Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death(ICD),making it a promising strategy for clinical application....Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death(ICD),making it a promising strategy for clinical application.Alantolactone(A)was found to augment the anticancer efficacy of paclitaxel(P)at a molar ratio of 1:0.5(P:A)through induction of more potent ICD via modulation of STAT3 signaling pathways.Nano drug delivery systems can synergistically combine natural drugs with conventional chemotherapeutic agents,thereby enhancing multi-drug chemoimmunotherapy.To improve tumor targeting ability and bioavailability of hydrophobic drugs,an amphiphilic prodrug conjugate(HA-PTX)was chemically modified with paclitaxel(PTX)and hyaluronic acid(HA)as a backbone.Based on this concept,CD44-targeted nanodrugs(A@HAP NPs)were developed for co-delivery of A and P in colorectal cancer treatment,aiming to achieve synergistic toxicity-based chemo-immunotherapy.The uniform size and high drug loading capacity of A@HAP NPs facilitated their accumulation within tumors through enhanced permeability and retention effect as well as HA-mediated targeting,providing a solid foundation for subsequent synergistic therapy and immunoregulation.In vitro and in vivo studies demonstrated that A@HAP NPs exhibited potent cytotoxicity against tumor cells while also remodeling the immune-suppressive tumor microenvironment by promoting antigen presentation and inducing dendritic cell maturation,thus offering a novel approach for colorectal cancer chemoimmunotherapy.展开更多
Antibody humanization is critical to reduce immunogenicity and enhance efficacy in the preclinical phase of the development of therapeutic antibodies originated from animal models.Computational suggestions have long b...Antibody humanization is critical to reduce immunogenicity and enhance efficacy in the preclinical phase of the development of therapeutic antibodies originated from animal models.Computational suggestions have long been desired,but available tools focused on immunogenicity calculation of whole antibody sequences and sequence segments,missing the individual residue sites.This study introduces Site-specific Immunogenicity for Therapeutic Antibody(SITA),a novel computational framework that predicts B-cell immunogenicity score for not only the overall antibody,but also individual residues,based on a comprehensive set of amino acid descriptors characterizing physicochemical and spatial features for antibody structures.A transfer-learning-inspired framework was purposely adopted to overcome the scarcity of Antibody-Antibody structural complexes.On an independent testing dataset derived from 13 Antibody-Antibody structural complexes,SITA successfully predicted the epitope sites for Antibody-Antibody structures with a receiver operating characteristic(ROC)-area unver the ROC curve(AUC)of 0.85 and a precision-recall(PR)-AUC of 0.305 at the residue level.Furthermore,the SITA score can significantly distinguish immunogenicity levels of whole human antibodies,therapeutic antibodies and non-human-derived antibodies.More importantly,analysis of an additional 25 thera-peutic antibodies revealed that over 70%of them were detected with decreased immunogenicity after modification compared to their parent variants.Among these,nearly 66%antibodies successfully iden-tified actual modification sites from the top five sites with the highest SITA scores,suggesting the ability of SITA scores for guide the humanization of antibody.Overall,these findings highlight the potential of SITA in optimizing immunogenicity assessments during the process of therapeutic antibody design.展开更多
BACKGROUND Radiotherapy(RT)is a cornerstone of cancer treatment.Compared with conven-tional high-dose radiation,low-dose radiation(LDR)causes less damage to normal tissues while potentially modulating immune responses...BACKGROUND Radiotherapy(RT)is a cornerstone of cancer treatment.Compared with conven-tional high-dose radiation,low-dose radiation(LDR)causes less damage to normal tissues while potentially modulating immune responses and inhibiting tumor growth.LDR stimulates both innate and adaptive immunity,enhancing the activity of natural killer cells,dendritic cells,and T cells.However,the me-chanisms underlying the effects of LDR on the immune system remain unclear.AIM To explore the history,research hotspots,and emerging trends in immune response to LDR literature over the past two decades.METHODS Publications on immune responses to LDR were retrieved from the Web of Science Core Collection.Bibliometric tools,including CiteSpace and HistCite,were used to identify historical features,active topics,and emerging trends in this field.RESULTS Analysis of 1244 publications over the past two decades revealed a significant surge in research on immune responses to LDR,particularly in the last decade.Key journals such as INR J Radiat Biol,Cancers,and Radiat Res published pivotal studies.Citation networks identified key studies by authors like Twyman-Saint Victor C(2015)and Vanpouille-Box C(2017).Keyword analysis revealed hotspots such as ipilimumab,stereotactic body RT,and targeted therapy,possibly identifying future research directions.Temporal variations in keyword clusters and alluvial flow maps illustrate the evolution of research themes over time.CONCLUSION This bibliometric analysis provides valuable insights into the evolution of studies on responses to LDR,highlights research trends,and identifies emerging areas for further investigation.展开更多
African swine fever(ASF),caused by African swine fever virus(ASFV),is a highly contagious swine disease that has spread globally.Effective control strategies are not yet available.In this study,we prepared K205R mRNA,...African swine fever(ASF),caused by African swine fever virus(ASFV),is a highly contagious swine disease that has spread globally.Effective control strategies are not yet available.In this study,we prepared K205R mRNA,which was then formulated using Lipid Nanoparticle(LNP).The resulting K205R mRNA-LNP showed a particle size of approximately 86.27 nm and an mRNA encapsulation efficiency of 96.24%.Efficient expression of the K205R protein was confirmed in both HEK293T and PK15 cells.We further evaluated the immunogenicity of K205R mRNA-LNP in mice and pigs.All immunized animals developed significantly higher levels of IgG antibodies against K205R compared to the control group in the first week after the second immunization,with antibody titers reaching up to 105.Challenge experiments showed that K205R mRNA delayed the time of death.Our results suggested the successful implementation of the mRNA platform in the preparation and application of ASFV mRNA.展开更多
Ferroptosis in combination with immune therapy emerges as a promising approach for cancer therapy.Herein,dual-responsive metal-polyphenol coordinated nanomedicines were developed for pH/glutathione(GSH)-responsive syn...Ferroptosis in combination with immune therapy emerges as a promising approach for cancer therapy.Herein,dual-responsive metal-polyphenol coordinated nanomedicines were developed for pH/glutathione(GSH)-responsive synergistic ferroptosis and immunotherapy.Our innovative strategy involves the development of a manganese-polyphenol coordinated nanostructure,leveraging the biocompatibility of bovine serum albumin(BSA)as a template to encapsulate the anticancer drug sorafenib.The tumor microenvironment(pH/GSH)prompts the disassembly of MnO_(2)and epigallocatechin gallate(EGCG),thereby releases the anticancer payload.Concurrently,MnO_(2)acts to deplete intracellular GSH,which in turn suppresses glutathione peroxidase activity,leading to an accumulation of lipid peroxides with cell ferroptosis.Additionally,the release of Mn^(2+)ions bolster the cyclic guanosine monophosphlic acid(GMP)-adenosine monophosphlic acid(AMP)synthase-stimulator of interferon gene(cGAS-STING)pathway,which,in conjunction with the immunogenic cell death(ICD)effect induced by tumor cell apoptosis,significantly promotes dendritic cell(DC)maturation and enhances the presentation of tumor antigens.This successively ignites a robust innate and adaptive immune response.Both in vitro and in vivo experiments have demonstrated that the concurrent administration of ferroptosis-inducing and immune-stimulating therapies can significantly inhibit tumor growth.展开更多
Scrub typhus is an acute undifferentiated febrile infectious disease transmitted by a chigger(genus Leptotrombidium)bite carrying Orientia(O.)tsutsugamushi,affecting millions of people annually while more than one bil...Scrub typhus is an acute undifferentiated febrile infectious disease transmitted by a chigger(genus Leptotrombidium)bite carrying Orientia(O.)tsutsugamushi,affecting millions of people annually while more than one billion people are susceptible.Endemic areas are expanding to Africa,Europe,Middle East,and South America which is concerning,as despite best efforts,there is no vaccine to combat the bacteria.There are now three species of Orientia and over 20 strains of O.tsutsugamushi.The past attempts to develop a vaccine have been ineffective as they confer homologous strain-specific immunity.Various immunogenic proteins of O.tsutsugamushi have been identified that interact with the extracellular matrix(fibronectin)or vMLL5 receptor and modify the cytoskeleton of non-phagocytic host cells,which aids in host cell adhesion and invasion.These highly conserved proteins involve type specific antigen 56(TSA56),47 kDa,OmpA,and autotransporter proteins(ScaA,ScaB and ScaC).TSA56 is the most immunogenic and contains four types of hypervariable regions.Out of all autotransporter proteins,ScaA provides the homologous strains specific immunity and when coupled with TSA56 it shows better protective immunity against heterologous strains.The review provides detailed insight into the potential immunogenic proteins of Orientia which can be utilized to develop the vaccine.Furthermore,studies focused on highly antigenic proteins will provide more insight into their roles in developing therapeutics and easy-to-handle rapid diagnostic kits.展开更多
Innovative anti-cancer therapies that activate the immune system show promise in combating cancers resistant to conventional treatments.Photodynamic therapy(PDT)is one such treatment,which not only directly eliminates...Innovative anti-cancer therapies that activate the immune system show promise in combating cancers resistant to conventional treatments.Photodynamic therapy(PDT)is one such treatment,which not only directly eliminates tumor cells but also functions as an in situ tumor vaccine by enhancing tumor immunogenicity and triggering anti-tumor immune responses through immunogenic cell death(ICD).However,the effectiveness of PDT in enhancing immune responses is influenced by factors,such as photosensitizers and the tumor microenvironment,particularly hypoxia.Current clinically used PDT heavily relies on oxygen(O_(2))availability and can be limited by tumor hypoxia.Additionally,the tumor immunosuppressive microenvironment induced by hypoxia affects the anti-tumor immunity of tumor-infiltrating effector T cells.Meanwhile,the immunosuppressive myeloid-lineage cells are recruited to the hypoxic tumor tissue and exhibit higher immunosuppressive capabilities under hypoxia conditions.Consequently,numerous strategies have been developed to modulate tumor hypoxia or to create hypoxia-compatible PDT,aiming to reduce the effects of tumor hypoxia on PDT-driven immunotherapy.This review investigates these strategies,including approaches to alleviate,exploit,and disregard tumor hypoxia within the context of PDT/immunotherapy.It also emphasizes the role of advanced nanomedicine and its benefits in these strategies,while outlining current challenges and future prospects in the field.展开更多
Therapeutic antibodies are valued for their high specificity and selectivity in immu-notherapy.However,the potential toxicity they may elicit underscores the necessity of assessing their preclinical efficacy and safet...Therapeutic antibodies are valued for their high specificity and selectivity in immu-notherapy.However,the potential toxicity they may elicit underscores the necessity of assessing their preclinical efficacy and safety using suitable animal models.In this context,we review the various categories and applications of humanized mice,which have been engrafted with human cells or tissues to mimic the human immune system.These models are extensively utilized in the nonclinical assessment and development of various antibody drugs,acting as a conduit to clinical research.However,several challenges remain,including the limited lifespan of humanized mice,inadequate en-graftment of human cells,and the rudimentary nature of the immune environment in these models.The development of humanized immune system models in mice pre-sents both opportunities and challenges,potentially leading to new insights into the evolution and application of antibody therapeutics.展开更多
Chemotherapeutic drugs such as doxorubicin(DOx)and oxaliplatin can induce immunogenic cell death(ICD)in tumor cells.Current studies have demonstrated that peptide-based drugs can also induce ICD in tumor cells.Unlike ...Chemotherapeutic drugs such as doxorubicin(DOx)and oxaliplatin can induce immunogenic cell death(ICD)in tumor cells.Current studies have demonstrated that peptide-based drugs can also induce ICD in tumor cells.Unlike small molecule drugs,peptide drugs not only enhance the effectiveness of immunotherapy but also offer the advantage of low biotoxicity[1].展开更多
The Salmonella pathogenicity islands(SPIs) play crucial roles in the progression of Salmonella infection. In this study, we constructed an improved λ Red homologous recombination system to prepare single and triple d...The Salmonella pathogenicity islands(SPIs) play crucial roles in the progression of Salmonella infection. In this study, we constructed an improved λ Red homologous recombination system to prepare single and triple deletion mutants of 3 prominent SPIs(SPI-1, 2, and 3), aiming at the impact of deletion on morphology, carbon source metabolism, adhesion and invasion capacity, in vivo colonization, and immune efficacy in chicks. Our examination revealed that the surface of the single deletion mutants(SM6ΔSPI1, ΔSPI2, and ΔSPI3) exhibited a more rugged texture and appeared to be enveloped in a layer of transparent colloid, whereas the morphology of the triple deletion mutant(SM6ΔSPI1&2&3) remained unaltered when compared to the parent strain. The carbon metabolic spectrum of the SPI mutants underwent profound alterations, with a notable and statistically significant modification observed in 30 out of 95 carbon sources, primarily carbohydrates(17 out of 30). Furthermore, the adhesion capacity of the 4 mutants to Caco-2 cells was significantly reduced when compared to that of the parent strain. Moreover,the invasion capacity of mutants SM6ΔSPI1 and SM6ΔSPI1&2&3 exhibited a substantial decrease, while it was enhanced to varying degrees for SM6ΔSPI3 and SM6ΔSPI2. Importantly, none of the 4 mutants induced any clinical symptoms in the chicks. However, they did transiently colonize the spleen and liver. Notably, the SM6ΔSPI1&2&3mutant was rapidly cleared from both the spleen and liver within 8 days post-infection and no notable pathological changes were observed in the organs. Additionally, when challenged, the mutants immunized groups displayed a significant increase in antibody levels and alterations in the CD3+CD4+ and CD3+CD8+ subpopulations, and the levels of IL-4 and IFN-γ cytokines in the SM6ΔSPI1&2&3 immunized chicken serum surpassed those of other groups.In summary, the successful construction of the 4 SPI mutants lays the groundwork for further exploration into the pathogenic(including metabolic) mechanisms of SPIs and the development of safe and effective live attenuated Salmonella vaccines or carriers.展开更多
Chemodynamic therapy(CDT),using Fenton agents to generate highly cytotoxic•OH from H_(2)O_(2)has been demonstrated as a powerful anticancer method.However,the insufficient endogenous H_(2)O_(2)in tumor cells greatly l...Chemodynamic therapy(CDT),using Fenton agents to generate highly cytotoxic•OH from H_(2)O_(2)has been demonstrated as a powerful anticancer method.However,the insufficient endogenous H_(2)O_(2)in tumor cells greatly limited its therapeutic effect.Herein,we prepared a pH-responsiveβ-lapachone-loaded ironpolyphenol nanocomplex(LIPN)through a one-pot method.β-Lapachone in LIPN selectively enhanced H_(2)O_(2)concentration in tumor cells,and ferrous ions cascadely generated abundant cytotoxic•OH.Therefore,LIPN with cascade amplification of reactive oxygen species(ROS)showed high chemodynamic cytotoxicity in tumor cells,efficiently improving the expression of damage-associated molecular patterns(DAMPs),and exerting strong immunogenic cell death(ICD).As a result,LIPN exhibited efficient tumor inhibition ability in 4T1 subcutaneous tumor model in vivo with great biocompatibility.Additionally,the infiltration of cytotoxic CD8^(+)T lymphocytes and inhibition of regulatory CD4^(+)FoxP3^(+)T lymphocytes in tumors demonstrated the activation of immunosuppressive tumor microenvironment by LIPN-induced ICD.Therefore,this work provided a new approach to enhance ICD of chemodynamic therapy through selective cascade amplification of ROS in cancer cells.展开更多
To treat cancer and inhibit its metastasis to the greatest extent,we proposed to develop an Au(III)agent to induce immunogenic cell death(ICD)and establish long-term immunity.To this end,we optimized a series of Au(II...To treat cancer and inhibit its metastasis to the greatest extent,we proposed to develop an Au(III)agent to induce immunogenic cell death(ICD)and establish long-term immunity.To this end,we optimized a series of Au(III)2-benzoylpyridine thiosemicarbazone complexes to obtain an Au(III)agent(5b)with excellent cytotoxicity to cancer.The results show that 5b effectively inhibits tumor growth and its metastasis in vivo.Interestingly,we revealed a new mechanism of 5b inhibiting tumor growth and metastasis:5b releases ICD-related damage-associated molecular patterns(DAMPs),such as calreticulin(CRT),ATP and high mobility group box 1(HMGB1)by inducing endoplasmic reticulum stress(ERS)and mitochondrial dysfunction,which then stimulated an antitumor CD8^(+)T cell response and Foxp^(3+)T cell depletion,thus establishing long-action antitumor immunity.展开更多
As PEGylated liposomes have witnessed remarkable advancements in drug delivery,their immunogenicity has emerged as a notable challenge.In this study,we discovered that a simple pre-injection of folic acid(FA)effective...As PEGylated liposomes have witnessed remarkable advancements in drug delivery,their immunogenicity has emerged as a notable challenge.In this study,we discovered that a simple pre-injection of folic acid(FA)effectively mitigated the immunogenicity of PEGylated liposomes and enhanced their in vivo performance by tolerating splenic marginal zone B cells.FA specifically inhibited the internalization of PEGylated liposomes by splenic marginal zone B cells,thereby reducing splenic lymphocyte proliferation and specific IgM secretion.This modulation alleviated Ig M-mediated accelerated blood clearance and adverse accumulation of the PEGylated liposomes in the skin.These findings provide new insights into the immunomodulatory effects of FA and promising avenues to enhance the efficacy and safety of PEGylated liposomal nanomedicines.展开更多
Melanomas are aggressive cancers,with a high rate of metastatic disease.Cutaneous(CM)and uveal(UM)melanomas are intrinsically different diseases,and most cell death inducers effective for CM do not function for UM.Thi...Melanomas are aggressive cancers,with a high rate of metastatic disease.Cutaneous(CM)and uveal(UM)melanomas are intrinsically different diseases,and most cell death inducers effective for CM do not function for UM.This is primarily due to the fact the eye is an immunologically privileged organ,and it fails to achieve the efficacy of immune checkpoint inhibitors(ICIs)comparable to that for CM.However,approaches utilizing specific melanomaassociated antigens are being developed for metastatic forms of CM and UM.The most promising to date are gp100 and tyrosinase related protein 1(TYRP1),primarily for the design of targeting chimeric molecules and for autologous T-/NK-cell products with a chimeric antigen receptor.The difference in the mutational profile of apoptosis-related genes in CM and UM also makes counterproductive the use of the same drugs re-activators of the intrinsic pathway of apoptosis.Therefore,the discovery of novel pathways of regulated cell death such as ferroptosis and cuproptosis may help in the development of new drugs for melanomas resistant to already available inducers of regulated cell death.Here we consistently discuss the latest advances in the therapy of melanomas,and above all-UM,which is classified as an orphan disease.展开更多
Established evidence has unveiled two strategies for treating cancer:depleting tumor-associated macrophages(TAMs)and reprogramming M2-like TAMs into an antitumor M1 phenotype.Here,we designed novel p H-sensitive biomi...Established evidence has unveiled two strategies for treating cancer:depleting tumor-associated macrophages(TAMs)and reprogramming M2-like TAMs into an antitumor M1 phenotype.Here,we designed novel p H-sensitive biomimetic hybrid nanovesicles(EDHPA)loaded with doxorubicin(DOX).DOX@EDHPA can specifically target TAMs by activating macrophage-derived exosomes(M1-Exos)and anisamide(AA)as cancer-specific targeting ligands.In vitro and in vivo studies demonstrated that DOX@EDHPA could efficiently be delivered to the tumor site and taken up by cells.Meanwhile,it synergistically enhanced immunogenic cell death(ICD)and induced a subsequent antigen-specific T cell immune response.The tumor inhibitory rate of the DOX@EDHPA group was 1.42 times that of the free DOX group.Further analysis showed that the excellent antitumor effects of DOX@EDHPA should ascribe to the homing effect of M1-Exos on macrophages and the repolarization to antitumor M1 TAMs,which induced the elevated secretion of pro-infiammatory factors.Therefore,the hybrid EDHPA targeting TAMs to reshape the tumor microenvironment constituted a novel immunochemotherapy strategy to inhibit tumor growth.展开更多
Objectives:Hepatocellular carcinoma(HCC)is among the most frequently occurring malignant tumors of the digestive tract and is associated with an increased mortality rate worldwide.This study aimed to develop and valid...Objectives:Hepatocellular carcinoma(HCC)is among the most frequently occurring malignant tumors of the digestive tract and is associated with an increased mortality rate worldwide.This study aimed to develop and validate a prognostic model based on immunogenic cell death(ICD)-related genes to predict patient survival and guide individualized treatment strategies for HCC.Methods:ICD-related genes were identified from the GeneCards database using a relevance score threshold of A combination of least absolute shrinkage and selection operator(LASSO)>10.regression and multivariate Cox analysis was used to screen prognostic genes and construct a risk score model.Immune cell infiltration was evaluated through single-sample gene set enrichment analysis(ssGSEA)and cell-type identification by estimating relative subsets of RNA transcripts(CIBERSORT)algorithms.Associations between risk groups and the tumor microenvironment(TME),N6-methyladenosine(m6A)regulators,and immune checkpoint expression were analyzed.Drug sensitivity was predicted based on the risk stratification.The reliability of the model was validated in internal cohorts and further confirmed by quantitative reverse transcription polymerase chain reaction(qRT-PCR)and immunohistochemistry(IHC).Results:A six-gene signature(CFHR3,G6PD,IGHM,KPNA2,PON1,and SERPINE1)was identified and used to calculate the risk scores.This study found that high-risk patients exhibited significantly poorer overall survival in both the training and validation datasets.The nomogram integrating the risk score and clinical factors showed strong predictive performance.High-risk patients demonstrated reduced immune cell infiltration,altered expression of immune checkpoints and immunosuppressive factors,and a distinct m6A modification pattern,suggesting a higher likelihood of immune escape.This study also revealed that the risk model effectively predicted sensitivity to multiple anticancer drugs.Conclusion:This study developed a robust ICD-related six-gene prognostic model for HCC that can accurately stratify patient risk,reflect the tumor immune landscape,and provide guidance for immunotherapy and personalized treatment strategies.展开更多
BACKGROUND The gluten-free diet(GFD)has limitations,and there is intense research in the development of adjuvant therapies.AIM To examine the effects of orally administered Aspergillus niger prolyl endopeptidase prote...BACKGROUND The gluten-free diet(GFD)has limitations,and there is intense research in the development of adjuvant therapies.AIM To examine the effects of orally administered Aspergillus niger prolyl endopeptidase protease(AN-PEP)on inadvertent gluten exposure and symptom prevention in adult celiac disease(CeD)patients following their usual GFD.METHODS This was an exploratory,double-blind,randomized,placebo-controlled trial that enrolled CeD patients on a long-term GFD.After a 4-wk run-in period,patients were randomized to 4 wk of two AN-PEP capsules(GliadinX;AVI Research,LLC,United States)at each of three meals per day or placebo.Outcome endpoints were:(1)Average weekly stool gluten immunogenic peptides(GIP)between the run-in and end of treatments and between AN-PEP and placebo;(2)celiac symptom index(CSI);(3)CeD-specific serology;and(4)quality of life.Stool samples were collected for GIP testing by ELISA every Tuesday and Friday during run-ins and treatments.RESULTS Forty patients were randomized for the intention-to-treat analysis,and three were excluded from the per-protocol assessment.Overall,628/640(98.1%)stool samples were collected.GIP was undetectable(<0.08μg/g)in 65.6%of samples,and no differences between treatment arms were detected.Only 0.5%of samples had GIP concentrations sufficiently high(>0.32μg/g)to potentially cause mucosal damage.Median GIP concentration in the AN-PEP arm was 44.7%lower than in the run-in period.One-third of patients exhibiting GIP>0.08μg/g during run-in had lower or undetectable GIP after AN-PEP treatment.Compared with the run-in period,the proportion of symptomatic patients(CSI>38)in the AN-PEP arm was significantly lower(P<0.03).AN-PEP did not result in changes in specific serologies.CONCLUSION This exploratory study conducted in a real-life setting revealed high adherence to the GFD.The AN-PEP treatment did not significantly reduce the overall GIP stool concentration.However,given the observation of a significantly lower prevalence of patients with severe symptoms in the AN-PEP arm,further clinical research is warranted.展开更多
Tumor vaccines are a promising avenue in cancer immunotherapy.Despite the progress in targeting specific immune epitopes,tumor cells lacking these epitopes can evade the treatment.Here,we aimed to construct an efficie...Tumor vaccines are a promising avenue in cancer immunotherapy.Despite the progress in targeting specific immune epitopes,tumor cells lacking these epitopes can evade the treatment.Here,we aimed to construct an efficient in situ tumor vaccine called Vac-SM,utilizing shikonin(SKN)to induce immunogenic cell death(ICD)and Mycobacterium smegmatis as an immune adjuvant to enhance in situ tumor vaccine efficacy.SKN showed a dose-dependent and time-dependent cytotoxic effect on the tumor cell line and induced ICD in tumor cells as evidenced by the CCK-8 assay and the detection of the expression of relevant indicators,respectively.Compared with the control group,the in situ Vac-SM injection in mouse subcutaneous metastatic tumors significantly inhibited tumor growth and distant tumor metastasis,while also improving survival rates.Mycobacterium smegmatis effectively induced maturation and activation of bone marrow-derived dendritic cells(DCs),and in vivo tumor-draining lymph nodes showed an increased maturation of DCs and a higher proportion of effector memory T-cell subsets with the Vac-SM treatment,based on flow cytometry analysis results.Collectively,the Vac-SM vaccine effectively induces ICD,improves antigen presentation by DCs,activates a specific systemic antitumor T-cell immune response,exhibits a favorable safety profile,and holds the promise for clinical translation for local tumor immunotherapy.展开更多
Objective The present study aimed to evaluate the immunogenicity of BA.2 variant receptor binding domain(RBD)recombinant protein formulated with CpG 1826 plus alum dual adjuvant.Methods The BA.2 variant RBD(residues 3...Objective The present study aimed to evaluate the immunogenicity of BA.2 variant receptor binding domain(RBD)recombinant protein formulated with CpG 1826 plus alum dual adjuvant.Methods The BA.2 variant RBD(residues 308-548)fusing TT-P2 epitope was obtained from prokaryotic expression system,purification technology and dialysis renaturation,which was designated as Sot protein.The soluble Sot protein formulated with CpG 1826 plus alum dual adjuvant was designated as Sot/CA subunit vaccine and then the BALB/c mice were intramuscularly administrated with two doses of the Sot/CA subunit vaccine at 14-day interval(day 0 and 14).On day 28,the number of effector T lymphocytes secreting IFN-γand IL-4 in mice spleen were determined by enzyme-linked immunospot(ELISpot)assay.The serum IgG,IgG1 and IgG2a antibodies were examined by enzyme-linked immunosorbent assay(ELISA).In addition,the level of neutralizing antibodies(NAbs)induced by Sot/CA subunit vaccine was also evaluated by the microneutralization assay.Results The high-purity soluble Sot protein with antigenicity was successfully obtained by the prokaryotic expression,protein purification and dialysis renaturation.The Sot/CA subunit vaccine induced a high level of IgG antibodies and NAbs,which were of cross-neutralizing activity against SARS-CoV-2 BA.2 and XBB.1.5 variants.Meanwhile,Sot/CA subunit vaccine also induced a high level of effector T lymphocytes secreting IFN-γ(635.00±17.62)and IL-4(279.20±13.10),respectively.Combined with a decreased IgG1/IgG2a ratio in the serum,which indicating Sot/CA subunit vaccine induced a Th1-type predominant immune response.Conclusion The Sot protein formulated with CpG 1826 plus alum dual adjuvant showed that the excellent cellular and humoral immunogenicity,which provided a scientific basis for the development of BA.2 variant subunit vaccines and references for the adjuvant application of subunit vaccines.展开更多
AIEgens can serve as an effective platform for the construction of photosensitizer-based immunogenic cell death(ICD)inducers.To date,several mitochondria or endoplasmic reticulum(ER)-targeted aggregationinduced emissi...AIEgens can serve as an effective platform for the construction of photosensitizer-based immunogenic cell death(ICD)inducers.To date,several mitochondria or endoplasmic reticulum(ER)-targeted aggregationinduced emission(AIE)molecules have been developed and have evoked massive ICD in cells.However,due to the complex physicochemical environment in cells,these small AIE molecules cannot maintain a stable aggregate state,which not only affects the fluorescence intensity of the photosensitizer but also decreases the generation of reactive oxygen species(ROS),and thus reducing the effect of the photosensitizer to elicit ICD.AIEgen-based nanomicelles,which maintain a stable micellar structure,can prevent defects of AIE molecules in photodynamic therapy(PDT)applications.Therefore,in this study,a mitochondria-targeted AIE nanophotosensitizer was synthesized and used as a highly potent ICD inducer for vaccine preparation and tumor prevention.展开更多
基金supported by Zhejiang Provincial Natural Science Foundation(LYY22H300001,LGF22H150016)Wenzhou Municipal Science and Technology Bureau(Y20210212)+2 种基金Application Basic Research Project of Liaoning Provincial Department of Science and Technology(2023JH2/101700072)Zhejiang Medical Doctor Association(YS2022-2-001)Health innovation talents program(Longfa Kou)from Health Commission of Zhejiang Province.
文摘Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death(ICD),making it a promising strategy for clinical application.Alantolactone(A)was found to augment the anticancer efficacy of paclitaxel(P)at a molar ratio of 1:0.5(P:A)through induction of more potent ICD via modulation of STAT3 signaling pathways.Nano drug delivery systems can synergistically combine natural drugs with conventional chemotherapeutic agents,thereby enhancing multi-drug chemoimmunotherapy.To improve tumor targeting ability and bioavailability of hydrophobic drugs,an amphiphilic prodrug conjugate(HA-PTX)was chemically modified with paclitaxel(PTX)and hyaluronic acid(HA)as a backbone.Based on this concept,CD44-targeted nanodrugs(A@HAP NPs)were developed for co-delivery of A and P in colorectal cancer treatment,aiming to achieve synergistic toxicity-based chemo-immunotherapy.The uniform size and high drug loading capacity of A@HAP NPs facilitated their accumulation within tumors through enhanced permeability and retention effect as well as HA-mediated targeting,providing a solid foundation for subsequent synergistic therapy and immunoregulation.In vitro and in vivo studies demonstrated that A@HAP NPs exhibited potent cytotoxicity against tumor cells while also remodeling the immune-suppressive tumor microenvironment by promoting antigen presentation and inducing dendritic cell maturation,thus offering a novel approach for colorectal cancer chemoimmunotherapy.
基金supported by funding from the National Key R&D Program of China(Grant Nos.:2023YFC3404000 and 2019YFA0905900)the National Natural Science Foundation of China(Grant Nos.:32370697 and 32070657)AI for the Science project of Fudan University,China(Project No.:XM06231724)。
文摘Antibody humanization is critical to reduce immunogenicity and enhance efficacy in the preclinical phase of the development of therapeutic antibodies originated from animal models.Computational suggestions have long been desired,but available tools focused on immunogenicity calculation of whole antibody sequences and sequence segments,missing the individual residue sites.This study introduces Site-specific Immunogenicity for Therapeutic Antibody(SITA),a novel computational framework that predicts B-cell immunogenicity score for not only the overall antibody,but also individual residues,based on a comprehensive set of amino acid descriptors characterizing physicochemical and spatial features for antibody structures.A transfer-learning-inspired framework was purposely adopted to overcome the scarcity of Antibody-Antibody structural complexes.On an independent testing dataset derived from 13 Antibody-Antibody structural complexes,SITA successfully predicted the epitope sites for Antibody-Antibody structures with a receiver operating characteristic(ROC)-area unver the ROC curve(AUC)of 0.85 and a precision-recall(PR)-AUC of 0.305 at the residue level.Furthermore,the SITA score can significantly distinguish immunogenicity levels of whole human antibodies,therapeutic antibodies and non-human-derived antibodies.More importantly,analysis of an additional 25 thera-peutic antibodies revealed that over 70%of them were detected with decreased immunogenicity after modification compared to their parent variants.Among these,nearly 66%antibodies successfully iden-tified actual modification sites from the top five sites with the highest SITA scores,suggesting the ability of SITA scores for guide the humanization of antibody.Overall,these findings highlight the potential of SITA in optimizing immunogenicity assessments during the process of therapeutic antibody design.
文摘BACKGROUND Radiotherapy(RT)is a cornerstone of cancer treatment.Compared with conven-tional high-dose radiation,low-dose radiation(LDR)causes less damage to normal tissues while potentially modulating immune responses and inhibiting tumor growth.LDR stimulates both innate and adaptive immunity,enhancing the activity of natural killer cells,dendritic cells,and T cells.However,the me-chanisms underlying the effects of LDR on the immune system remain unclear.AIM To explore the history,research hotspots,and emerging trends in immune response to LDR literature over the past two decades.METHODS Publications on immune responses to LDR were retrieved from the Web of Science Core Collection.Bibliometric tools,including CiteSpace and HistCite,were used to identify historical features,active topics,and emerging trends in this field.RESULTS Analysis of 1244 publications over the past two decades revealed a significant surge in research on immune responses to LDR,particularly in the last decade.Key journals such as INR J Radiat Biol,Cancers,and Radiat Res published pivotal studies.Citation networks identified key studies by authors like Twyman-Saint Victor C(2015)and Vanpouille-Box C(2017).Keyword analysis revealed hotspots such as ipilimumab,stereotactic body RT,and targeted therapy,possibly identifying future research directions.Temporal variations in keyword clusters and alluvial flow maps illustrate the evolution of research themes over time.CONCLUSION This bibliometric analysis provides valuable insights into the evolution of studies on responses to LDR,highlights research trends,and identifies emerging areas for further investigation.
基金funded by the National Key Research and Development Program of China(2022YFD1800500,2021YFD1801401,2023YFD1802600)the Central Public-interest Scientific Institution Basal Research Fund,China(Y2022PT11)the Shanghai Sailing Program,China(23YF1457400).
文摘African swine fever(ASF),caused by African swine fever virus(ASFV),is a highly contagious swine disease that has spread globally.Effective control strategies are not yet available.In this study,we prepared K205R mRNA,which was then formulated using Lipid Nanoparticle(LNP).The resulting K205R mRNA-LNP showed a particle size of approximately 86.27 nm and an mRNA encapsulation efficiency of 96.24%.Efficient expression of the K205R protein was confirmed in both HEK293T and PK15 cells.We further evaluated the immunogenicity of K205R mRNA-LNP in mice and pigs.All immunized animals developed significantly higher levels of IgG antibodies against K205R compared to the control group in the first week after the second immunization,with antibody titers reaching up to 105.Challenge experiments showed that K205R mRNA delayed the time of death.Our results suggested the successful implementation of the mRNA platform in the preparation and application of ASFV mRNA.
基金supported by the National Key R&D Program of China(No.2022YFC2304205)National Natural Science Foundation of China(Nos.51903062,52273128)the Plan on Enhancing Scientific Research in GMU(No.02-410-2405033).
文摘Ferroptosis in combination with immune therapy emerges as a promising approach for cancer therapy.Herein,dual-responsive metal-polyphenol coordinated nanomedicines were developed for pH/glutathione(GSH)-responsive synergistic ferroptosis and immunotherapy.Our innovative strategy involves the development of a manganese-polyphenol coordinated nanostructure,leveraging the biocompatibility of bovine serum albumin(BSA)as a template to encapsulate the anticancer drug sorafenib.The tumor microenvironment(pH/GSH)prompts the disassembly of MnO_(2)and epigallocatechin gallate(EGCG),thereby releases the anticancer payload.Concurrently,MnO_(2)acts to deplete intracellular GSH,which in turn suppresses glutathione peroxidase activity,leading to an accumulation of lipid peroxides with cell ferroptosis.Additionally,the release of Mn^(2+)ions bolster the cyclic guanosine monophosphlic acid(GMP)-adenosine monophosphlic acid(AMP)synthase-stimulator of interferon gene(cGAS-STING)pathway,which,in conjunction with the immunogenic cell death(ICD)effect induced by tumor cell apoptosis,significantly promotes dendritic cell(DC)maturation and enhances the presentation of tumor antigens.This successively ignites a robust innate and adaptive immune response.Both in vitro and in vivo experiments have demonstrated that the concurrent administration of ferroptosis-inducing and immune-stimulating therapies can significantly inhibit tumor growth.
基金funded by Department of Health Research,Government of India,New Delhi,India(grant number:YSS/2020/000116/PRCYSS).
文摘Scrub typhus is an acute undifferentiated febrile infectious disease transmitted by a chigger(genus Leptotrombidium)bite carrying Orientia(O.)tsutsugamushi,affecting millions of people annually while more than one billion people are susceptible.Endemic areas are expanding to Africa,Europe,Middle East,and South America which is concerning,as despite best efforts,there is no vaccine to combat the bacteria.There are now three species of Orientia and over 20 strains of O.tsutsugamushi.The past attempts to develop a vaccine have been ineffective as they confer homologous strain-specific immunity.Various immunogenic proteins of O.tsutsugamushi have been identified that interact with the extracellular matrix(fibronectin)or vMLL5 receptor and modify the cytoskeleton of non-phagocytic host cells,which aids in host cell adhesion and invasion.These highly conserved proteins involve type specific antigen 56(TSA56),47 kDa,OmpA,and autotransporter proteins(ScaA,ScaB and ScaC).TSA56 is the most immunogenic and contains four types of hypervariable regions.Out of all autotransporter proteins,ScaA provides the homologous strains specific immunity and when coupled with TSA56 it shows better protective immunity against heterologous strains.The review provides detailed insight into the potential immunogenic proteins of Orientia which can be utilized to develop the vaccine.Furthermore,studies focused on highly antigenic proteins will provide more insight into their roles in developing therapeutics and easy-to-handle rapid diagnostic kits.
基金supported by the Qin Chuangyuan Traditional Chinese Medicine(TCM)and Innovation Research and Development Project of Shaanxi Provincial Administration of TCM(No.2022-QCYZH-017)Natural Science Foundation of Zhejiang Province(No.LY24E030010)+5 种基金Natural Science Foundation of Shaanxi Province(Nos.2022JM183,2024JC-YBMS-272)the Shaanxi Fundamental Science Research Project for Chemistry&Biology(No.22JHQ072)Shaanxi Provincial Key R&D Program(No.2022SF-342HZ)the Fundamental Research Funds for the Central Universities(Nos.xzy012022037,xzy012023002)the Postdoctoral Science Foundation of Shaanxi Province(No.2023BSHYDZZ05)Foundation by Shaanxi Provincial Administration of TCM(No.2021-ZZ-JC032)。
文摘Innovative anti-cancer therapies that activate the immune system show promise in combating cancers resistant to conventional treatments.Photodynamic therapy(PDT)is one such treatment,which not only directly eliminates tumor cells but also functions as an in situ tumor vaccine by enhancing tumor immunogenicity and triggering anti-tumor immune responses through immunogenic cell death(ICD).However,the effectiveness of PDT in enhancing immune responses is influenced by factors,such as photosensitizers and the tumor microenvironment,particularly hypoxia.Current clinically used PDT heavily relies on oxygen(O_(2))availability and can be limited by tumor hypoxia.Additionally,the tumor immunosuppressive microenvironment induced by hypoxia affects the anti-tumor immunity of tumor-infiltrating effector T cells.Meanwhile,the immunosuppressive myeloid-lineage cells are recruited to the hypoxic tumor tissue and exhibit higher immunosuppressive capabilities under hypoxia conditions.Consequently,numerous strategies have been developed to modulate tumor hypoxia or to create hypoxia-compatible PDT,aiming to reduce the effects of tumor hypoxia on PDT-driven immunotherapy.This review investigates these strategies,including approaches to alleviate,exploit,and disregard tumor hypoxia within the context of PDT/immunotherapy.It also emphasizes the role of advanced nanomedicine and its benefits in these strategies,while outlining current challenges and future prospects in the field.
基金supported by the Independent Research and Development Projects Foundation of Shanghai InnoStar Bio-Techology Co.,Ltd.(H23ZZYF01 and H24ZZYF01).
文摘Therapeutic antibodies are valued for their high specificity and selectivity in immu-notherapy.However,the potential toxicity they may elicit underscores the necessity of assessing their preclinical efficacy and safety using suitable animal models.In this context,we review the various categories and applications of humanized mice,which have been engrafted with human cells or tissues to mimic the human immune system.These models are extensively utilized in the nonclinical assessment and development of various antibody drugs,acting as a conduit to clinical research.However,several challenges remain,including the limited lifespan of humanized mice,inadequate en-graftment of human cells,and the rudimentary nature of the immune environment in these models.The development of humanized immune system models in mice pre-sents both opportunities and challenges,potentially leading to new insights into the evolution and application of antibody therapeutics.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82073975,81673563,81102762,82204715,and 82304743).
文摘Chemotherapeutic drugs such as doxorubicin(DOx)and oxaliplatin can induce immunogenic cell death(ICD)in tumor cells.Current studies have demonstrated that peptide-based drugs can also induce ICD in tumor cells.Unlike small molecule drugs,peptide drugs not only enhance the effectiveness of immunotherapy but also offer the advantage of low biotoxicity[1].
基金supported by the National KeyR&DProgramof China(2022YFF0710500)the National Natural Science Foundation of China(32172853 and 32373013)the Central Public-interest Scientific Institution Basal Research Fund,China(1610302022001).
文摘The Salmonella pathogenicity islands(SPIs) play crucial roles in the progression of Salmonella infection. In this study, we constructed an improved λ Red homologous recombination system to prepare single and triple deletion mutants of 3 prominent SPIs(SPI-1, 2, and 3), aiming at the impact of deletion on morphology, carbon source metabolism, adhesion and invasion capacity, in vivo colonization, and immune efficacy in chicks. Our examination revealed that the surface of the single deletion mutants(SM6ΔSPI1, ΔSPI2, and ΔSPI3) exhibited a more rugged texture and appeared to be enveloped in a layer of transparent colloid, whereas the morphology of the triple deletion mutant(SM6ΔSPI1&2&3) remained unaltered when compared to the parent strain. The carbon metabolic spectrum of the SPI mutants underwent profound alterations, with a notable and statistically significant modification observed in 30 out of 95 carbon sources, primarily carbohydrates(17 out of 30). Furthermore, the adhesion capacity of the 4 mutants to Caco-2 cells was significantly reduced when compared to that of the parent strain. Moreover,the invasion capacity of mutants SM6ΔSPI1 and SM6ΔSPI1&2&3 exhibited a substantial decrease, while it was enhanced to varying degrees for SM6ΔSPI3 and SM6ΔSPI2. Importantly, none of the 4 mutants induced any clinical symptoms in the chicks. However, they did transiently colonize the spleen and liver. Notably, the SM6ΔSPI1&2&3mutant was rapidly cleared from both the spleen and liver within 8 days post-infection and no notable pathological changes were observed in the organs. Additionally, when challenged, the mutants immunized groups displayed a significant increase in antibody levels and alterations in the CD3+CD4+ and CD3+CD8+ subpopulations, and the levels of IL-4 and IFN-γ cytokines in the SM6ΔSPI1&2&3 immunized chicken serum surpassed those of other groups.In summary, the successful construction of the 4 SPI mutants lays the groundwork for further exploration into the pathogenic(including metabolic) mechanisms of SPIs and the development of safe and effective live attenuated Salmonella vaccines or carriers.
基金supported by the National Natural Science Foundation of China(Nos.T2293753,52203194)the National Key R&D Program of China(No.2021YFA1201200)+1 种基金the Natural Science Foundation of Zhejiang Province(No.LR18E030002)2023 Hangzhou West Lake Pearl Project Leading Innovative Youth Team Project.
文摘Chemodynamic therapy(CDT),using Fenton agents to generate highly cytotoxic•OH from H_(2)O_(2)has been demonstrated as a powerful anticancer method.However,the insufficient endogenous H_(2)O_(2)in tumor cells greatly limited its therapeutic effect.Herein,we prepared a pH-responsiveβ-lapachone-loaded ironpolyphenol nanocomplex(LIPN)through a one-pot method.β-Lapachone in LIPN selectively enhanced H_(2)O_(2)concentration in tumor cells,and ferrous ions cascadely generated abundant cytotoxic•OH.Therefore,LIPN with cascade amplification of reactive oxygen species(ROS)showed high chemodynamic cytotoxicity in tumor cells,efficiently improving the expression of damage-associated molecular patterns(DAMPs),and exerting strong immunogenic cell death(ICD).As a result,LIPN exhibited efficient tumor inhibition ability in 4T1 subcutaneous tumor model in vivo with great biocompatibility.Additionally,the infiltration of cytotoxic CD8^(+)T lymphocytes and inhibition of regulatory CD4^(+)FoxP3^(+)T lymphocytes in tumors demonstrated the activation of immunosuppressive tumor microenvironment by LIPN-induced ICD.Therefore,this work provided a new approach to enhance ICD of chemodynamic therapy through selective cascade amplification of ROS in cancer cells.
基金supported by the Natural Science Foundation of Guangxi(No.2022GXNSFGA035003)the National Natural Science Foundation of China(No.22077021).
文摘To treat cancer and inhibit its metastasis to the greatest extent,we proposed to develop an Au(III)agent to induce immunogenic cell death(ICD)and establish long-term immunity.To this end,we optimized a series of Au(III)2-benzoylpyridine thiosemicarbazone complexes to obtain an Au(III)agent(5b)with excellent cytotoxicity to cancer.The results show that 5b effectively inhibits tumor growth and its metastasis in vivo.Interestingly,we revealed a new mechanism of 5b inhibiting tumor growth and metastasis:5b releases ICD-related damage-associated molecular patterns(DAMPs),such as calreticulin(CRT),ATP and high mobility group box 1(HMGB1)by inducing endoplasmic reticulum stress(ERS)and mitochondrial dysfunction,which then stimulated an antitumor CD8^(+)T cell response and Foxp^(3+)T cell depletion,thus establishing long-action antitumor immunity.
基金supported by the National Natural Science Foundation of China(Nos.82373817 and 82003659)Shanghai Natural Science Foundation(No.23ZR1477500)Pudong Health Bureau of Shanghai(No.YC-2023-0401)。
文摘As PEGylated liposomes have witnessed remarkable advancements in drug delivery,their immunogenicity has emerged as a notable challenge.In this study,we discovered that a simple pre-injection of folic acid(FA)effectively mitigated the immunogenicity of PEGylated liposomes and enhanced their in vivo performance by tolerating splenic marginal zone B cells.FA specifically inhibited the internalization of PEGylated liposomes by splenic marginal zone B cells,thereby reducing splenic lymphocyte proliferation and specific IgM secretion.This modulation alleviated Ig M-mediated accelerated blood clearance and adverse accumulation of the PEGylated liposomes in the skin.These findings provide new insights into the immunomodulatory effects of FA and promising avenues to enhance the efficacy and safety of PEGylated liposomal nanomedicines.
基金supported by the Russian Science Foundation,project no.23-14-00285。
文摘Melanomas are aggressive cancers,with a high rate of metastatic disease.Cutaneous(CM)and uveal(UM)melanomas are intrinsically different diseases,and most cell death inducers effective for CM do not function for UM.This is primarily due to the fact the eye is an immunologically privileged organ,and it fails to achieve the efficacy of immune checkpoint inhibitors(ICIs)comparable to that for CM.However,approaches utilizing specific melanomaassociated antigens are being developed for metastatic forms of CM and UM.The most promising to date are gp100 and tyrosinase related protein 1(TYRP1),primarily for the design of targeting chimeric molecules and for autologous T-/NK-cell products with a chimeric antigen receptor.The difference in the mutational profile of apoptosis-related genes in CM and UM also makes counterproductive the use of the same drugs re-activators of the intrinsic pathway of apoptosis.Therefore,the discovery of novel pathways of regulated cell death such as ferroptosis and cuproptosis may help in the development of new drugs for melanomas resistant to already available inducers of regulated cell death.Here we consistently discuss the latest advances in the therapy of melanomas,and above all-UM,which is classified as an orphan disease.
基金supported by the National Natural Science Foundation of China(No.NSFC31872754)。
文摘Established evidence has unveiled two strategies for treating cancer:depleting tumor-associated macrophages(TAMs)and reprogramming M2-like TAMs into an antitumor M1 phenotype.Here,we designed novel p H-sensitive biomimetic hybrid nanovesicles(EDHPA)loaded with doxorubicin(DOX).DOX@EDHPA can specifically target TAMs by activating macrophage-derived exosomes(M1-Exos)and anisamide(AA)as cancer-specific targeting ligands.In vitro and in vivo studies demonstrated that DOX@EDHPA could efficiently be delivered to the tumor site and taken up by cells.Meanwhile,it synergistically enhanced immunogenic cell death(ICD)and induced a subsequent antigen-specific T cell immune response.The tumor inhibitory rate of the DOX@EDHPA group was 1.42 times that of the free DOX group.Further analysis showed that the excellent antitumor effects of DOX@EDHPA should ascribe to the homing effect of M1-Exos on macrophages and the repolarization to antitumor M1 TAMs,which induced the elevated secretion of pro-infiammatory factors.Therefore,the hybrid EDHPA targeting TAMs to reshape the tumor microenvironment constituted a novel immunochemotherapy strategy to inhibit tumor growth.
基金supported by 1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYJC21046)1.3.5 project for disciplines of excellence-Clinical Research Incubation Project,West China Hospital,Sichuan University(2021HXFH001)+4 种基金Natural Science Foundation of Sichuan Province(2022NSFSC0806)National Natural Science Foundation of China for Young Scientists Fund(82203782)Sichuan University-Zigong School-Local Cooperation Project(2021CDZG-23)Sichuan University-Sui Lin School-Local Cooperation Project(2022CDSN-18)China Telecom Sichuan Company Biliary tract Tumor Big Data Platform and Application Phase I R&D Project(312230752).
文摘Objectives:Hepatocellular carcinoma(HCC)is among the most frequently occurring malignant tumors of the digestive tract and is associated with an increased mortality rate worldwide.This study aimed to develop and validate a prognostic model based on immunogenic cell death(ICD)-related genes to predict patient survival and guide individualized treatment strategies for HCC.Methods:ICD-related genes were identified from the GeneCards database using a relevance score threshold of A combination of least absolute shrinkage and selection operator(LASSO)>10.regression and multivariate Cox analysis was used to screen prognostic genes and construct a risk score model.Immune cell infiltration was evaluated through single-sample gene set enrichment analysis(ssGSEA)and cell-type identification by estimating relative subsets of RNA transcripts(CIBERSORT)algorithms.Associations between risk groups and the tumor microenvironment(TME),N6-methyladenosine(m6A)regulators,and immune checkpoint expression were analyzed.Drug sensitivity was predicted based on the risk stratification.The reliability of the model was validated in internal cohorts and further confirmed by quantitative reverse transcription polymerase chain reaction(qRT-PCR)and immunohistochemistry(IHC).Results:A six-gene signature(CFHR3,G6PD,IGHM,KPNA2,PON1,and SERPINE1)was identified and used to calculate the risk scores.This study found that high-risk patients exhibited significantly poorer overall survival in both the training and validation datasets.The nomogram integrating the risk score and clinical factors showed strong predictive performance.High-risk patients demonstrated reduced immune cell infiltration,altered expression of immune checkpoints and immunosuppressive factors,and a distinct m6A modification pattern,suggesting a higher likelihood of immune escape.This study also revealed that the risk model effectively predicted sensitivity to multiple anticancer drugs.Conclusion:This study developed a robust ICD-related six-gene prognostic model for HCC that can accurately stratify patient risk,reflect the tumor immune landscape,and provide guidance for immunotherapy and personalized treatment strategies.
基金Supported by the Asociación de Celíacos y Sensibles al Gluten de Madrid,No.ACM2020)and Research Committee Argentine Society of Gastroenterology,No.2020.
文摘BACKGROUND The gluten-free diet(GFD)has limitations,and there is intense research in the development of adjuvant therapies.AIM To examine the effects of orally administered Aspergillus niger prolyl endopeptidase protease(AN-PEP)on inadvertent gluten exposure and symptom prevention in adult celiac disease(CeD)patients following their usual GFD.METHODS This was an exploratory,double-blind,randomized,placebo-controlled trial that enrolled CeD patients on a long-term GFD.After a 4-wk run-in period,patients were randomized to 4 wk of two AN-PEP capsules(GliadinX;AVI Research,LLC,United States)at each of three meals per day or placebo.Outcome endpoints were:(1)Average weekly stool gluten immunogenic peptides(GIP)between the run-in and end of treatments and between AN-PEP and placebo;(2)celiac symptom index(CSI);(3)CeD-specific serology;and(4)quality of life.Stool samples were collected for GIP testing by ELISA every Tuesday and Friday during run-ins and treatments.RESULTS Forty patients were randomized for the intention-to-treat analysis,and three were excluded from the per-protocol assessment.Overall,628/640(98.1%)stool samples were collected.GIP was undetectable(<0.08μg/g)in 65.6%of samples,and no differences between treatment arms were detected.Only 0.5%of samples had GIP concentrations sufficiently high(>0.32μg/g)to potentially cause mucosal damage.Median GIP concentration in the AN-PEP arm was 44.7%lower than in the run-in period.One-third of patients exhibiting GIP>0.08μg/g during run-in had lower or undetectable GIP after AN-PEP treatment.Compared with the run-in period,the proportion of symptomatic patients(CSI>38)in the AN-PEP arm was significantly lower(P<0.03).AN-PEP did not result in changes in specific serologies.CONCLUSION This exploratory study conducted in a real-life setting revealed high adherence to the GFD.The AN-PEP treatment did not significantly reduce the overall GIP stool concentration.However,given the observation of a significantly lower prevalence of patients with severe symptoms in the AN-PEP arm,further clinical research is warranted.
基金supported by grants from the Natural Science Foundation of Huai'an Science and Technology Bureau(Grant No.HAB202312)the Science and Technology Development Fund of the Affiliated Hospital of Xuzhou Medical University(Grant No.XYFY2021018).
文摘Tumor vaccines are a promising avenue in cancer immunotherapy.Despite the progress in targeting specific immune epitopes,tumor cells lacking these epitopes can evade the treatment.Here,we aimed to construct an efficient in situ tumor vaccine called Vac-SM,utilizing shikonin(SKN)to induce immunogenic cell death(ICD)and Mycobacterium smegmatis as an immune adjuvant to enhance in situ tumor vaccine efficacy.SKN showed a dose-dependent and time-dependent cytotoxic effect on the tumor cell line and induced ICD in tumor cells as evidenced by the CCK-8 assay and the detection of the expression of relevant indicators,respectively.Compared with the control group,the in situ Vac-SM injection in mouse subcutaneous metastatic tumors significantly inhibited tumor growth and distant tumor metastasis,while also improving survival rates.Mycobacterium smegmatis effectively induced maturation and activation of bone marrow-derived dendritic cells(DCs),and in vivo tumor-draining lymph nodes showed an increased maturation of DCs and a higher proportion of effector memory T-cell subsets with the Vac-SM treatment,based on flow cytometry analysis results.Collectively,the Vac-SM vaccine effectively induces ICD,improves antigen presentation by DCs,activates a specific systemic antitumor T-cell immune response,exhibits a favorable safety profile,and holds the promise for clinical translation for local tumor immunotherapy.
基金funded by the National Key R&D Program of China(2023YFC2605302).
文摘Objective The present study aimed to evaluate the immunogenicity of BA.2 variant receptor binding domain(RBD)recombinant protein formulated with CpG 1826 plus alum dual adjuvant.Methods The BA.2 variant RBD(residues 308-548)fusing TT-P2 epitope was obtained from prokaryotic expression system,purification technology and dialysis renaturation,which was designated as Sot protein.The soluble Sot protein formulated with CpG 1826 plus alum dual adjuvant was designated as Sot/CA subunit vaccine and then the BALB/c mice were intramuscularly administrated with two doses of the Sot/CA subunit vaccine at 14-day interval(day 0 and 14).On day 28,the number of effector T lymphocytes secreting IFN-γand IL-4 in mice spleen were determined by enzyme-linked immunospot(ELISpot)assay.The serum IgG,IgG1 and IgG2a antibodies were examined by enzyme-linked immunosorbent assay(ELISA).In addition,the level of neutralizing antibodies(NAbs)induced by Sot/CA subunit vaccine was also evaluated by the microneutralization assay.Results The high-purity soluble Sot protein with antigenicity was successfully obtained by the prokaryotic expression,protein purification and dialysis renaturation.The Sot/CA subunit vaccine induced a high level of IgG antibodies and NAbs,which were of cross-neutralizing activity against SARS-CoV-2 BA.2 and XBB.1.5 variants.Meanwhile,Sot/CA subunit vaccine also induced a high level of effector T lymphocytes secreting IFN-γ(635.00±17.62)and IL-4(279.20±13.10),respectively.Combined with a decreased IgG1/IgG2a ratio in the serum,which indicating Sot/CA subunit vaccine induced a Th1-type predominant immune response.Conclusion The Sot protein formulated with CpG 1826 plus alum dual adjuvant showed that the excellent cellular and humoral immunogenicity,which provided a scientific basis for the development of BA.2 variant subunit vaccines and references for the adjuvant application of subunit vaccines.
基金supported by the National Natural Science Foundation of China(Nos.52173137 and 51873163).
文摘AIEgens can serve as an effective platform for the construction of photosensitizer-based immunogenic cell death(ICD)inducers.To date,several mitochondria or endoplasmic reticulum(ER)-targeted aggregationinduced emission(AIE)molecules have been developed and have evoked massive ICD in cells.However,due to the complex physicochemical environment in cells,these small AIE molecules cannot maintain a stable aggregate state,which not only affects the fluorescence intensity of the photosensitizer but also decreases the generation of reactive oxygen species(ROS),and thus reducing the effect of the photosensitizer to elicit ICD.AIEgen-based nanomicelles,which maintain a stable micellar structure,can prevent defects of AIE molecules in photodynamic therapy(PDT)applications.Therefore,in this study,a mitochondria-targeted AIE nanophotosensitizer was synthesized and used as a highly potent ICD inducer for vaccine preparation and tumor prevention.
