In clinic,the combination of intravenous pembrolizumab(PD-1 monoclonal antibody)with oral Lenvatinib(LEN)exhibited an enhanced synergistic benefit for cancer therapy.However,the clinical outcomes were always limited b...In clinic,the combination of intravenous pembrolizumab(PD-1 monoclonal antibody)with oral Lenvatinib(LEN)exhibited an enhanced synergistic benefit for cancer therapy.However,the clinical outcomes were always limited by the problems of inconsistent pharmacokinetic profiles of two drugs,lower drug accumulation in tumor and obvious side effects during the combination therapy.Here,in situ-forming thermosensitive hydrogels based on PLGA-PEG-PLGA triblock copolymers were prepared for local administration of anti-PD1 and LEN(P&L@Gel)to improve therapeutic efficacy and safety.After peritumoral or surgical resection site injection,the significant increased concentrations of both drugs in tumor were observed with the local sustained release of P&L@Gel.In comparison with the group of intraperitoneal anti-PD1 plus oral LEN(P-ip&L-po),significantly higher tumor inhibition efficiency on CT26 tumor models could be obtained in P&L@Gel group,even at the dose of one-eighth of the former,same tumorinhibition effects could be achieved.The enhanced antitumor efficacy of P&L@Gel group was probably associated with the 2.2 folds of increased level of CD8+T cells and the polarization of tumor associated macrophage from M2 to M1 along with the increased drug accumulation.Moreover,compared with the obvious side effects of P-ip&L-po group,no significant changes of PLT,ALT and UA in blood,as well as IL-1αand IL-1βin mice paws were observed between P&L@Gel group and untreated group.These results suggested that local administration of anti-PD1 and LEN with thermosensitive hydrogel could offer a potential strategy for tumors or tumor postoperative adjuvant treatment.展开更多
Tumor vaccines trigger tumor-specific immune responses to prevent or treat tumors by activating the hosts’immune systems,and therefore,these vaccines have potential clinical applications.However,the low immunogenicit...Tumor vaccines trigger tumor-specific immune responses to prevent or treat tumors by activating the hosts’immune systems,and therefore,these vaccines have potential clinical applications.However,the low immunogenicity of the tumor antigen itself and the low efficiency of the vaccine delivery system hinder the efficacy of tumor vaccines that cannot produce high-efficiency and long-lasting antitumor immune effects.Here,we constructed a nanovaccine by integrating CD47KO/CRT dual-bioengineered B16F10 cancer cell membranes and the unmethylated cytosine-phosphate-guanine(CpG)adjuvant.Hyperbranched PEI25k was used to load unmethylated cytosine-phosphate-guanine(CpG)through electrostatic adsorption to prepare PEI25k/CpG nanoparticles(PEI25k/CpG-NPs).CD47KO/CRT dual-bioengineered cells were obtained by CRISPR-Cas9 gene editing technology,followed by the cell surface translocation of calreticulin(CRT)to induce immunogenic cell death(ICD)in vitro.Finally,the extracted cell membranes were coextruded with PEI25k/CpG-NPs to construct the CD47KO/CRT dual-bioengineered cancer cell membrane-coated nanoparticles(DBE@CCNPs).DBE@CCNPs could promote endocytosis of antigens and adjuvants in murine bone marrow derived dendritic cells(BMDCs)and induce their maturation and antigen cross-presentation.To avoid immune checkpoint molecule-induced T cell dysfunction,the immune checkpoint inhibitor,the anti-PD-L1 antibody,was introduced to boost tumor immunotherapy through a combination with the DBE@CCNPs nanovaccine.This combination therapy strategy can significantly alleviate tumor growth and may open up a potential strategy for clinical tumor immunotherapy.展开更多
Natural killer(NK)cells are considered to be critical players in anticancer immunity.However,cancers are able to develop mechanisms to escape NK cell attack or to induce defective NK cells.Current NK cell-based cancer...Natural killer(NK)cells are considered to be critical players in anticancer immunity.However,cancers are able to develop mechanisms to escape NK cell attack or to induce defective NK cells.Current NK cell-based cancer immunotherapy is aimed at overcoming NK cell paralysis through several potential approaches,including activating autologous NK cells,expanding allogeneic NK cells,usage of stable allogeneic NK cell lines and genetically modifying fresh NK cells or NK cell lines.The stable allogeneic NK cell line approach is more practical for quality-control and large-scale production.Additionally,genetically modifying NK cell lines by increasing their expression of cytokines and engineering chimeric tumor antigen receptors could improve their specificity and cytotoxicity.In this review,NK cells in tumor immunotherapy are discussed,and a list of therapeutic NK cell lines currently undergoing preclinical and clinical trials of several kinds of tumors are reviewed.展开更多
Tumor immunotherapy has emerged as a promising method in cancer treatment,but patient responses vary,necessitating personalized strategies and prognostic biomarkers.This study aimed to identify prognostic factors and ...Tumor immunotherapy has emerged as a promising method in cancer treatment,but patient responses vary,necessitating personalized strategies and prognostic biomarkers.This study aimed to identify prognostic factors and construct a predictive model for patient survival outcomes and immunotherapy response.We curated six immunotherapy datasets representing diverse cancer types and treatment regimens.After data preprocessing,patients were stratified based on immunotherapy response.Differential gene expression analysis identified 22 genes consistently dysregulated across multiple datasets.Functional analysis provided critical insights,highlighting the enrichment of these dysregulated genes in immune response pathways and tumor microenvironment-related processes.To create a robust prognostic model,we meticulously employed a multistep approach.Initially,the identified 22 genes underwent rigorous univariate Cox regression analysis to evaluate their individual associations with patient survival outcomes.Genes showing statistical significance(p-values<0.05)at this stage advanced to the subsequent multivariate Cox regression analysis,which aimed to address potential confounding factors and collinearity among genes.From this analysis,we ultimately identified four key genes—ST6GALNAC2,SNORA65,MFAP2,and CDKN2B—that were significantly associated with patient survival outcomes.Incorporating these four key genes along with their corresponding coefficients,we constructed a predictive model.This model’s efficacy was validated through extensive Cox regression analyses,demonstrating its robustness in predicting patient survival outcomes.Furthermore,our model exhibited promising predictive capability for immunotherapy response,providing a potential tool for anticipating treatment efficacy.These findings provide insights into immunotherapy response mechanisms and suggest potential prognostic biomarkers for personalized treatment.Our study contributes to advancing cancer immunotherapy and personalized medicine.展开更多
Objective To investigate the effect of dendritic cells pulsed with brain tumor stem cells which are used to treat on intracranial glioma. Methods We obtained murine brain tumor stem cells by grow ing C6 cells in epide...Objective To investigate the effect of dendritic cells pulsed with brain tumor stem cells which are used to treat on intracranial glioma. Methods We obtained murine brain tumor stem cells by grow ing C6 cells in epidermal grow th factor/basic fibroblast grow th factor w ithout serum.Dendritic cells isolated from rat bone marrow w ere pulsed w ith BTSCs. Rat brain展开更多
Currently,the cancer immunotherapy has made great progress while antitumor vaccine attracts substantial attention.Still,the selection of adjuvants as well as antigens are always the most crucial issues for better vacc...Currently,the cancer immunotherapy has made great progress while antitumor vaccine attracts substantial attention.Still,the selection of adjuvants as well as antigens are always the most crucial issues for better vaccination.In this study,we proposed a biomimetic antitumor nanovaccine based on biocompatible nanocarriers and tumor cell membrane antigens.Briefly,endogenous calcium pyrophosphate nanogranules with possible immune potentiating effect are designed and engineered,both as delivery vehicles and adjuvants.Then,these nanocarriers are coated with lipids and B16-OVA tumor cell membranes,so the biomembrane proteins can serve as tumor-specific antigens.It was found that calcium pyrophosphate nanogranules themselves were compatible and possessed adjuvant effect,while membrane proteins including tumor associated antigen were transferred onto the nanocarriers.It was demonstrated that such a biomimetic nanovaccine could be well endocytosed by dendritic cells,promote their maturation and antigen-presentation,facilitate lymph retention,and trigger obvious immune response.It was confirmed that the biomimetic vaccine could induce strong T-cell response,exhibit excellent tumor therapy and prophylactic effects,and simultaneously possess nice biocompatibility.In general,the present investigation might provide insights for the further design and application of antitumor vaccines.展开更多
Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using world...Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products.Methods:We constructed a trispecific killer engager(TriKE)consisting of anti-CD16,IL-15,and anti-CD19.This TriKE was designed to attract CD19^(+)tumor cells to CD16^(+)NK cells,whereas IL-15 sustained the proliferation,development,and survival of NK cells.Results:Treatment with 161519 TriKE in the presence of CD19^(+)targets upregulated expression of CD69,CD107 a,TRAIL,IFN-γ,and TNF-α in NK cells,and significantly improved the proliferation and cytotoxicity of NK cells.NK cells"armed"with 161519 TriKE showed stronger cytolysis against CD19+targets compared with that of"unarmed"NK cells.A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE,when compared with that in control mice or mice treated with 1619 BiKE.Combined use of IL-2 was a more effective treatment with 1619 BiKE,when compared with that using 161519 TriKE.Conclusions:The newly generated 161519 TriKE enhanced the proliferation,activation,cytokine secretion,and cytotoxicity of NK cells in the presence of CD19+tumor cells.The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts,and could be used to treat CD19-positive cancers.展开更多
Macrophages are important antigen-presenting cells to combat tumor via both innate and adaptive immunity,while they are programmed toM2 phenotype in established tumors and instead promote cancer development and metast...Macrophages are important antigen-presenting cells to combat tumor via both innate and adaptive immunity,while they are programmed toM2 phenotype in established tumors and instead promote cancer development and metastasis.Here,we develop a nanomedicine that can re-educate M2 polarized macrophages to restore their anti-tumor activities.The nanomedicine has a core-shell structure to co-load IPI549,a PI3Kγinhibitor,and CpG,a Toll-like receptor 9 agonist.Specifically,the hydrophobic IPI549 is self-assembled into a pure drug nano-core,while MOF shell layer is coated for CpG encapsulation,achieving extra-high total drugs loading of 44%.Such nanosystem could facilitate intracellular delivery of the payloads but without any cytotoxicity,displaying excellent biocompatibility.After entering macrophages,the released IPI549 and CpG exert a synergistic effect to switch macrophages from M2 to M1 phenotype,which enables anti-tumor activities via directly engulfing tumor cells or excreting tumor killing cytokines.Moreover,tumor antigens released from the dying tumor cells could be effectively presented by the re-educated macrophages owing to the up-regulation of various antigen presenting mediators,resulting in infiltration and activation of cytotoxic T lymphocytes.As a result,the nanosystem triggers a robust antitumor immune response in combination with PD-L1 antibody to inhibit tumor growth and metastasis.This work provides a non-cytotoxic nanomedicine to modulate tumor immune microenvironment by reprograming macrophages.展开更多
Tumor microenvironment(TME)is highly heterogeneous and composed of complex cellular components,including multiple kinds of immune cells.Among all immune cells in TME,tumor-infiltrating myeloid cells(TIMs)account for a...Tumor microenvironment(TME)is highly heterogeneous and composed of complex cellular components,including multiple kinds of immune cells.Among all immune cells in TME,tumor-infiltrating myeloid cells(TIMs)account for a large proportion and play roles as key regulators in a variety of functions,ranging from immune-mediated tumor killing to tumor immune evasion.Understanding the heterogeneity of TIMs will provide valuable insights for new therapeutic targeting of myeloid cells.Single-cell genomic technologies deciphering cell composition and gene expression at single-cell resolution have largely improved our understanding of the cellular heterogeneity of TIMs and highlighted several novel cell subtypes contributing to the variation of patient survival and treatment response.However,these cell subtypes were defined based on limited data without a concordant nomenclature,which makes it difficult to understand whether they exist in different studies.Thus,in this review,we comprehensively summarized the common agreements and current different opinions on the heterogeneity of TIMs gained from single-cell studies;evaluated the feasibility of current myeloid cell targets at single-cell level and proposed a uniform nomenclature for TIM subsets.展开更多
Tumorigenesis are closely associated with the immune function of the human body.Immunotherapy has emerged as a novel and promising treatment strategy in multiple malignancies in the 21st century.Traditional Chinese me...Tumorigenesis are closely associated with the immune function of the human body.Immunotherapy has emerged as a novel and promising treatment strategy in multiple malignancies in the 21st century.Traditional Chinese medicine(TCM)has been extensively used for cancer treatment in China and surrounding countries for it exerts efficient therapeutic effects with few side effects.In recent years,studies have demonstrated that TCM plays a unique and reliable role in regulating tumor immunity.TCM can enhance the antitumor immune response function by regulating the secretion of cytokines,reshaping the balance of immune cells,and regulating immune checkpoints to relieve the immunosuppression.In addition,TCM can reduce the side effects(e.g.,cytokine storm)of cancer immunotherapy.Based on the current research of active immunotherapy and passive immunotherapy,this review summarizes the potential applications and existing problems of TCM in tumor immunotherapy.This review may be helpful in illuminating the scientific basis of TCM in tumor immunotherapy,promoting its internationalization,as well as shedding innovating new strategies for the development of tumor immunotherapy.展开更多
The low objective response rates and severe side effects largely limit the clinical outcomes of immune checkpoint blockade(ICB)therapy.Here,a tumor“self-killing”therapy based on gene-guided OX40L anchoring to tumor ...The low objective response rates and severe side effects largely limit the clinical outcomes of immune checkpoint blockade(ICB)therapy.Here,a tumor“self-killing”therapy based on gene-guided OX40L anchoring to tumor cell membrane was reported to boost ICB therapy.We developed a highly efficient delivery system HA/PEI-KT(HKT)to co-deliver the OX40L plasmids and unmethylated CG-enriched oligodeoxynucleotide(CpG).On the one hand,CpG induced the expression of OX40 on T cells within tumors.On the other hand,OX40L plasmids achieved the OX40L anchoring on the tumor cell membrane to next promote T cells responses via OX40/OX40L axis.Such synergistic tumor“self-killing”strategy finally turned“cold”tumors to“hot”,to sensitize tumors to programmed cell death protein 1/programmed cell death ligand 1(PD-1/PD-L1)blockade therapy,and promoted an immune-mediated tumor regression in both B16F10 and 4T1 tumor models,with prevention of tumor recurrence and metastasis.To avoid the side effects,the gene-guided OX40L anchoring and PD-L1 silencing was proposed to replace the existing antibody therapy,which showed negligible toxicity in vivo.Our work provided a new possibility for tumor“self-killing”immunotherapy to treated various solid tumors.展开更多
The clinical study of nasopharyngeal carcinoma(NPC)often reveals a large number of lymphocytes infiltrating the primary tumor site.As an important part of the tumor microenvironment,tumor-infiltrating lymphocytes(TILs...The clinical study of nasopharyngeal carcinoma(NPC)often reveals a large number of lymphocytes infiltrating the primary tumor site.As an important part of the tumor microenvironment,tumor-infiltrating lymphocytes(TILs)do not exist alone but as a complex multicellular population with high heterogeneity.TILs play an extremely significant role in the occurrence,development,invasion and metastasis of NPC.The latest research shows that they participate in tumorigenesis and treatment,and the composition,quantity,functional status and distribution of TILs subsets have good predictive value for the prognosis of NPC patients.TILs are an independent prognostic factor for TNM stage and significantly correlated with better prognosis.Additionally,adoptive immunotherapy using anti-tumor TILs has achieved good results in a variety of solid tumors including NPC.This review evaluates recent clinical and preclinical studies of NPC,summarizes the role of TILs in promoting and inhibiting tumor growth,evaluates the predictive value of TILs,and explores the potential benefits of TILs-based immunotherapy in the treatment of NPC.展开更多
Summary:Cancer testis(CT)antigens have received particular attention in cancer immunotherapy.OY-TES-1 is a member of CT antigens.This study was to evaluate OY-TES-1 expression and immunogenicity in hepatocelluar carci...Summary:Cancer testis(CT)antigens have received particular attention in cancer immunotherapy.OY-TES-1 is a member of CT antigens.This study was to evaluate OY-TES-1 expression and immunogenicity in hepatocelluar carcinoma(HCC).OY-TES-1 mRNA expression was detected in 56 HCC tissues and 5 normal liver tissues by reverse transcriptase PCR(RT-PCR).Of the 56 cases of HCC tissues tested,37 cases had tumor and matched adjacent non-cancer tissues and were subjected to both RT-PCR and quantitative real-time PCR.OY-TES-1 protein was subsequently observed on a panel of tissue microarrays.Sera from patients were tested for OY-TES-1 antibody by ELISA.To identify OY-TES-1 capable of inducing cellular immune response,OY-TES-1 protein was used to sensitize dentritic cells and the cytotoxicity effect was measured in vitro.The results showed that OY-TES-1 mRNA was highly expressed in 41 of the 56(73.21%)HCC tissues,whereas none in 5 normal liver tissues.OY-TES-1 mRNA was frequently expressed not only in HCC tissues(72.97%,27/37),but also in paired adjacent non-cancer tissues(64.86%,24/37).But the mean expression level of OY-TES-1 mRNA in HCC tissues was significantly higher than that in adjacent non-cancer tissues(0.76854 vs.0.09834,P=0.021).Immunohistochemistry showed that OY-TES-1 protein expression was detected in 6 of the 49 cases of HCC tissues,and absent in 9 cases of normal liver and 6 cases of cirrhosis tissues.Seropositivity was detected in 10 of the 45 HCC patients,but not detected in 17 cirrhosis patients and 76 healthy donors.The specific cytotoxic T cells elicited by OY-TES-1 could kill HLA-A2^+HCC cell line which expressed OY-TES-1.The target lysis was mainly HLA class I-dependent and could be blocked by antibodies against monomorphic HLA class I but not HLA class II molecule.In summary,OY-TES-1 expression is upregulated in HCC tissues and can be recognized by humoral and cellular responses,which suggests that OY-TES-1 is an attractive target for tumor immunotherapy in HCC.展开更多
Nanomaterial-based delivery vehicles such as lipid-based,polymer-based,inorganics-based,and bio-inspired vehicles often carry distinct and attractive advantages in the development of therapeutic cancer vaccines.Based ...Nanomaterial-based delivery vehicles such as lipid-based,polymer-based,inorganics-based,and bio-inspired vehicles often carry distinct and attractive advantages in the development of therapeutic cancer vaccines.Based on various delivery vehicles,specifically designed nanomaterials-based vaccines are highly advantageous in boosting therapeutic and prophylactic antitumor immunities.Specifically,therapeutic vaccines featuring unique properties have made major contributions to the enhancement of antigen immunogenicity,encapsulation efficiency,biocompatibility,and stability,as well as promoting antigen cross-presentation and specific CD8^(+)T cell responses.However,for clinical applications,tumor-associated antigen-derived vaccines could be an obstacle,involving immune tolerance and deficiency of tumor specificities,in achieving maximum therapeutic indices.However,when using bioinformatics predictions with emerging innovations of in silico tools,neoantigen-based therapeutic vaccines might become potent personalized vaccines for tumor treatments.In this review,we summarize the development of preclinical therapeutic cancer vaccines and the advancements of nanomaterial-based delivery vehicles for cancer immunotherapies,which provide the basis for a personalized vaccine delivery platform.Moreover,we review the existing challenges and future perspectives of nanomaterial-based personalized vaccines for novel tumor immunotherapies.展开更多
Thermal ablation(TA)as an effective method treating hepatocellular carcinoma(HCC)in clinics is facing great challenges of high recurrence and metastasis.Although immune-checkpoint blockade(ICB)-based immuno-therapy ha...Thermal ablation(TA)as an effective method treating hepatocellular carcinoma(HCC)in clinics is facing great challenges of high recurrence and metastasis.Although immune-checkpoint blockade(ICB)-based immuno-therapy has shown potential to inhibit recurrence and metastasis,the combination strategy of ICB and thermal ablation has shown little progress in HCC treatments.The tremendous hurdle for combining ICB with thermal ablation lies with the insufficient antigen internalization and immaturity of tumor-infiltrating dendritic cells(TIDCs)which leads to an inferior immune response to distant tumor growth and metastasis.Herein,an antigen-capturing nanoplatform,whose surface was modified with mannose as a targeting ligand,was constructed for co-delivering tumor-associated antigens(TAAs)and m6A demethylases inhibitor(i.e.,fat mass and obesity asso-ciated gene(FTO)inhibitor)into TIDCs.In vivo results demonstrate that the intratumoral injection of nanodrug followed by HCC thermal ablation promotes dendritic cells(DCs)maturation,improves tumor infiltration of effector T cells and generates immune memory,which synergize with ICB treatment to inhibit the distant tumor growth and lung metastasis.Therefore,the antigen-capturing and FTO-inhibiting nanodrug holds potential to boost the ICB-based immunotherapy against HCC after thermal ablation.展开更多
The activation of the stimulating factor of the interferon gene(STING)pathway can enhance the immune response within the tumor.Cyclic diguanylate monophosphate(c-di-GMP)is a negatively charged,hydrophilic STING agonis...The activation of the stimulating factor of the interferon gene(STING)pathway can enhance the immune response within the tumor.Cyclic diguanylate monophosphate(c-di-GMP)is a negatively charged,hydrophilic STING agonist,however,its effectiveness is limited due to the poor membrane permeability and low bioavailability.Herein,we introduced KL-7 peptide derived from Aβamyloid fibrils that can self-assemble to form nanotubes to load and deliver c-di-GMP,which significantly enhanced c-di-GMP’s effectiveness and then exhibited a robust“in situ immunity”to kill melanoma cells.KL-7 peptide nanotube,also called PNT,was loaded with negatively charged c-di-GMP via electrostatic interaction,which prepared a nanocomposite named c-di-GMP-PNT.Treatment of RAW 264.7 cells(leukemia cells in mouse macrophage)with c-di-GMP-PNT markedly stimulated the secretion of IL-6 and INF-βalong with phospho-STING(Ser365)protein expression,indicating the activation of the STING pathway.In the unilateral flank B16-F10(murine melanoma cells)tumor-bearing mouse model,compared to PNT and cdi-GMP,c-di-GMP-PNT can promote the expression of INF-β,TNF-α,IL-6,and IL-1β.At the same time,up-regulated CD4 and CD8 active T cells kill tumors and enhance the immune response in tumor tissues,resulting in significant inhibition of tumor growth in tumor-bearing mice.More importantly,in a bilateral flank B16-F10 tumor model,both primary and distant tumor growth can also be significantly inhibited by c-di-GMP-PNT.Moreover,c-di-GMP-PNT demonstrated no obvious biological toxicity on the main organs(heart,liver,spleen,lung,and kidney)and biochemical indexes of mice.In summary,our study provides a strategy to overcome the barriers of free c-di-GMP in the tumor microenvironment and c-di-GMP-PNT may be an attractive nanomaterial for anti-tumor immunity.展开更多
In recent years,neoantigens have been recognized as ideal targets for tumor immunotherapy.With the development of neoantigen-based tumor immunotherapy,comprehensive neoantigen databases are urgently needed to meet the...In recent years,neoantigens have been recognized as ideal targets for tumor immunotherapy.With the development of neoantigen-based tumor immunotherapy,comprehensive neoantigen databases are urgently needed to meet the growing demand for clinical studies.We have built the tumor-specific neoantigen database(TSNAdb)previously,which has attracted much attention.In this study,we provide TSNAdb v2.0,an updated version of the TSNAdb.TSNAdb v2.0 offers several new features,including(1)adopting more stringent criteria for neoantigen identification,(2)providing predicted neoantigens derived from three types of somatic mutations,and(3)collecting experimentally validated neoantigens and dividing them according to the experimental level.展开更多
As one of the main tumor-infiltrating immune cell types, tumor-associated macrophages (TAMs) determine the efficacy of immunotherapy. However, limited knowledge about their phenotypically and functionally heterogeneou...As one of the main tumor-infiltrating immune cell types, tumor-associated macrophages (TAMs) determine the efficacy of immunotherapy. However, limited knowledge about their phenotypically and functionally heterogeneous nature restricts their application in tumor immunotherapy. In this study, we identified a subpopulation of CD146+ TAMs that exerted antitumor activity in both human samples and animal models. CD146 expression in TAMs was negatively controlled by STAT3 signaling. Reducing this population of TAMs promoted tumor development by facilitating myeloid-derived suppressor cell recruitment via activation of JNK signaling. Interestingly, CD146 was involved in the NLRP3 inflammasome-mediated activation of macrophages in the tumor microenvironment, partially by inhibiting transmembrane protein 176B (TMEM176B), an immunoregulatory cation channel. Treatment with a TMEM176B inhibitor enhanced the antitumor activity of CD146+ TAMs. These data reveal a crucial antitumor role of CD146+ TAMs and highlight the promising immunotherapeutic approach of inhibiting CD146 and TMEM176B.展开更多
Our improved knowledge of tumor immunology laid a solid foundation for the clinical use of tumor immunotherapies such as immune checkpoint blockers,and the efficacy of these drugs increased our confidence that immunom...Our improved knowledge of tumor immunology laid a solid foundation for the clinical use of tumor immunotherapies such as immune checkpoint blockers,and the efficacy of these drugs increased our confidence that immunomodulation was a viable way of treating cancer.The basis of immunotherapy is to break the immune escape of the tumor and resolve the immune suppressive microenvironment of tumors.Nanomaterial-mediated dynamic therapy(NDT)is an emerging immuno-regulatable type for tumor therapy,whose effects are mediated by increased cellular levels of reactive oxygen species(ROS).ROS is a potent trigger of immunogenic cell death,and this process initiates antitumor immunity.Nanomaterials for use in NDT can be engineered to interact with almost all cell types in the tumor microenvironment to remodel this environment.In this review,we systematically examined the effects of NDT on four major cell types in the tumor microenvironment,namely tumor cells,lymphocytes,myeloid cells,and tumor stromal cells.We believe that this review will improve researchers’understanding of the anti-tumor immunity triggered by NDT,and provide ideas and inspiration for how optimally designed NDT schemes can be used to target the cells in the tumor microenvironment.展开更多
Activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes(cGAS/STING)signaling has emerged as a promising anti-tumor strategy due to the important role of the pathwa...Activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes(cGAS/STING)signaling has emerged as a promising anti-tumor strategy due to the important role of the pathway in innate and adaptive immunity,yet the selective delivery of STING agonists to tumors following systemic administration remains challenging.Herein,we develop a nano-STING agonist-decorated microrobot platform to achieve the enhanced anti-tumor effect.Fe ions and the STING agonist 2’3’-cyclic guanosine monophosphate-adenosine monophosphate(cGAMP)are co-encapsulated in the mitochondria-targeting nanoparticles(mTNPs),which can trigger the release of mitochondrial DNA(mtDNA)by Fenton reactioninduced mitochondria oxidative damage.The exogenous cGAMP and the endogenous mtDNA can work synergistically to induce potent cGAS/STING signaling activation.Furthermore,we decorate mTNPs onto Salmonella typhimurium VNP20009(VNP)bacteria to facilitate tumor accumulation and deep penetration.We demonstrate that the systemic administration of this microrobot activates both innate and adaptive immunity,improving the immunotherapeutic efficacy of the STING agonists.展开更多
基金supported by National Natural Science Foundation of China(Nos.81690264 and 81973259)the Open Project from Key Laboratory of Carcinogenesis and Translational Research,Ministry of Education/Beijing.
文摘In clinic,the combination of intravenous pembrolizumab(PD-1 monoclonal antibody)with oral Lenvatinib(LEN)exhibited an enhanced synergistic benefit for cancer therapy.However,the clinical outcomes were always limited by the problems of inconsistent pharmacokinetic profiles of two drugs,lower drug accumulation in tumor and obvious side effects during the combination therapy.Here,in situ-forming thermosensitive hydrogels based on PLGA-PEG-PLGA triblock copolymers were prepared for local administration of anti-PD1 and LEN(P&L@Gel)to improve therapeutic efficacy and safety.After peritumoral or surgical resection site injection,the significant increased concentrations of both drugs in tumor were observed with the local sustained release of P&L@Gel.In comparison with the group of intraperitoneal anti-PD1 plus oral LEN(P-ip&L-po),significantly higher tumor inhibition efficiency on CT26 tumor models could be obtained in P&L@Gel group,even at the dose of one-eighth of the former,same tumorinhibition effects could be achieved.The enhanced antitumor efficacy of P&L@Gel group was probably associated with the 2.2 folds of increased level of CD8+T cells and the polarization of tumor associated macrophage from M2 to M1 along with the increased drug accumulation.Moreover,compared with the obvious side effects of P-ip&L-po group,no significant changes of PLT,ALT and UA in blood,as well as IL-1αand IL-1βin mice paws were observed between P&L@Gel group and untreated group.These results suggested that local administration of anti-PD1 and LEN with thermosensitive hydrogel could offer a potential strategy for tumors or tumor postoperative adjuvant treatment.
基金The authors are thankful to the National Key R&D Program of China(2021YFB3800900)National Natural Science Foundation of China(51925305,51873208,51973217)+2 种基金Taishan Scholar Foundation of Shandong Province(qnts20161035)Natural Science Foundation of Shandong Province(ZR2019ZD24,ZR2019YQ30)Jilin Province Science and Technology Development Program(20200201075JC,20210509005RQ).
文摘Tumor vaccines trigger tumor-specific immune responses to prevent or treat tumors by activating the hosts’immune systems,and therefore,these vaccines have potential clinical applications.However,the low immunogenicity of the tumor antigen itself and the low efficiency of the vaccine delivery system hinder the efficacy of tumor vaccines that cannot produce high-efficiency and long-lasting antitumor immune effects.Here,we constructed a nanovaccine by integrating CD47KO/CRT dual-bioengineered B16F10 cancer cell membranes and the unmethylated cytosine-phosphate-guanine(CpG)adjuvant.Hyperbranched PEI25k was used to load unmethylated cytosine-phosphate-guanine(CpG)through electrostatic adsorption to prepare PEI25k/CpG nanoparticles(PEI25k/CpG-NPs).CD47KO/CRT dual-bioengineered cells were obtained by CRISPR-Cas9 gene editing technology,followed by the cell surface translocation of calreticulin(CRT)to induce immunogenic cell death(ICD)in vitro.Finally,the extracted cell membranes were coextruded with PEI25k/CpG-NPs to construct the CD47KO/CRT dual-bioengineered cancer cell membrane-coated nanoparticles(DBE@CCNPs).DBE@CCNPs could promote endocytosis of antigens and adjuvants in murine bone marrow derived dendritic cells(BMDCs)and induce their maturation and antigen cross-presentation.To avoid immune checkpoint molecule-induced T cell dysfunction,the immune checkpoint inhibitor,the anti-PD-L1 antibody,was introduced to boost tumor immunotherapy through a combination with the DBE@CCNPs nanovaccine.This combination therapy strategy can significantly alleviate tumor growth and may open up a potential strategy for clinical tumor immunotherapy.
基金Our research was supported by Important National Science and Technology Specific Projects(2009ZX09503-012,2009ZX09102-222,2012ZX10002-014)Knowledge Innovation Project of the Chinese Academy of Sciences(KSCX1-YW-22)+3 种基金Ministry of Health Special Fund for Healthy Industry(200902002-2)Science Fund for Creative Research Groups of the National Natural Science Foundation of China(Grant No.31021061)National Natural Science Foundation of China(Grant No.81102221)the Fundamental Research Funds for the Central Universities(WK 2070000014).
文摘Natural killer(NK)cells are considered to be critical players in anticancer immunity.However,cancers are able to develop mechanisms to escape NK cell attack or to induce defective NK cells.Current NK cell-based cancer immunotherapy is aimed at overcoming NK cell paralysis through several potential approaches,including activating autologous NK cells,expanding allogeneic NK cells,usage of stable allogeneic NK cell lines and genetically modifying fresh NK cells or NK cell lines.The stable allogeneic NK cell line approach is more practical for quality-control and large-scale production.Additionally,genetically modifying NK cell lines by increasing their expression of cytokines and engineering chimeric tumor antigen receptors could improve their specificity and cytotoxicity.In this review,NK cells in tumor immunotherapy are discussed,and a list of therapeutic NK cell lines currently undergoing preclinical and clinical trials of several kinds of tumors are reviewed.
文摘Tumor immunotherapy has emerged as a promising method in cancer treatment,but patient responses vary,necessitating personalized strategies and prognostic biomarkers.This study aimed to identify prognostic factors and construct a predictive model for patient survival outcomes and immunotherapy response.We curated six immunotherapy datasets representing diverse cancer types and treatment regimens.After data preprocessing,patients were stratified based on immunotherapy response.Differential gene expression analysis identified 22 genes consistently dysregulated across multiple datasets.Functional analysis provided critical insights,highlighting the enrichment of these dysregulated genes in immune response pathways and tumor microenvironment-related processes.To create a robust prognostic model,we meticulously employed a multistep approach.Initially,the identified 22 genes underwent rigorous univariate Cox regression analysis to evaluate their individual associations with patient survival outcomes.Genes showing statistical significance(p-values<0.05)at this stage advanced to the subsequent multivariate Cox regression analysis,which aimed to address potential confounding factors and collinearity among genes.From this analysis,we ultimately identified four key genes—ST6GALNAC2,SNORA65,MFAP2,and CDKN2B—that were significantly associated with patient survival outcomes.Incorporating these four key genes along with their corresponding coefficients,we constructed a predictive model.This model’s efficacy was validated through extensive Cox regression analyses,demonstrating its robustness in predicting patient survival outcomes.Furthermore,our model exhibited promising predictive capability for immunotherapy response,providing a potential tool for anticipating treatment efficacy.These findings provide insights into immunotherapy response mechanisms and suggest potential prognostic biomarkers for personalized treatment.Our study contributes to advancing cancer immunotherapy and personalized medicine.
文摘Objective To investigate the effect of dendritic cells pulsed with brain tumor stem cells which are used to treat on intracranial glioma. Methods We obtained murine brain tumor stem cells by grow ing C6 cells in epidermal grow th factor/basic fibroblast grow th factor w ithout serum.Dendritic cells isolated from rat bone marrow w ere pulsed w ith BTSCs. Rat brain
基金supported by the National Key R&D Program of China(2017YFA0205600)the National Natural Science Foundation of China(81690264,81821004).
文摘Currently,the cancer immunotherapy has made great progress while antitumor vaccine attracts substantial attention.Still,the selection of adjuvants as well as antigens are always the most crucial issues for better vaccination.In this study,we proposed a biomimetic antitumor nanovaccine based on biocompatible nanocarriers and tumor cell membrane antigens.Briefly,endogenous calcium pyrophosphate nanogranules with possible immune potentiating effect are designed and engineered,both as delivery vehicles and adjuvants.Then,these nanocarriers are coated with lipids and B16-OVA tumor cell membranes,so the biomembrane proteins can serve as tumor-specific antigens.It was found that calcium pyrophosphate nanogranules themselves were compatible and possessed adjuvant effect,while membrane proteins including tumor associated antigen were transferred onto the nanocarriers.It was demonstrated that such a biomimetic nanovaccine could be well endocytosed by dendritic cells,promote their maturation and antigen-presentation,facilitate lymph retention,and trigger obvious immune response.It was confirmed that the biomimetic vaccine could induce strong T-cell response,exhibit excellent tumor therapy and prophylactic effects,and simultaneously possess nice biocompatibility.In general,the present investigation might provide insights for the further design and application of antitumor vaccines.
基金supported by grants from the National Key R&D Program of China(Grant No.2019YFA0508502)the CAMS Innovation Fund for Medical Sciences(Grant No.2019-I2M-5-073)the National Natural Science Foundation of China(Grant Nos.81788101,81972679,and 81821001)。
文摘Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products.Methods:We constructed a trispecific killer engager(TriKE)consisting of anti-CD16,IL-15,and anti-CD19.This TriKE was designed to attract CD19^(+)tumor cells to CD16^(+)NK cells,whereas IL-15 sustained the proliferation,development,and survival of NK cells.Results:Treatment with 161519 TriKE in the presence of CD19^(+)targets upregulated expression of CD69,CD107 a,TRAIL,IFN-γ,and TNF-α in NK cells,and significantly improved the proliferation and cytotoxicity of NK cells.NK cells"armed"with 161519 TriKE showed stronger cytolysis against CD19+targets compared with that of"unarmed"NK cells.A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE,when compared with that in control mice or mice treated with 1619 BiKE.Combined use of IL-2 was a more effective treatment with 1619 BiKE,when compared with that using 161519 TriKE.Conclusions:The newly generated 161519 TriKE enhanced the proliferation,activation,cytokine secretion,and cytotoxicity of NK cells in the presence of CD19+tumor cells.The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts,and could be used to treat CD19-positive cancers.
基金supported by National Natural Science Foundation of China (Nos. 21804144, 81974000, U1903125, 82073799)Natural Science Foundation of Hunan province in China (Nos. 2021JJ10077, 2021JJ20084, 2022JJ30903)+1 种基金Natural Science Foundation of Changsha City in Hunan province,China (No. kq2202421)the Science and Technology Innovation Program of Hunan Province (No. 2021RC3020)
文摘Macrophages are important antigen-presenting cells to combat tumor via both innate and adaptive immunity,while they are programmed toM2 phenotype in established tumors and instead promote cancer development and metastasis.Here,we develop a nanomedicine that can re-educate M2 polarized macrophages to restore their anti-tumor activities.The nanomedicine has a core-shell structure to co-load IPI549,a PI3Kγinhibitor,and CpG,a Toll-like receptor 9 agonist.Specifically,the hydrophobic IPI549 is self-assembled into a pure drug nano-core,while MOF shell layer is coated for CpG encapsulation,achieving extra-high total drugs loading of 44%.Such nanosystem could facilitate intracellular delivery of the payloads but without any cytotoxicity,displaying excellent biocompatibility.After entering macrophages,the released IPI549 and CpG exert a synergistic effect to switch macrophages from M2 to M1 phenotype,which enables anti-tumor activities via directly engulfing tumor cells or excreting tumor killing cytokines.Moreover,tumor antigens released from the dying tumor cells could be effectively presented by the re-educated macrophages owing to the up-regulation of various antigen presenting mediators,resulting in infiltration and activation of cytotoxic T lymphocytes.As a result,the nanosystem triggers a robust antitumor immune response in combination with PD-L1 antibody to inhibit tumor growth and metastasis.This work provides a non-cytotoxic nanomedicine to modulate tumor immune microenvironment by reprograming macrophages.
文摘Tumor microenvironment(TME)is highly heterogeneous and composed of complex cellular components,including multiple kinds of immune cells.Among all immune cells in TME,tumor-infiltrating myeloid cells(TIMs)account for a large proportion and play roles as key regulators in a variety of functions,ranging from immune-mediated tumor killing to tumor immune evasion.Understanding the heterogeneity of TIMs will provide valuable insights for new therapeutic targeting of myeloid cells.Single-cell genomic technologies deciphering cell composition and gene expression at single-cell resolution have largely improved our understanding of the cellular heterogeneity of TIMs and highlighted several novel cell subtypes contributing to the variation of patient survival and treatment response.However,these cell subtypes were defined based on limited data without a concordant nomenclature,which makes it difficult to understand whether they exist in different studies.Thus,in this review,we comprehensively summarized the common agreements and current different opinions on the heterogeneity of TIMs gained from single-cell studies;evaluated the feasibility of current myeloid cell targets at single-cell level and proposed a uniform nomenclature for TIM subsets.
基金supported by the National Natural Science Foundation of China(82074165,81873306,81973526,81703749,81703764)Guangdong Science and Technology Department(2016A030306025)+7 种基金Guangdong High-level Personnel of Special Support Program(A1-3002-16-111-003)Department of Education of Guangdong Province(2018KZDXM022,A1-2606-19-111-009)the Ph.D.Start-up Fund of Natural Science Foundation of Guangdong Province(2017A030310213)Science and Technology Planning Project of Guangdong Province(2017B030314166)Guangzhou science and technology project(201904010407)the Specific Research Fund for TCM Science and Technology of Guangdong provincial Hospital of Chinese Medicine(YN2018MJ07)and the Foundation for Young Scholars of Guangzhou University of Chinese Medicine(QNYC20190101)Guangdong-Hong Kong-Macao Joint Lab on Chinese Medicine and Immune Disease Research(2020B1212030006).
文摘Tumorigenesis are closely associated with the immune function of the human body.Immunotherapy has emerged as a novel and promising treatment strategy in multiple malignancies in the 21st century.Traditional Chinese medicine(TCM)has been extensively used for cancer treatment in China and surrounding countries for it exerts efficient therapeutic effects with few side effects.In recent years,studies have demonstrated that TCM plays a unique and reliable role in regulating tumor immunity.TCM can enhance the antitumor immune response function by regulating the secretion of cytokines,reshaping the balance of immune cells,and regulating immune checkpoints to relieve the immunosuppression.In addition,TCM can reduce the side effects(e.g.,cytokine storm)of cancer immunotherapy.Based on the current research of active immunotherapy and passive immunotherapy,this review summarizes the potential applications and existing problems of TCM in tumor immunotherapy.This review may be helpful in illuminating the scientific basis of TCM in tumor immunotherapy,promoting its internationalization,as well as shedding innovating new strategies for the development of tumor immunotherapy.
基金This work was financially supported by the National Key R&D Program of China(2021YFB3800900)National Natural Science Foundation of China(51925305,51873208,51833010,51803210,51973217)Jilin province science and technology development program(20200201075JC).
文摘The low objective response rates and severe side effects largely limit the clinical outcomes of immune checkpoint blockade(ICB)therapy.Here,a tumor“self-killing”therapy based on gene-guided OX40L anchoring to tumor cell membrane was reported to boost ICB therapy.We developed a highly efficient delivery system HA/PEI-KT(HKT)to co-deliver the OX40L plasmids and unmethylated CG-enriched oligodeoxynucleotide(CpG).On the one hand,CpG induced the expression of OX40 on T cells within tumors.On the other hand,OX40L plasmids achieved the OX40L anchoring on the tumor cell membrane to next promote T cells responses via OX40/OX40L axis.Such synergistic tumor“self-killing”strategy finally turned“cold”tumors to“hot”,to sensitize tumors to programmed cell death protein 1/programmed cell death ligand 1(PD-1/PD-L1)blockade therapy,and promoted an immune-mediated tumor regression in both B16F10 and 4T1 tumor models,with prevention of tumor recurrence and metastasis.To avoid the side effects,the gene-guided OX40L anchoring and PD-L1 silencing was proposed to replace the existing antibody therapy,which showed negligible toxicity in vivo.Our work provided a new possibility for tumor“self-killing”immunotherapy to treated various solid tumors.
基金supported by the National Natural Science Foundation of China(No.81872200,31900558)the Natural Science Foundation of Hubei Province(No.2020CFB298)+1 种基金the Zhongnan Hospital of Wuhan University Science,Technology and Innovation Seed Fund(No.ZNPY2018090,ZNPY2019002)the Fundamental Research Funds for the Central Universities(No.2042019kf0139).
文摘The clinical study of nasopharyngeal carcinoma(NPC)often reveals a large number of lymphocytes infiltrating the primary tumor site.As an important part of the tumor microenvironment,tumor-infiltrating lymphocytes(TILs)do not exist alone but as a complex multicellular population with high heterogeneity.TILs play an extremely significant role in the occurrence,development,invasion and metastasis of NPC.The latest research shows that they participate in tumorigenesis and treatment,and the composition,quantity,functional status and distribution of TILs subsets have good predictive value for the prognosis of NPC patients.TILs are an independent prognostic factor for TNM stage and significantly correlated with better prognosis.Additionally,adoptive immunotherapy using anti-tumor TILs has achieved good results in a variety of solid tumors including NPC.This review evaluates recent clinical and preclinical studies of NPC,summarizes the role of TILs in promoting and inhibiting tumor growth,evaluates the predictive value of TILs,and explores the potential benefits of TILs-based immunotherapy in the treatment of NPC.
基金This work was supported by grants from the National Natural Science Foundation of China(No.81860445,No.81960453,No.81560408,and No.81660429)Natural Science Foundation of Guangxi Province(No.2016GXNSFBA380159,No.2018GXNSFAA281251,No.2018GXNSFAA050151,No.2017GXNSFAA198001,No.2018GXNSFAA281050,and No.2018GXNSFBA281187)+2 种基金Key Laboratory ofEarly Prevention and Treatment for Regional High Frequency Tumor(Guangxi Medical University)Ministry ofEducation(No.GK2018-09,No.GKE 2019-08,and No.K2015-TKF03)Basic Ability Improvement Project for Young and Middle-aged Teachers in Colleges and Universities of Guangxi Province(No.2018KY0109).
文摘Summary:Cancer testis(CT)antigens have received particular attention in cancer immunotherapy.OY-TES-1 is a member of CT antigens.This study was to evaluate OY-TES-1 expression and immunogenicity in hepatocelluar carcinoma(HCC).OY-TES-1 mRNA expression was detected in 56 HCC tissues and 5 normal liver tissues by reverse transcriptase PCR(RT-PCR).Of the 56 cases of HCC tissues tested,37 cases had tumor and matched adjacent non-cancer tissues and were subjected to both RT-PCR and quantitative real-time PCR.OY-TES-1 protein was subsequently observed on a panel of tissue microarrays.Sera from patients were tested for OY-TES-1 antibody by ELISA.To identify OY-TES-1 capable of inducing cellular immune response,OY-TES-1 protein was used to sensitize dentritic cells and the cytotoxicity effect was measured in vitro.The results showed that OY-TES-1 mRNA was highly expressed in 41 of the 56(73.21%)HCC tissues,whereas none in 5 normal liver tissues.OY-TES-1 mRNA was frequently expressed not only in HCC tissues(72.97%,27/37),but also in paired adjacent non-cancer tissues(64.86%,24/37).But the mean expression level of OY-TES-1 mRNA in HCC tissues was significantly higher than that in adjacent non-cancer tissues(0.76854 vs.0.09834,P=0.021).Immunohistochemistry showed that OY-TES-1 protein expression was detected in 6 of the 49 cases of HCC tissues,and absent in 9 cases of normal liver and 6 cases of cirrhosis tissues.Seropositivity was detected in 10 of the 45 HCC patients,but not detected in 17 cirrhosis patients and 76 healthy donors.The specific cytotoxic T cells elicited by OY-TES-1 could kill HLA-A2^+HCC cell line which expressed OY-TES-1.The target lysis was mainly HLA class I-dependent and could be blocked by antibodies against monomorphic HLA class I but not HLA class II molecule.In summary,OY-TES-1 expression is upregulated in HCC tissues and can be recognized by humoral and cellular responses,which suggests that OY-TES-1 is an attractive target for tumor immunotherapy in HCC.
基金supported by the National Key R&D Program of China(Grant Nos.2018YFA0208900 and 2018YFE0205300)the Beijing Natural Science Foundation of China(Grant No.Z200020)+5 种基金the Beijing Nova Program(Grant No.Z201100006820031)the Taishan Scholars Program of Shandong Province(Grant No.ts20190987)the National Natural Science Foundation of China(Grant Nos.31800838,31820103004,31730032,and 31800799)the Key Research Project of Frontier Science of the Chinese Academy of Sciences(Grant No.QYZDJSSW-SLH022)the Innovation Research Group of National Natural Science Foundation(Grant No.11621505)the Hundred-Talent Program of the Chinese Academy of Sciences。
文摘Nanomaterial-based delivery vehicles such as lipid-based,polymer-based,inorganics-based,and bio-inspired vehicles often carry distinct and attractive advantages in the development of therapeutic cancer vaccines.Based on various delivery vehicles,specifically designed nanomaterials-based vaccines are highly advantageous in boosting therapeutic and prophylactic antitumor immunities.Specifically,therapeutic vaccines featuring unique properties have made major contributions to the enhancement of antigen immunogenicity,encapsulation efficiency,biocompatibility,and stability,as well as promoting antigen cross-presentation and specific CD8^(+)T cell responses.However,for clinical applications,tumor-associated antigen-derived vaccines could be an obstacle,involving immune tolerance and deficiency of tumor specificities,in achieving maximum therapeutic indices.However,when using bioinformatics predictions with emerging innovations of in silico tools,neoantigen-based therapeutic vaccines might become potent personalized vaccines for tumor treatments.In this review,we summarize the development of preclinical therapeutic cancer vaccines and the advancements of nanomaterial-based delivery vehicles for cancer immunotherapies,which provide the basis for a personalized vaccine delivery platform.Moreover,we review the existing challenges and future perspectives of nanomaterial-based personalized vaccines for novel tumor immunotherapies.
基金National Natural Science Foundation of China(51933011,31971296,52173125,82102194,81873920,82001930)Key Areas Research and Development Program of Guangzhou(202007020006)+2 种基金Natural Science Foundation of the Guangdong Province(2021A1515010250,2020A1515111206,2021A1515111006)China Postdoctoral Science Foundation(2020M680119,2021M703763)Funding of the Southern Medical University Nanfang Hospital(2019C015).
文摘Thermal ablation(TA)as an effective method treating hepatocellular carcinoma(HCC)in clinics is facing great challenges of high recurrence and metastasis.Although immune-checkpoint blockade(ICB)-based immuno-therapy has shown potential to inhibit recurrence and metastasis,the combination strategy of ICB and thermal ablation has shown little progress in HCC treatments.The tremendous hurdle for combining ICB with thermal ablation lies with the insufficient antigen internalization and immaturity of tumor-infiltrating dendritic cells(TIDCs)which leads to an inferior immune response to distant tumor growth and metastasis.Herein,an antigen-capturing nanoplatform,whose surface was modified with mannose as a targeting ligand,was constructed for co-delivering tumor-associated antigens(TAAs)and m6A demethylases inhibitor(i.e.,fat mass and obesity asso-ciated gene(FTO)inhibitor)into TIDCs.In vivo results demonstrate that the intratumoral injection of nanodrug followed by HCC thermal ablation promotes dendritic cells(DCs)maturation,improves tumor infiltration of effector T cells and generates immune memory,which synergize with ICB treatment to inhibit the distant tumor growth and lung metastasis.Therefore,the antigen-capturing and FTO-inhibiting nanodrug holds potential to boost the ICB-based immunotherapy against HCC after thermal ablation.
基金supported by the National Natural Science Foundation of China(Nos.21877036 and 32201044)the Key Project of Developmental Biology and Breeding from Hunan Province(No.2022XKQ0205)+1 种基金the Hunan Natural Science Foundation(No.2021JJ40335)the Science and Technology Planning Project of Hunan Province(No.2018TP1017).
文摘The activation of the stimulating factor of the interferon gene(STING)pathway can enhance the immune response within the tumor.Cyclic diguanylate monophosphate(c-di-GMP)is a negatively charged,hydrophilic STING agonist,however,its effectiveness is limited due to the poor membrane permeability and low bioavailability.Herein,we introduced KL-7 peptide derived from Aβamyloid fibrils that can self-assemble to form nanotubes to load and deliver c-di-GMP,which significantly enhanced c-di-GMP’s effectiveness and then exhibited a robust“in situ immunity”to kill melanoma cells.KL-7 peptide nanotube,also called PNT,was loaded with negatively charged c-di-GMP via electrostatic interaction,which prepared a nanocomposite named c-di-GMP-PNT.Treatment of RAW 264.7 cells(leukemia cells in mouse macrophage)with c-di-GMP-PNT markedly stimulated the secretion of IL-6 and INF-βalong with phospho-STING(Ser365)protein expression,indicating the activation of the STING pathway.In the unilateral flank B16-F10(murine melanoma cells)tumor-bearing mouse model,compared to PNT and cdi-GMP,c-di-GMP-PNT can promote the expression of INF-β,TNF-α,IL-6,and IL-1β.At the same time,up-regulated CD4 and CD8 active T cells kill tumors and enhance the immune response in tumor tissues,resulting in significant inhibition of tumor growth in tumor-bearing mice.More importantly,in a bilateral flank B16-F10 tumor model,both primary and distant tumor growth can also be significantly inhibited by c-di-GMP-PNT.Moreover,c-di-GMP-PNT demonstrated no obvious biological toxicity on the main organs(heart,liver,spleen,lung,and kidney)and biochemical indexes of mice.In summary,our study provides a strategy to overcome the barriers of free c-di-GMP in the tumor microenvironment and c-di-GMP-PNT may be an attractive nanomaterial for anti-tumor immunity.
基金supported by the National Natural Science Foundation of China(Grant Nos.31971371 and U20A20409)the Key R&D Program of Zhejiang Province,China(Grant No.2020C03010)+1 种基金the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(Grant No.LHDMZ22H300002)the AlibabaZhejiang University Joint Research Center of Future Digital Healthcare.
文摘In recent years,neoantigens have been recognized as ideal targets for tumor immunotherapy.With the development of neoantigen-based tumor immunotherapy,comprehensive neoantigen databases are urgently needed to meet the growing demand for clinical studies.We have built the tumor-specific neoantigen database(TSNAdb)previously,which has attracted much attention.In this study,we provide TSNAdb v2.0,an updated version of the TSNAdb.TSNAdb v2.0 offers several new features,including(1)adopting more stringent criteria for neoantigen identification,(2)providing predicted neoantigens derived from three types of somatic mutations,and(3)collecting experimentally validated neoantigens and dividing them according to the experimental level.
基金supported in part by grants from the Beijing Natural Science Foundation of China(Grant No.7192123,7222117)the National Natural Science Foundation of China(Grant No.31770793,82000812)the Youth Innovation Promotion Association of Chinese Academy of Sciences(Grant No.2018122).
文摘As one of the main tumor-infiltrating immune cell types, tumor-associated macrophages (TAMs) determine the efficacy of immunotherapy. However, limited knowledge about their phenotypically and functionally heterogeneous nature restricts their application in tumor immunotherapy. In this study, we identified a subpopulation of CD146+ TAMs that exerted antitumor activity in both human samples and animal models. CD146 expression in TAMs was negatively controlled by STAT3 signaling. Reducing this population of TAMs promoted tumor development by facilitating myeloid-derived suppressor cell recruitment via activation of JNK signaling. Interestingly, CD146 was involved in the NLRP3 inflammasome-mediated activation of macrophages in the tumor microenvironment, partially by inhibiting transmembrane protein 176B (TMEM176B), an immunoregulatory cation channel. Treatment with a TMEM176B inhibitor enhanced the antitumor activity of CD146+ TAMs. These data reveal a crucial antitumor role of CD146+ TAMs and highlight the promising immunotherapeutic approach of inhibiting CD146 and TMEM176B.
基金supported by the National Key Research and Development Program of China(No.2022YFC2408000)the National Natural Science Foundation of China(NSFC)(Nos.82072063,32001005,32101136,and 82202306)+3 种基金Key Research and Development Program of Shaanxi Province(No.2023-YBSF-132)Shaanxi Province Youth Science and Technology New Star(No.2022KJXX-09)Natural Science Foundation of Shaanxi Province(No.2020JQ610)Science Foundation of Nanjing Chia Tai Tianqing project(No.TQ202215).
文摘Our improved knowledge of tumor immunology laid a solid foundation for the clinical use of tumor immunotherapies such as immune checkpoint blockers,and the efficacy of these drugs increased our confidence that immunomodulation was a viable way of treating cancer.The basis of immunotherapy is to break the immune escape of the tumor and resolve the immune suppressive microenvironment of tumors.Nanomaterial-mediated dynamic therapy(NDT)is an emerging immuno-regulatable type for tumor therapy,whose effects are mediated by increased cellular levels of reactive oxygen species(ROS).ROS is a potent trigger of immunogenic cell death,and this process initiates antitumor immunity.Nanomaterials for use in NDT can be engineered to interact with almost all cell types in the tumor microenvironment to remodel this environment.In this review,we systematically examined the effects of NDT on four major cell types in the tumor microenvironment,namely tumor cells,lymphocytes,myeloid cells,and tumor stromal cells.We believe that this review will improve researchers’understanding of the anti-tumor immunity triggered by NDT,and provide ideas and inspiration for how optimally designed NDT schemes can be used to target the cells in the tumor microenvironment.
基金This work was supported by the start-up package from the University of Wisconsin-Madison(to Q.Y.H.).
文摘Activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes(cGAS/STING)signaling has emerged as a promising anti-tumor strategy due to the important role of the pathway in innate and adaptive immunity,yet the selective delivery of STING agonists to tumors following systemic administration remains challenging.Herein,we develop a nano-STING agonist-decorated microrobot platform to achieve the enhanced anti-tumor effect.Fe ions and the STING agonist 2’3’-cyclic guanosine monophosphate-adenosine monophosphate(cGAMP)are co-encapsulated in the mitochondria-targeting nanoparticles(mTNPs),which can trigger the release of mitochondrial DNA(mtDNA)by Fenton reactioninduced mitochondria oxidative damage.The exogenous cGAMP and the endogenous mtDNA can work synergistically to induce potent cGAS/STING signaling activation.Furthermore,we decorate mTNPs onto Salmonella typhimurium VNP20009(VNP)bacteria to facilitate tumor accumulation and deep penetration.We demonstrate that the systemic administration of this microrobot activates both innate and adaptive immunity,improving the immunotherapeutic efficacy of the STING agonists.
