor-derived autophagosomes (DRibbles) from tumor cells as an antitumor vaccine by inhibiting the functions of proteasomes and lysosomes. Methods: Dendritic cells (DCs) generat...Background: To induce and collect tumor-derived autophagosomes (DRibbles) from tumor cells as an antitumor vaccine by inhibiting the functions of proteasomes and lysosomes. Methods: Dendritic cells (DCs) generated from peripheral blood mononuclear cell (PBMC) of hepatocellular carcinoma (HCC) patients were cocultured with DRibbles, and then surface molecules of DCs, as well as surface molecules on DCs, were determined by flow cytometry. Meanwhile, immune responses of the DCs-DRibbles were examined by mixed lymphocyte reactions. Results: DRibbles significantly induced the expression of CD80, CD83, CD86 and HLA-DR on DCs. The enzyme-linked immunosorbnent assay (ELISA) showed that IFN-γ, levels after vaccination increased than before in most patients, but CDS+ proportion of PBMC increased only in nine patients. Higher levels of IFN-γ, were detected in the CD8+ cells than CD4+ T cells. These results suggested that DCs-DRibbles vaccine could induce antigen-specific cellular immune response on HCC and could prime strong CD8+ T cell responses, supporting it as a tumor vaccine candidate. Conclusions: Our results demonstrate that HCC/DRibbles-pulsed DCs immunotherapy might be deployed as an effective antitumor vaccine for HCC immunotherapy in clinical trials.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
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
Immunotherapy has revolutionized cancer treatment and substantially improved patient outcomes with respect to multiple types of tumors.However,most patients cannot benefit from such therapies,mainly due to the intrins...Immunotherapy has revolutionized cancer treatment and substantially improved patient outcomes with respect to multiple types of tumors.However,most patients cannot benefit from such therapies,mainly due to the intrinsic low immunogenicity of cancer cells(CCs)that allows them to escape recognition by immune cells of the body.Immunogenic cell death(ICD),which is a form of regulated cell death,engages in a complex dialogue between dying CCs and immune cells in the tumor microenvironment(TME),ultimately evoking the damage-associated molecular pattern(DAMP)signals to activate tumor-specific immunity.The ICD inducers mediate the death of CCs and improve both antigenicity and adjuvanticity.At the same time,they reprogram TME with a“cold-warmhot”immune status,ultimately amplifying and sustaining dendritic cell-and T cell-dependent innate sensing as well as the antitumor immune responses.In this review,we discuss how to stimulate ICD based upon the biological properties of CCs that have evolved under diverse stress conditions.Additionally,we highlight how this dynamic interaction contributes to priming tumor immunogenicity,thereby boosting anticancer immune responses.We believe that a deep understanding of these ICD processes will provide a framework for evaluating its vital role in cancer immunotherapy.展开更多
The coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has resulted in more than two million deaths.Underlying diseases,including cancer,are high-risk facto...The coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has resulted in more than two million deaths.Underlying diseases,including cancer,are high-risk factors for severe COVID-19 outcomes.Angiotensin-converting enzyme 2(ACE2),as a SARS-CoV-2 host cell receptor,plays a crucial role in SARS-CoV-2 invading human cells.ACE2 also has significant associations with cancer.Recent studies showed that ACE2 was inversely correlated with the activities of multiple oncogenic pathways and tumor progression phenotypes,and was positively correlated with antitumor immune response and survival prognosis in diverse cancers,suggesting a potential protective role of ACE2 in cancer progression.Positive expression of ACE2 is also correlated with programmed death-ligand 1(PD-L1)in cancer.The positive associations of ACE2 expression with antitumor immune signatures and PD-L1 expression indicate that ACE2 expression is a positive predictor for the response to immune checkpoint inhibitors(ICIs).This was evidenced in multiple cancer cohorts treated with ICIs.Thus,ACE2 may build potential connections between COVID-19 and cancer and cancer immunotherapy.The potential connections suggest that ACE2 inhibitors may not be a good option for treating COVID-19 patients with cancer,particularly in cancer patients who are receiving immunotherapy.Furthermore,the relationships between ACE2,COVID-19,and cancer are worth confirming by more experimental and clinical data,considering that many cancer patients are at high risk for COVID-19.展开更多
Although transcatheter arterial chemo-embolization(TACE)plays a key role on clinical treatment of hepatocellular carcinoma(HCC),it was greatly limited by the poor synergistic effect between chemotherapeutics and physi...Although transcatheter arterial chemo-embolization(TACE)plays a key role on clinical treatment of hepatocellular carcinoma(HCC),it was greatly limited by the poor synergistic effect between chemotherapeutics and physical embolization to tumor-feeding arteries.In the present work,a temperature sensitive polymer poly(N-isopropylacrylamide-b-methacrylic acid)(PNA),which was modified with gold nanoparticles(AuNP@PNA),was successfully used to encapsulate doxorubicin(DOX)by electrostatic binding with their carboxyl groups.The resultant gold nanomedicines(AuNP@PNA/DOX)exhibited temperature responsive sol-gel phase transition,favorable shear thinning effect and X-ray angiography.By in vivo evaluation of vascular embolization on VX2-tumor-bearing rabbits,AuNP@PNA/DOX exhibited far better antitumor efficacy than Lipiodol/DOX,on either tumor growth inhibition,proliferation,apoptosis,necrosis or anti-metastasis.Owing to sufficient embolization to tumor vascular networks,AuNP@PNA/DOX down-regulated the expression levels of HIF-1α,VEGF and MMP-9,and prompted more efficient activation on CD3+/CD8+T cells and the related cytokines,suggesting the synergistic effect between AuNP@PNA and DOX on the improvement of post-operative tumor immunosuppressive microenvironment.With their favorable pharmcokinetics and biocompatibility,AuNP@PNA/DOX is promising to be developed as a multi-functional artery-imaging/embolic agent with immune-chemo-embolization for enhancing TACE efficacy on HCC.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
Mitochondrial ATP synthase has been recently detected at the surface of different cell types, where it is a high affinity receptor for apoA-I, the major protein component in high density lipoproteins (HDL). Cell surfa...Mitochondrial ATP synthase has been recently detected at the surface of different cell types, where it is a high affinity receptor for apoA-I, the major protein component in high density lipoproteins (HDL). Cell surface ATP synthase (namely ecto-F1-ATPase) expression is related to different biological effects, such as regulation of HDL uptake by hepatocytes, endothelial cell proliferation or antitumor activity of Vγ9/Vδ2 T lymphocytes. This paper reviews the recently discovered functions and regulations of ecto-F1-ATPase. Particularly, the role of the F1-ATPase pathway(s) in HDL-cholesterol uptake and apoA-Imediated endothelial protection suggests its potential importance in reverse cholesterol transport and its regulation might represent a potential therapeutic target for HDL-related therapy for cardiovascular diseases. Therefore, it is timely for us to better understand how this ecto-enzyme and downstream pathways are regulated and to develop pharmacologic interventions.展开更多
Recombinant adenoviruses encoding murine IL 2 gene or IL 3 gene were directly injected into established subcutaneous tumor model of G422 glioblastoma cells. After treatment, the tumor size and survival of the gliobl...Recombinant adenoviruses encoding murine IL 2 gene or IL 3 gene were directly injected into established subcutaneous tumor model of G422 glioblastoma cells. After treatment, the tumor size and survival of the glioblastoma bearing mice were observed. The splenic NK and CTL cytotoxicities were detected by standard 4 hour 51 Cr release assay. We also examined the histopathological changes of tumor by hematoxylin and eosin staining. The results showed that intratumoral injection of adenoviruses encoding murine IL 2 gene or IL 3 gene significantly inhibited the growth of G422 glioblastoma and prolonged the survival period of glioblastoma bearing mice. The CTL cytotoxicity of the gene therapy groups was significantly higher than that of the control groups, but NK activity remained unchanged, indicating that specific immunity contributes to the in vivo antitumor effect of the direct gene therapy. There were much more tumor necrosis and inflammatory cell infiltration in the tumor of the gene therapy groups. Combined IL 2/IL 3 gene therapy could induce higher level of CTL and enhance the therapeutic potential further. The results suggest that intratumoral injection of recombinant adenoviruses encoding certain kind of cytokines may be a useful approach in the treatment of a malignancy of the central nervous system.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
Immune checkpoint blockade(ICB),including anti-cytotoxic T-lymphocyte associated protein 4(CTLA-4),benefits only a limited number of patients with cancer.Understanding the in-depth regulatory mechanism of CTLA-4 prote...Immune checkpoint blockade(ICB),including anti-cytotoxic T-lymphocyte associated protein 4(CTLA-4),benefits only a limited number of patients with cancer.Understanding the in-depth regulatory mechanism of CTLA-4 protein stability and its functional significance may help identify ICB resistance mechanisms and assist in the development of novel immunotherapeutic modalities to improve ICB efficacy.Here,we identified that TNF receptor-associated factor 6(TRAF6)mediates Lys63-linked ubiquitination and subsequent lysosomal degradation of CTLA-4.Moreover,by using TRAF6-deficient mice and retroviral overexpression experiments,we demonstrated that TRAF6 promotes CTLA-4 degradation in a T-cell-intrinsic manner,which is dependent on the RING domain of TRAF6.This intrinsic regulatory mechanism contributes to CD8+T-cell-mediated antitumor immunity in vivo.Additionally,by using an OX40 agonist,we demonstrated that the OX40-TRAF6 axis is responsible for CTLA-4 degradation,thereby controlling antitumor immunity in both tumor-bearing mice and patients with cancer.Overall,our findings demonstrate that the OX40-TRAF6 axis promotes CTLA-4 degradation and is a potential therapeutic target for the improvement of T-cell-based immunotherapies.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
Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer therapy.They induce long-term tumor regress...Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer therapy.They induce long-term tumor regression and overall survival benefit in many types of cancer.With the advances in our knowledge about the tumor immune microenvironment,remarkable progress has been made in the development of small-molecule drugs for immunotherapy.Small molecules targeting PRR-associated pathways,immune checkpoints,oncogenic signaling,metabolic pathways,cytokine/chemokine signaling,and immune-related kinases have been extensively investigated.Monotherapy of smallmolecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance.Here,we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.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
Although PD-L1/PD-1 blockade therapy has been approved to treat many types of cancers,the majority of patients with solid tumors do not respond well,but the underlying reason remains unclear.Here,we studied ovarian ca...Although PD-L1/PD-1 blockade therapy has been approved to treat many types of cancers,the majority of patients with solid tumors do not respond well,but the underlying reason remains unclear.Here,we studied ovarian cancer(OvCa),a tumor type generally resistant to current immunotherapies,to investigate PD-1-independent immunosuppression.We found that PD-L1 was not highly expressed in the tumor microenvironment(TME)of human OvCa.Instead,B7-H3,another checkpoint molecule,was highly expressed by both tumor cells and tumor-infiltrating antigen-presenting cells(APCs),which correlated with T-cell exhaustion in patients.Using ID8 OvCa mouse models,we found that B7-H3 expressed on tumor cells,but not host cells,had a dominant role in suppressing antitumor immunity.Therapeutically,B7-H3 blockade,but not PD-1 blockade,prolonged the survival of ID8 tumorbearing mice.Collectively,our results demonstrate that tumor-expressed B7-H3 inhibits the function of CD8^(+)T cells and suggest that B7-H3 may be a target in patients who are not responsive to PD-L1/PD-1 inhibition,particularly OvCa patients.展开更多
Direct intratumoral introduction of therapeutic or regulatory genes is a developing technology with potential application for cancer gene therapy.Macrophage inflammatory protein-I beta(MIP-Iβ)is a chemokine which can...Direct intratumoral introduction of therapeutic or regulatory genes is a developing technology with potential application for cancer gene therapy.Macrophage inflammatory protein-I beta(MIP-Iβ)is a chemokine which can chemoattract immune cells such as T cells.In the present study,murine colorectal adenocarcinoma CT26 cells were transfected with a recombinant adenovirus (AdhMIP-Iβ)carrying the human MIP-Iβ gene.24 h post-transfection,hMIP-1β levels reached approximately 980 pg/ml in supernatants of 10~6 hMIP-Iβ-transfected CT26 cells.Moreover,the supernatants exhibited chemotactic activity for CD8^+ T cells,CD4^+ T cells,NK cells and immature DCs.Intratumoral injection of AdhMIP-Iβ significantly inhibited tumor growth and prolonged the survival time of tumor-bearing mice.Intratumoral hMIP-Iβ gene transfer also induced powerful tumor-specific CTL responses in vivo.The therapeutic effects of hMIP-Iβ gene therapy were greatly reduced following in vivo depletion of both CD4^+ and CD8^+ cells,but were unaffected by depletion of single T cell subsets.Immune cell depletion experiments also revealed that NK cells played an important role in hMIP-1β-induced antitumor responses.These results suggest that intratumoral expression of hMIP-1β has the potential effect to induce host antitumor immunity and may prove to be a useful form of cancer gene therapy. Cellular & Molecular Immunology.2004;1(3):199-204.展开更多
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.
基金supported by National Key R&D Program of China(2017YFA0205400)National Natural Science Foundation of China(No.31872755,81872811,32171372)+1 种基金Jiangsu Outstanding Youth Funding(BK20190007)supported by the Central Fundamental Research Funds for the Central Universities(02141438473).
文摘The ideal photodynamic therapy(PDT)should effectively remove the primary tumor,and produce a stronger immune memory effect to inhibit the tumor recurrence and tumor metastasis.However,limited by the hypoxic and immunosuppressive microenvironment,the PDT efficiency is apparently low.Here,Chlorella(Chl.)is exploited to enhance local effect by producing oxygen to reverse hypoxia,and release adjuvants to reverse immunosuppressive microenvironment to enhance abscopal effect afterwards.Results from different animal models indicated that Chl.could enhance local effect and PDT related immune response.Ultimately,Chl.coupled PDT elicited anti-tumor effects toward established primary tumors(inhibition rate:90%)and abscopal tumors(75%),controlled the challenged tumors(100%)and alleviated metastatic tumors(90%).This Chl.coupled PDT strategy can also produce a stronger anti-tumor immune memory effect.Overall,this Chl.coupled PDT strategy generates enhanced local tumor killing,boosts PDT-induced immune responses and promotes anti-tumor immune memory effect,which may be a great progress for realizing systemic effect of PDT.
基金This project was financially supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2M-1-047 and 2019-I2M-5-049)National Science Funds of China(82073181,81802870 and 82102371)+5 种基金Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences(2020-PT310-006,2019XK310002 and 2018TX31001)as well as NIH R01AI069120,AI158154,and AI140718 grants,the UCLA AIDS InstituteUCLA David Geffen School of Medicine-Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Award ProgramH.Y.is supported by science funds from Jiangsu Province(BK20211554,BK20170407)the Innovative and Entrepreneurial Team grant(2018-2021)from Jiangsu ProvinceL.L.is supported by Innovative and Entrepreneurial Doctor grant(2020-2022)from Jiangsu Province.
文摘Background In 2015,herpes simplex virus 1(HSV-1)-derived talimogene laherparepvec(T-VEC)was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment.However,its antitumor application is limited to local treatment of melanoma,and there is a lack of understanding of the mechanisms underlying the regulation of HSV-1 replication in cancer cells and the associated antitumor immunity.We hypothesized that increasing the replication capacity of HSV-1 in tumor cells would enhance the antitumor effect of this virus.Methods We systematically identified IFN-stimulated genes induced by HSV-1 by performing functional screens and clarified the mechanism by which BACH1 acts against HSV-1.Then,we tested the effect of BACH1 deficiency on immunogenic cell death induced by HSV-1.Furthermore,we investigated the antitumor effect of BACH1 deficiency on HSV-1 in MCA205 and B16 murine tumor models.Results We identified eight IFN-stimulated genes(ISGs)controlling HSV-1 replication,among which BTB and CNC homology 1(BACH1)suppressed HSV-1 replication by inhibiting the transcription of ICP4,ICP27,and UL39.Loss of Bach1 function not only increased HSV-1 proliferation but also promoted HSV-1-induced cell apoptosis,HMGB1 secretion,and calreticulin exposure in tumor cells.More importantly,hemin,an FDA-approved drug known to downregulate BACH1,significantly enhanced HSV-1-mediated antitumor activity with increased T lymphocyte infiltration at the tumor site.Conclusions Our studies uncovered a novel antiviral activity of BACH1 and provided a new strategy for improving the clinical efficiency of the oncolytic virus HSV-1.
基金supported by Nanjing Medical Science and Technique Development Foundation,Nanjing Department of Health (Grant:QRX11235 and Grant:ZDX12008)Jiangsu Science and Technology Project of Clinical Medicine Foundation,Science and Technology Department of Jiangsu Province (BL2014005)
文摘Background: To induce and collect tumor-derived autophagosomes (DRibbles) from tumor cells as an antitumor vaccine by inhibiting the functions of proteasomes and lysosomes. Methods: Dendritic cells (DCs) generated from peripheral blood mononuclear cell (PBMC) of hepatocellular carcinoma (HCC) patients were cocultured with DRibbles, and then surface molecules of DCs, as well as surface molecules on DCs, were determined by flow cytometry. Meanwhile, immune responses of the DCs-DRibbles were examined by mixed lymphocyte reactions. Results: DRibbles significantly induced the expression of CD80, CD83, CD86 and HLA-DR on DCs. The enzyme-linked immunosorbnent assay (ELISA) showed that IFN-γ, levels after vaccination increased than before in most patients, but CDS+ proportion of PBMC increased only in nine patients. Higher levels of IFN-γ, were detected in the CD8+ cells than CD4+ T cells. These results suggested that DCs-DRibbles vaccine could induce antigen-specific cellular immune response on HCC and could prime strong CD8+ T cell responses, supporting it as a tumor vaccine candidate. Conclusions: Our results demonstrate that HCC/DRibbles-pulsed DCs immunotherapy might be deployed as an effective antitumor vaccine for HCC immunotherapy in clinical trials.
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.
基金supported by the National Natural Science Foundation of China (No. 31971378, 81830002, 31870873 and 31991171)
文摘Immunotherapy has revolutionized cancer treatment and substantially improved patient outcomes with respect to multiple types of tumors.However,most patients cannot benefit from such therapies,mainly due to the intrinsic low immunogenicity of cancer cells(CCs)that allows them to escape recognition by immune cells of the body.Immunogenic cell death(ICD),which is a form of regulated cell death,engages in a complex dialogue between dying CCs and immune cells in the tumor microenvironment(TME),ultimately evoking the damage-associated molecular pattern(DAMP)signals to activate tumor-specific immunity.The ICD inducers mediate the death of CCs and improve both antigenicity and adjuvanticity.At the same time,they reprogram TME with a“cold-warmhot”immune status,ultimately amplifying and sustaining dendritic cell-and T cell-dependent innate sensing as well as the antitumor immune responses.In this review,we discuss how to stimulate ICD based upon the biological properties of CCs that have evolved under diverse stress conditions.Additionally,we highlight how this dynamic interaction contributes to priming tumor immunogenicity,thereby boosting anticancer immune responses.We believe that a deep understanding of these ICD processes will provide a framework for evaluating its vital role in cancer immunotherapy.
文摘The coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has resulted in more than two million deaths.Underlying diseases,including cancer,are high-risk factors for severe COVID-19 outcomes.Angiotensin-converting enzyme 2(ACE2),as a SARS-CoV-2 host cell receptor,plays a crucial role in SARS-CoV-2 invading human cells.ACE2 also has significant associations with cancer.Recent studies showed that ACE2 was inversely correlated with the activities of multiple oncogenic pathways and tumor progression phenotypes,and was positively correlated with antitumor immune response and survival prognosis in diverse cancers,suggesting a potential protective role of ACE2 in cancer progression.Positive expression of ACE2 is also correlated with programmed death-ligand 1(PD-L1)in cancer.The positive associations of ACE2 expression with antitumor immune signatures and PD-L1 expression indicate that ACE2 expression is a positive predictor for the response to immune checkpoint inhibitors(ICIs).This was evidenced in multiple cancer cohorts treated with ICIs.Thus,ACE2 may build potential connections between COVID-19 and cancer and cancer immunotherapy.The potential connections suggest that ACE2 inhibitors may not be a good option for treating COVID-19 patients with cancer,particularly in cancer patients who are receiving immunotherapy.Furthermore,the relationships between ACE2,COVID-19,and cancer are worth confirming by more experimental and clinical data,considering that many cancer patients are at high risk for COVID-19.
基金supported by the National Basic Research Program of China(Nos.2020YFA0710700 and 2018YFA0208900)the National Natural Science Foundation of China(Nos.82172758,81873919,and 81801810).
文摘Although transcatheter arterial chemo-embolization(TACE)plays a key role on clinical treatment of hepatocellular carcinoma(HCC),it was greatly limited by the poor synergistic effect between chemotherapeutics and physical embolization to tumor-feeding arteries.In the present work,a temperature sensitive polymer poly(N-isopropylacrylamide-b-methacrylic acid)(PNA),which was modified with gold nanoparticles(AuNP@PNA),was successfully used to encapsulate doxorubicin(DOX)by electrostatic binding with their carboxyl groups.The resultant gold nanomedicines(AuNP@PNA/DOX)exhibited temperature responsive sol-gel phase transition,favorable shear thinning effect and X-ray angiography.By in vivo evaluation of vascular embolization on VX2-tumor-bearing rabbits,AuNP@PNA/DOX exhibited far better antitumor efficacy than Lipiodol/DOX,on either tumor growth inhibition,proliferation,apoptosis,necrosis or anti-metastasis.Owing to sufficient embolization to tumor vascular networks,AuNP@PNA/DOX down-regulated the expression levels of HIF-1α,VEGF and MMP-9,and prompted more efficient activation on CD3+/CD8+T cells and the related cytokines,suggesting the synergistic effect between AuNP@PNA and DOX on the improvement of post-operative tumor immunosuppressive microenvironment.With their favorable pharmcokinetics and biocompatibility,AuNP@PNA/DOX is promising to be developed as a multi-functional artery-imaging/embolic agent with immune-chemo-embolization for enhancing TACE efficacy on HCC.
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.
基金Supported by An INSERM Avenir Grant (Martinez LO)ANR (Martinez LO and Lichtenstein L, #GENO 102 01)+1 种基金the French Association pour la Recherche sur le Cancer (Vantourout P and Champagne E, #3711-3913-4847)An INSERM young scientist fellowship (Pons V)
文摘Mitochondrial ATP synthase has been recently detected at the surface of different cell types, where it is a high affinity receptor for apoA-I, the major protein component in high density lipoproteins (HDL). Cell surface ATP synthase (namely ecto-F1-ATPase) expression is related to different biological effects, such as regulation of HDL uptake by hepatocytes, endothelial cell proliferation or antitumor activity of Vγ9/Vδ2 T lymphocytes. This paper reviews the recently discovered functions and regulations of ecto-F1-ATPase. Particularly, the role of the F1-ATPase pathway(s) in HDL-cholesterol uptake and apoA-Imediated endothelial protection suggests its potential importance in reverse cholesterol transport and its regulation might represent a potential therapeutic target for HDL-related therapy for cardiovascular diseases. Therefore, it is timely for us to better understand how this ecto-enzyme and downstream pathways are regulated and to develop pharmacologic interventions.
文摘Recombinant adenoviruses encoding murine IL 2 gene or IL 3 gene were directly injected into established subcutaneous tumor model of G422 glioblastoma cells. After treatment, the tumor size and survival of the glioblastoma bearing mice were observed. The splenic NK and CTL cytotoxicities were detected by standard 4 hour 51 Cr release assay. We also examined the histopathological changes of tumor by hematoxylin and eosin staining. The results showed that intratumoral injection of adenoviruses encoding murine IL 2 gene or IL 3 gene significantly inhibited the growth of G422 glioblastoma and prolonged the survival period of glioblastoma bearing mice. The CTL cytotoxicity of the gene therapy groups was significantly higher than that of the control groups, but NK activity remained unchanged, indicating that specific immunity contributes to the in vivo antitumor effect of the direct gene therapy. There were much more tumor necrosis and inflammatory cell infiltration in the tumor of the gene therapy groups. Combined IL 2/IL 3 gene therapy could induce higher level of CTL and enhance the therapeutic potential further. The results suggest that intratumoral injection of recombinant adenoviruses encoding certain kind of cytokines may be a useful approach in the treatment of a malignancy of the central nervous system.
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(82071803,82241217,and 82271811)Fundamental Research Funds for the Central Universities(2021GCRC037)Project Funded by China Postdoctoral Science Foundation(2021M691155).
文摘Immune checkpoint blockade(ICB),including anti-cytotoxic T-lymphocyte associated protein 4(CTLA-4),benefits only a limited number of patients with cancer.Understanding the in-depth regulatory mechanism of CTLA-4 protein stability and its functional significance may help identify ICB resistance mechanisms and assist in the development of novel immunotherapeutic modalities to improve ICB efficacy.Here,we identified that TNF receptor-associated factor 6(TRAF6)mediates Lys63-linked ubiquitination and subsequent lysosomal degradation of CTLA-4.Moreover,by using TRAF6-deficient mice and retroviral overexpression experiments,we demonstrated that TRAF6 promotes CTLA-4 degradation in a T-cell-intrinsic manner,which is dependent on the RING domain of TRAF6.This intrinsic regulatory mechanism contributes to CD8+T-cell-mediated antitumor immunity in vivo.Additionally,by using an OX40 agonist,we demonstrated that the OX40-TRAF6 axis is responsible for CTLA-4 degradation,thereby controlling antitumor immunity in both tumor-bearing mice and patients with cancer.Overall,our findings demonstrate that the OX40-TRAF6 axis promotes CTLA-4 degradation and is a potential therapeutic target for the improvement of T-cell-based immunotherapies.
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supported by the National Natural Science Foundation of China(Nos.U21A20421,82073882,82073317,81772540 and 82272996)the Key Project of Science Technology Program of Guangzhou(No.2023B03J0029,China)+1 种基金the National Key R&D Program of China(No.2022YFE0209700)the Science and Technology Program of Guangzhou(Nos.202201010819 and 202206010081,China)。
文摘Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer therapy.They induce long-term tumor regression and overall survival benefit in many types of cancer.With the advances in our knowledge about the tumor immune microenvironment,remarkable progress has been made in the development of small-molecule drugs for immunotherapy.Small molecules targeting PRR-associated pathways,immune checkpoints,oncogenic signaling,metabolic pathways,cytokine/chemokine signaling,and immune-related kinases have been extensively investigated.Monotherapy of smallmolecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance.Here,we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.
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The authors are grateful to Dr.Xueguang Zhang(Soochow University,China)and Jiajia Li(Fudan University Shanghai Cancer Center)for providing the mouse and human OvCa cell lines.This project was funded in part by the Key Program of the National Natural Science Foundation of China(81730039&81671460 to L.-P.J.)the National Key Research and Development Program of China(2017YFC1001401 to L.-P.J.)+2 种基金Beijing Municipal Science and Technology Projects(Z181100006318015 and Z181100001318007 to C.D.)Shanghai Municipal Medical and Health Discipline Construction Projects(2017ZZ02015 to L.-P.J.)the National Basic Research Program of China(2015CB943300 to L.-P.J.).
文摘Although PD-L1/PD-1 blockade therapy has been approved to treat many types of cancers,the majority of patients with solid tumors do not respond well,but the underlying reason remains unclear.Here,we studied ovarian cancer(OvCa),a tumor type generally resistant to current immunotherapies,to investigate PD-1-independent immunosuppression.We found that PD-L1 was not highly expressed in the tumor microenvironment(TME)of human OvCa.Instead,B7-H3,another checkpoint molecule,was highly expressed by both tumor cells and tumor-infiltrating antigen-presenting cells(APCs),which correlated with T-cell exhaustion in patients.Using ID8 OvCa mouse models,we found that B7-H3 expressed on tumor cells,but not host cells,had a dominant role in suppressing antitumor immunity.Therapeutically,B7-H3 blockade,but not PD-1 blockade,prolonged the survival of ID8 tumorbearing mice.Collectively,our results demonstrate that tumor-expressed B7-H3 inhibits the function of CD8^(+)T cells and suggest that B7-H3 may be a target in patients who are not responsive to PD-L1/PD-1 inhibition,particularly OvCa patients.
基金supported by Grants from National Natural Science Foundation of China(30271202)Natural High Technology Research and Development Program of China(2003AA215040)the National Key Basic Research Program of China(2001CB510002).
文摘Direct intratumoral introduction of therapeutic or regulatory genes is a developing technology with potential application for cancer gene therapy.Macrophage inflammatory protein-I beta(MIP-Iβ)is a chemokine which can chemoattract immune cells such as T cells.In the present study,murine colorectal adenocarcinoma CT26 cells were transfected with a recombinant adenovirus (AdhMIP-Iβ)carrying the human MIP-Iβ gene.24 h post-transfection,hMIP-1β levels reached approximately 980 pg/ml in supernatants of 10~6 hMIP-Iβ-transfected CT26 cells.Moreover,the supernatants exhibited chemotactic activity for CD8^+ T cells,CD4^+ T cells,NK cells and immature DCs.Intratumoral injection of AdhMIP-Iβ significantly inhibited tumor growth and prolonged the survival time of tumor-bearing mice.Intratumoral hMIP-Iβ gene transfer also induced powerful tumor-specific CTL responses in vivo.The therapeutic effects of hMIP-Iβ gene therapy were greatly reduced following in vivo depletion of both CD4^+ and CD8^+ cells,but were unaffected by depletion of single T cell subsets.Immune cell depletion experiments also revealed that NK cells played an important role in hMIP-1β-induced antitumor responses.These results suggest that intratumoral expression of hMIP-1β has the potential effect to induce host antitumor immunity and may prove to be a useful form of cancer gene therapy. Cellular & Molecular Immunology.2004;1(3):199-204.