AIM:To assess the efficacy of immunotherapy with expanded activated autologous lymphocytes(EAALs) in gastric cancer.METHODS:An observational study was designed to retrospectively analyze the clinical data of 84 gastri...AIM:To assess the efficacy of immunotherapy with expanded activated autologous lymphocytes(EAALs) in gastric cancer.METHODS:An observational study was designed to retrospectively analyze the clinical data of 84 gastric cancer patients,of whom 42 were treated by EAAL immunotherapy plus conventional treatment and another 42 only received conventional treatment(control group).EAALs were obtained by proliferation of peripheral blood mononuclear cells from patients followed by phenotype determination.Clinical data including age,gender,clinical stage,chemotherapeutic regimens,hospitalization,surgical,radiotherapy,and survival data were collected along with EAAL therapy details and side effects.Patients were followed and the relationship between treatment and overall survival(OS) data obtained for the immunotherapy and control groups were compared retrospectively.The safety of EAAL immunotherapy was also evaluated.RESULTS:After in vitro culture and proliferation,the percentages of CD3+,CD3+CD8+,CD8+CD27+,CD8+CD28+,and CD3+CD16+/CD56+cells increased remarkably(P < 0.05),while the percentages of CD3+CD4+,CD4+CD25+,and CD3-CD16+/CD56+(natural killer cells) were overtly decreased(P < 0.05); no significant change was observed in CD4+CD25+CD127- cells(P =0.448).Interestingly,OS in the immunotherapy group was significantly higher than that in the control group,with 27.0 and 13.9 mo obtained for the two groups,respectively(P =0.028,HR =0.573,95%CI:0.347-0.945).These findings indicated a 42.7% decrease in the risk of death.In addition,we found that clinical stage and application of EAAL immunotherapy wereindependent prognostic factors for gastric cancer patients.Indeed,the OS in stage Ⅲc and Ⅳ patients that had received surgery was prolonged after EAAL immunotherapy(P < 0.05).Importantly,in vitro induction and proliferation of EAAL were easy and biologically safe.CONCLUSION:Overall,EAAL adoptive immunotherapy might prolong the OS in gastric cancer patients.展开更多
Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells(LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic ...Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells(LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic tumor-cell variants and the suppression of the active immune response. Despitethe introduction of new reagents and new therapeutic approaches, no treatment strategies have been able to definitively eradicate LSCs. However, recent adoptive immunotherapy in cancer is expected to revolutionize our way to fight against this disease, by redirecting the immune system in order to eliminate relapse issues. Initially described at the onset of the 90's, chimeric antigen receptors(CARs) are recombinant receptors transferred in various T cell subsets, providing specific antigens binding in a non-major histocompatibility complex restricted manner, and effective on a large variety of human leukocyte antigen-divers cell populations. Once transferred, engineered T cells act like an expanding "living drug" specifically targeting the tumor-associated antigen, and ensure long-term antitumor memory. Over the last decades, substantial improvements have been made in CARs design. CAR T cells have finally reached the clinical practice and first clinical trials have shown promising results. In acute lymphoblastic leukemia, high rate of complete and prolonged clinical responses have been observed after anti-CD19 CAR T cell therapy, with specific but manageable adverse events. In this review, our goal was to describe CAR structures and functions, and to summarize recent data regarding pre-clinical studies and clinical trials in acute leukemia.展开更多
Background: The importance of immunotherapy in cancer treatment has been increased owing to its non-toxicity and application to personalized medicine. However, precise estimation indices of immunotherapy have yet to b...Background: The importance of immunotherapy in cancer treatment has been increased owing to its non-toxicity and application to personalized medicine. However, precise estimation indices of immunotherapy have yet to be established. To determine effective evaluation indices of immunotherapy for cancer treatment, we analyzed the CD4/CD8 ratio under various conditions in clinical patients with advanced cancer. Patients and Methods: Thirty-four patients who underwent one course of adoptive activated immunotherapy with or without additional conventional chemotherapy were enrolled. Before and after one course of immunotherapy, changes in the CD4/CD8 ratio were estimated by flow cytometry. Results: All patients showed a tendency toward a decrease in the CD4/CD8 ratio during a 3-month period after one course of adoptive activated T lymphocyte immunotherapy. Patients who had undergone prior surgery showed a remarkable increase in CD8 T cell number. Thus, adoptive activated T lymphocyte immunotherapy improves immunological ability against cancer invasion. The Eastern Cooperative Oncology Group’s performance status during one course of immunotherapy was significantly improved in the antecedent surgery group, with no evidence of improved PS in the non-antecedent surgery group. Patients with an increased CD4/CD8 ratio (n = 6) may have a worse outcome during adoptive activated T lymphocyte immunotherapy even with an additional course of immunotherapy. Improved actuarial survival rate of patients in the antecedent surgery group showed significant long-term benefit compared to those in the non-antecedent surgery group (p = 0.0298), as previously reported. Conclusion: The CD4/CD8 ratio is a significant indicator of outcome of adoptive activated T lymphocyte immunotherapy.展开更多
In recent years, immunotherapy has been gradually established as the fourth frequently adopted antitumor therapy, following surgery, chemotherapy and radiotherapy, for advanced urologic malignancies with an improved u...In recent years, immunotherapy has been gradually established as the fourth frequently adopted antitumor therapy, following surgery, chemotherapy and radiotherapy, for advanced urologic malignancies with an improved understanding of theoretical basis, such as molecular biology and immunology. Thereinto, adoptive cellular immunotherapy （ACI） has become one of the hotspots, which comprises a variety of treatment approaches, such as TIL, CIK cell, ~＇~ T cell, CAR-engineered T cell and Allogeneie stem cell transplantation （alloSCT）. Although preclinical efficacy has been demonstrated remarkably, clinical trials could not consistently show the benefit due to multi-factors in complex immnnosuppressive microenvironment in vivo compared to that of in vitro. Here we review some timely aspects of ACI for advanced urologic malignancies, and describe the current status and limitation of immunotherapy from the cellular level. It＇s our expectation to provide prompting consideration of novel combinatorial ACI strategies and a resurgence of interest in ACI for advanced urologic malignancies.展开更多
The infused stem cell autograft in autologous stem cell transplantation(ASCT)has been viewed mainly as hematologic rescue from the myelosuppressive side effect of conditioning regimens.However,recent reports have show...The infused stem cell autograft in autologous stem cell transplantation(ASCT)has been viewed mainly as hematologic rescue from the myelosuppressive side effect of conditioning regimens.However,recent reports have shown that the immune effector cells collected at the same time as the stem cells can produce an autologous graft-versus-tumor effect,similar to the graft-versus-tumor effect seen in allogeneic stem cell transplantation without the detrimental effects of graftversus-host disease.In this article,we review the different immune effector cells collected and infused from the stem cell autograft and their association with clinical outcome post-ASCT,suggesting that ASCT can be viewed not only as a therapeutic maneuver to recover bone marrow function after deliver high-dose chemotherapy,but also as an adoptive immunotherapeutic intervention capable of eradicating residual tumor cells in patients with cancer.展开更多
T lymphocytes,the main participants of cellular immunity,can express a variety of surface molecules and form different lymphocyte subsets under the induction of different factors to play the functions of immune regula...T lymphocytes,the main participants of cellular immunity,can express a variety of surface molecules and form different lymphocyte subsets under the induction of different factors to play the functions of immune regulation and immune killing.Studies have shown that platelets play a crucial role in maintaining the stable differentiation of lymphocytes and the balance in immunomodulation.Therefore,it is necessary to study the effect of platelets on lymphocytes in vitro to better understand the role of platelets in the immune system and broaden the application of adoptive immunotherapy.Methods:Cell counting and microscopic observation were used to detect the effect of activated platelets on lymphocyte proliferation in vitro;Flow cytometry was used to detect whether changes in platelet activity affect the proportion of lymphocyte subpopulations in vitro,and to detect differences in the expression of granzyme B;lactate dehydrogenase assay(LDH)was used to determine the difference in lymphocyte killing activity caused by platelet activity in vitro.Results:This was the first to promote lymphocyte proliferation through the expression or release of certain molecules in vitro,demonstrating that platelet activation is one of the key factors.Secondly,activated platelets or inactivated platelets promoted lymphocyte subset differentiation by enhancing the proportion of CD3+CD8+T lymphocytes(CTL cells)but had a slight effect on the proportion of CD3+CD4+T(Th cells)and CD4+CD25+T lymphocytes(Treg cells).Then,it was found that either activated platelets or inactivated platelets down-regulated the proportion of natural killer(NK)T lymphocytes,while activated platelets significantly enhance the proportion of NK lymphocytes.Therefore,by further detecting the killing activity of PBMCs treated with platelets,it was found that activated platelets promoted the extensive anti-tumor activity of lymphocytes and significantly increased the expression of granzyme B.Conclusion:Our results suggest that activated platelets promote lymphocyte proliferation,optimize lymphocyte subpopulation ratio,and promote cytotoxic effect of lymphocytes in vitro,which may provide a new strategy for optimizing the adoptive immunotherapy culture system and improving its efficacy.展开更多
AIM:To analyze the correlation between cytokineinduced killer(CIK)cells adoptive immunotherapy and cancer-related death in gastric cancer patients.METHODS:One hundred and fifty-six gastric cancer patients after operat...AIM:To analyze the correlation between cytokineinduced killer(CIK)cells adoptive immunotherapy and cancer-related death in gastric cancer patients.METHODS:One hundred and fifty-six gastric cancer patients after operation at the Third Affiliated Hospital of Soochow University were enrolled in this study.Their clinical data including demographic characteristics,operation time,tumor size,pathological type and staging,tumor metastasis,outcome of chemotherapy or CIK cells adoptive immunotherapy,survival time or time of death were collected with a standard structured questionnaire.Kaplan-Meier method was used to estimate the median survival time,and the 2-and 5-year survival rates.Hazard risk(HR)and 95%confidence interval(95%CI)of CIK cells adoptive immunotherapy for gastric cancer were calculated using the two-stage time-dependent covariates Cox model.RESULTS:The survival time of gastric cancer patients was longer after CIK cells adoptive immunotherapy than after chemotherapy(χ2=10.907,P=0.001).The median survival time of gastric cancer patients was also longer after CIK cells adoptive immunotherapy than after chemotherapy(49 mo vs 27 mo,P<0.05).The 2-and 5-year survival rates of gastric cancer patients were significantly higher after CIK cells adoptive immunotherapy than after chemotherapy(73.5%vs 52.6%,40.4%vs 23.9%,P<0.05).A significant difference was observed in the survival curve for patients who received CIK cells adoptive immunotherapy(0,1-10,11-25,and over 25 frequencies)(χ2=14.534,P=0.002).The frequencies of CIK cells adoptive immunotherapy were significantly related with the decreasing risk of death in gastric cancer patients after adjustment for sex and age of the patients,tumor stage and relapse(HR=0.54,95%CI:0.36-0.80)when the first stage Cox model was used to define the subjects who remained alive beyond 36 mo as survivors.However,no correlation was observed between the frequencies of death in CIK cells adoptive immunotherapy and the risk of gastric cancer patients(HR=1.09,95%CI:0.63-0.89)when the second stage Cox model was used to define the subjects who survived for more than 36 mo as survivors.CONCLUSION:The survival time of the gastric cancer patients treated with chemotherapy combined with CIK cells adoptive immunotherapy is significantly longer than that of the patients treated with chemotherapy alone and increasing the frequency of CIK cells adoptive immunotherapy seems to benefit patients more.展开更多
Induction of tumor-specific cellular immune responseis very important in the cancer therapy. In this study,we used tumor antigen obtained by thaw of melanomacells to pulse M-CSF or/and IFN-γ gene-modificdmacrophages ...Induction of tumor-specific cellular immune responseis very important in the cancer therapy. In this study,we used tumor antigen obtained by thaw of melanomacells to pulse M-CSF or/and IFN-γ gene-modificdmacrophages before in viro infusion. Tumor membraneantigens could be phagocytosed by macrophages inculture. Antigen processing and mcxlulation of thepresentation can be achieved before macrophageinjection. The tumor antigens will be processedintracellularly by macrophages and thereafter展开更多
Establishing Epstein-Barr virus (EBV)-specific cytolytic T lymphocytes (EBV-CTLs) from peripheral blood mononuclear cells (PBMCs) for adoptive immunotherapy has been reported in EBV-associated malignancies including H...Establishing Epstein-Barr virus (EBV)-specific cytolytic T lymphocytes (EBV-CTLs) from peripheral blood mononuclear cells (PBMCs) for adoptive immunotherapy has been reported in EBV-associated malignancies including Hodgkin's lymphoma and nasopharyngeal carcinoma (NPC). In the current study,we performed ex vivo expansion of tumor-infiltrating lymphocytes (TILs) obtained from NPC biopsy specimens with a rapid expansion protocol using anti-CD3 monoclonal antibody (OKT3), recombinant human interleukin (IL)-2, and irradiated PBMCs from healthy donors to initiate the growth of TILs. Young TIL cultures comprised of more than 90% of CD3+T cells, a variable percentage of CD3+CD8+and CD3+CD4+T cells, and less than 10% of CD3-CD16+natural killer cells, a similar phenotype of EBV-CTL cultures from PBMCs. Interestingly, TIL cultures secreted high levels of the Th1 cytokines, interferon gamma (IFNγ) and tumor necrosis factor-alpha (TNF-α), and low levels of the Th2 cytokines, IL-4 and IL-10. Moreover, young TILs could recognize autologous EBV-transformed B lymphoblast cell lines, but not autologous EBV-negative blast cells or allogeneic EBV-negative tumor cells. Taken together, these data suggest that ex vivo expansion of TILs from NPC biopsy tissue is an appealing alternative method to establish T cell-based immunotherapy for NPC.展开更多
Background:Glioblastoma(GBM)prognosis has seen little improvement over the past two decades.While immunotherapy has revolutionized cancer treatment,its impact on GBM remains limited.To characterize the evolving resear...Background:Glioblastoma(GBM)prognosis has seen little improvement over the past two decades.While immunotherapy has revolutionized cancer treatment,its impact on GBM remains limited.To characterize the evolving research landscape and identify future directions in GBM immunotherapy,we conducted a comprehensive bibliometric review.Methods:All literature related to immunotherapy in GBM from 1999 to 2024 was collected from the Web of Science Core Collection.CtieSpace and VOSviewer were used to conduct bibliometric analysis and visualize the data.Results:Bibliometric analysis identified 5038 publications authored by 23,335 researchers from 4699 institutions across 96 countries/regions,published in 945 journals.The United States produced the highest number of publications,while Switzerland achieved the highest average citation rate.Duke University led in institutional output and citations.John H Sampson was the most productive author,and Roger Stupp was the most cited.Frontiers in Immunology published the most papers,while Clinical Cancer Research was the most cited journal.Research focus centered on adoptive T cell therapy,particularly chimeric antigen receptor(CAR)-T cells with 572 dedicated publications.Within CAR-T research for GBM,the University of Pennsylvania was the leading institution,Frontiers in Immunology the predominant journal,and Christine E Brown(City of Hope National Medical Center)was the most prolific and cited author.Conclusions:There has been a growing interest in GBM immunotherapy over past decades.The United States is the dominant contributor.CAR-T therapy represents the primary research focus.Emerging strategies like chimeric antigen receptor-modified natural killer(CAR-NK)cells,chimeric antigen receptor-engineered macrophages(CAR-M),and cytomegalovirus-specific T cell receptor(CMV-TCR)T cells are gaining prominence,aiming to address limitations in antigen recognition inherent to CAR-T therapy for GBM.展开更多
Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop met...Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance.This study aims to collect the most recent information on melanoma immunotherapy,discuss potential strategies to overcome resistance to immunotherapy,and identify areas that require further analysis.Methods:To achieve this goal,scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed.The databases were searched using the following terms:“melanoma”,“immunotherapy”,“Immune Checkpoint Blockade”,and“immunoresistance”.Results:The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1(TBK-1),fecal microbiota transplant(FMT),Toll-like Receptor 9(TLR9),lipid nanoparticles(LNPs)containing a stimulator of an interferon gene agonist(STING),BRAF inhibitors,Lymphocyte Activation Gene(LAG-3),T-Cell Immunoglobulin and ITIM Domain(TIGIT),and oncolytic viruses(OVs)as potential methods to enhance melanoma sensitivity to ICB.Discussion:To optimize immunotherapy,further research is needed to determine the detailed mechanisms of action,safety profiles,tolerability,and precise patient selection criteria for methods capable of overcoming melanoma’s immunoresistance.展开更多
Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regula...Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regulation is not fully understood.The study aimed to elucidate the function of E-twenty-six variant 4(ETV4)in tumor immune evasion and its potential as a predictive biomarker for immunotherapy in melanoma.Methods:The expression patterns of ETS family TFs were analyzed in melanoma and hepatocellular carcinoma(HCC).Single-cell RNA sequencing(scRNA-seq)was used to dissect the cellular expression and function of ETV4 in the tumor microenvironment.Functional studies and murine models were employed to investigate the role of ETV4 in T cell-mediated tumor killing and tumor growth.The correlation between ETV4 expression level and patient responsiveness to programmed cell death protein 1(PD-1)blockade therapy was evaluated.Results:TFs in the ETS family were found to effectively stratify melanoma and HCC patients into prognostic subgroups.In melanoma,the polyoma enhancer activator 3(PEA3)subfamily,particularly ETV4 and ETV5,showed a negative correlation with immune infiltration.scRNA-seq analysis showed that ETV4 is preferentially expressed in melanoma cells and involves in mediating tumor-immunocyte interactions.Functional studies demonstrated that ETV4 impairs T cell-mediated tumor killing by transcriptionally upregulating programmed death-ligand 1(PD-L1).In immunocompetent murine models,ETV4 downregulation significantly suppressed tumor growth.Furthermore,high ETV4 expression correlated with poor responses to anti-PD-1 therapy.Conclusion:Our findings identify ETV4 as a key transcriptional regulator of immune evasion in melanoma by controlling PD-L1 expression.ETV4 may act as a predictive biomarker for immunotherapy outcomes.展开更多
Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the...Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.展开更多
Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune check...Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune checkpoint-T cell”axis.Collagen not only constitutes a mechanical barrier that distinguishes between the periphery and core of solid tumors but also systematically remodels the orientation of metabolism,vasculature,and immune cell phenotypic plasticity through its spatial density,fiber arrangement,and crosslinking patterns(F igure 1)[1,2].Abundant evidence suggests that over-accumulated types I and III collagen drive CD8+T cell exhaustion,NK cell functional inhibition,and tumor-associated macrophage polarization through ligand-receptor networks involving LAIR-1,DDR2,andβ1/β3 integrins[3-6].Mechanistically,collagen engagement of LAIR-1 delivers inhibitory signals in effector lymphocytes,promoting dysfunctional or exhausted states[7-9].In parallel,collagen-β1/β3 integrin signaling activates mechanotransduction pathways(e.g.,FAK/SRC),reducing T-cell motility and immune-tumor contact,while DDR2 activation supports matrix-remodeling programs that limit lymphocyte trafficking.展开更多
Colorectal cancer is the third most diagnosed cancer worldwide,and immune checkpoint inhibitors have shown promising therapeutic outcomes in selected patient groups.This study performed a comprehensive analysis of mul...Colorectal cancer is the third most diagnosed cancer worldwide,and immune checkpoint inhibitors have shown promising therapeutic outcomes in selected patient groups.This study performed a comprehensive analysis of multi-omics data from The Cancer Genome Atlas colorectal adenocarcinoma cohort(TCGA-COADREAD),accessed through cBioPortal,to develop machine learning models for predicting progression-free survival(PFS)following immunotherapy.The dataset included clinical variables,genomic alterations in Kirsten Rat Sarcoma Viral Oncogene Homolog(KRAS),B-Raf Proto-Oncogene(BRAF),and Neuroblastoma RAS Viral Oncogene Homolog(NRAS),microsatellite instability(MSI)status,tumor mutation burden(TMB),and expression of immune checkpoint genes.Kaplan–Meier analysis showed that KRAS mutations were significantly associated with reduced PFS,while BRAF and NRAS mutations had no significant impact.MSI-high tumors exhibited elevated TMB and increased immune checkpoint expression,reflecting their immunologically active phenotype.We developed both survival and classification models,with the Extra Trees classifier achieving the best performance(accuracy=0.86,precision=0.67,recall=0.70,F1-score=0.68,AUC=0.84).These findings highlight the potential of combining genomic and immune biomarkers with machine learning to improve patient stratification and guide personalized immunotherapy decisions.An interactive web application was also developed to enable clinicians to input patient-specific molecular and clinical data and visualize individualized PFS predictions,supporting timely,data-driven treatment planning.展开更多
Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CR...Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CRC)and melanoma.Methods:A combination of in vitro and in vivo approaches was employed.Cell proliferation,apoptosis,migration,and invasion were assessed using Cell Counting Kit-8(CCK-8),colony formation,ATP viability,Western blotting,flow cytometry,wound-healing and Transwell assays.Subcutaneous,lung metastases,and Azoxymethane/Dextran Sulfate Sodium Salt(AOM/DSS)-induced colitis-associated CRC models were established to examine antitumor efficacy and safety.The functional role of mercury ions was validated using structural analogues.Mechanistic studies included RNA sequencing,Western blot,and immunohistochemical analysis of CD8^(+)T cell infiltration.The synergistic effect with programmed cell death protein 1(PD-1)antibody therapy was also evaluated.Results:Thimerosal potently inhibited tumor growth(with IC50 values ranging from 0.1 to 1μM in vitro)and significantly prolonged survival without overt toxicity in vivo.Mechanistically,mercury ions were identified as critical functional sites mediating Thimerosal’s antitumor effects.Specifically,Thimerosal inhibited the phosphorylation of Janus kinase 1(JAK1)and signal transducer and activator of transcription 3(STAT3).Furthermore,it enhanced the infiltration of CD8^(+)T cells into the tumor microenvironment and synergistically augmented the efficacy of anti-PD-1 therapy.Conclusion:Thimerosal exerts dual antitumor roles by direct JAK1/STAT3 inhibition and immune modulation via CD8^(+)T cell recruitment.It represents a promising repurposed drug and immunotherapeutic adjuvant for CRC and melanoma.展开更多
Despite existing curative options like surgical removal,tissue destruction techniques,and liver transplantation for early-stage hepatocellular carcinoma(HCC),the rising incidence and mortality rates of this global hea...Despite existing curative options like surgical removal,tissue destruction techniques,and liver transplantation for early-stage hepatocellular carcinoma(HCC),the rising incidence and mortality rates of this global health burden necessitate continuous exploration of novel therapeutic strategies.This review critically assesses the dynamic treatment panorama for HCC,focusing specifically on the burgeoning role of immunotherapy in two key contexts:early-stage HCC and downstaging advanced HCC to facilitate liver transplant candidacy.It delves into the unique immunobiology of the liver and HCC,highlighting tumor-mediated immune evasion mechanisms.Analyzing the diverse immunothera-peutic approaches including checkpoint inhibitors,cytokine modulators,vaccines,oncolytic viruses,antigen-targeting antibodies,and adoptive cell therapy,this review acknowledges the limitations of current diagnostic markers alpha-fetoprotein and glypican-3 and emphasizes the need for novel biomarkers for patient selection and treatment monitoring.Exploring the rationale for neoadjuvant and adjuvant immunotherapy in early-stage HCC,current research is actively exploring the safety and effectiveness of diverse immunothera-peutic approaches through ongoing clinical trials.The review further explores the potential benefits and challenges of combining immunotherapy and liver transplant,highlighting the need for careful patient selection,meticulous monitoring,and novel strategies to mitigate post-transplant complications.Finally,this review delves into the latest findings from the clinical research landscape and future directions in HCC management,paving the way for optimizing treatment strategies and improving long-term survival rates for patients with this challenging malignancy.展开更多
Colorectal cancer(CRC)is a digestive tract malignancy with the highest global incidence and mortality rate.In China,the number of patients with colorectal cancer has been increasing annually.In 2020,the numbers of new...Colorectal cancer(CRC)is a digestive tract malignancy with the highest global incidence and mortality rate.In China,the number of patients with colorectal cancer has been increasing annually.In 2020,the numbers of new cases and cancer deaths were 560,000 and 290,000,respectively,ranking second among new cancer cases and fifth among cancer deaths in China.Treatment of colorectal cancer involves a combined regimen of surgery supplemented with radiotherapy,chemotherapy,targeted therapy,and immunotherapy.This article comprehensively analyzed the classification and function of natural killer(NK)cells,their development and metabolic processes,expression and effector mechanisms,their effects on colorectal cancer,and the development prospects of using NK cells to treat colorectal cancer.Here,we comprehensively review preclinical and clinical investigations exploring the therapeutic effects and mechanisms of NK cell-based immunotherapy against CRC.This approach not only leverages NK cells’unique abilities to recognize and eliminate tumor cells but also overcomes the immunosuppressive tumor microenvironment in advanced CRC,providing a promising strategy for future therapeutic development.展开更多
Colorectal cancer(CRC)is the third most common cancer worldwide and remains a major treatment challenge,particularly in advanced and metastatic stages.Current standard treatments have limited efficacy,underscoring the...Colorectal cancer(CRC)is the third most common cancer worldwide and remains a major treatment challenge,particularly in advanced and metastatic stages.Current standard treatments have limited efficacy,underscoring the urgent need for innovative strategies.Adoptive cell therapy(ACT),which involves in vitro expansion or genetic engineering of immune cells,is a promising approach to bolster anti-tumor immune responses.Key ACT modalities include chimeric antigen receptor(CAR)T cells,tumor-infiltrating lymphocytes(TILs),and T cell receptor(TCR)-engineered T cells.CAR-T cell therapy has shown success in hematological malignancies but faces significant challenges in solid tumors like CRC.These challenges include antigen heterogeneity,an immunosuppressive tumor microenvironment,on-target off-tumor toxicity,among other factors.To address these limitations,combinatorial approaches,such as immune checkpoint inhibitors,cytokines,and advanced gene-editing tools like CRISPR/Cas9,are being actively explored.These strategies aim to enhance CAR-T cell specificity,improve resistance to immunosuppressive signals,and optimize in vivo functionality.This review summarizes ACT approaches for CRC,with a focus on CAR-T therapy.It briefly introduces TILs and TCR-T cells,while emphasizing the major challenges faced by CAR-T therapy in solid tumors and discusses potential strategies to improve therapeutic outcomes.展开更多
Objective:Immune checkpoint inhibitors(ICIs)have demonstrated substantial efficacy in patients with advanced non-small cell lung cancer(NSCLC).However,the optimal duration of ICI therapy remains unclear,and limited re...Objective:Immune checkpoint inhibitors(ICIs)have demonstrated substantial efficacy in patients with advanced non-small cell lung cancer(NSCLC).However,the optimal duration of ICI therapy remains unclear,and limited real-world data are available.The aim of this study was to evaluate the relationship between ICI therapy duration and overall survival(OS)in patients who achieved varying best overall response(BOR)during ICI treatment,and to compare patients treated for 6 to 18 months vs.at least 18 months.Methods:This retrospective cohort study included adult patients diagnosed with advanced NSCLC who received ICI therapy at the Zhejiang Cancer Hospital between 2017 and 2022.Data collection ended on May 1,2024,and statistical analysis was performed between May and June 2024.Results:Using strict entry criteria,we screened 487 patients with advanced NSCLC and identified 134 eligible patients.Among these patients,the median durations of immunotherapy and follow-up were 24.57 months and 43.60 months,respectively.The objective response rate(ORR)was 58.2%,and the median progression-free survival(PFS)was 10.6 months.Median OS was not reached.At the last follow-up,54 patients had no disease progression,and 118 patients remained alive.Patients treated with ICI therapy for≥18 months had superior survival to those treated for 6 to 18 months(P=0.039).Further analysis revealed that the survival benefit was associated with BOR during ICI therapy.Specifically,patients achieving complete response/partial response(CR/PR)who received≥18 months of ICI therapy had a trend toward longer median OS than those treated for 6 to 18 months,but the difference did not reach statistical significance(P=0.177).Patients with stable disease(SD)who received≥18 months of ICI therapy had a statistically longer median OS than those treated for 6 to 18 months(P=0.019).Among patients treated with ICIs for≥18 months,24 continued with ICI-based therapy and achieved a median PFS2 of 6.67 months,an ORR of 33.3%,and a disease control rate(DCR)of 83.3%.Conclusions:This study provides real-world evidence and novel insights into the need for continuing ICI therapy beyond 18 months in patients with advanced NSCLC who do not exhibit progressive disease.For patients achieving SD during ICI therapy,a treatment duration of at least 18 months appears appropriate.For patients achieving CR/PR,treatment decisions should be individualized according to patient-specific circumstances.However,owing to the retrospective study design,potential selection bias and confounding factors might have influenced the results.Therefore,our findings require further validation in prospective clinical studies.展开更多
基金Supported by National Science and Technology Infrastructure Program of China,No.2009BAI86B05
文摘AIM:To assess the efficacy of immunotherapy with expanded activated autologous lymphocytes(EAALs) in gastric cancer.METHODS:An observational study was designed to retrospectively analyze the clinical data of 84 gastric cancer patients,of whom 42 were treated by EAAL immunotherapy plus conventional treatment and another 42 only received conventional treatment(control group).EAALs were obtained by proliferation of peripheral blood mononuclear cells from patients followed by phenotype determination.Clinical data including age,gender,clinical stage,chemotherapeutic regimens,hospitalization,surgical,radiotherapy,and survival data were collected along with EAAL therapy details and side effects.Patients were followed and the relationship between treatment and overall survival(OS) data obtained for the immunotherapy and control groups were compared retrospectively.The safety of EAAL immunotherapy was also evaluated.RESULTS:After in vitro culture and proliferation,the percentages of CD3+,CD3+CD8+,CD8+CD27+,CD8+CD28+,and CD3+CD16+/CD56+cells increased remarkably(P < 0.05),while the percentages of CD3+CD4+,CD4+CD25+,and CD3-CD16+/CD56+(natural killer cells) were overtly decreased(P < 0.05); no significant change was observed in CD4+CD25+CD127- cells(P =0.448).Interestingly,OS in the immunotherapy group was significantly higher than that in the control group,with 27.0 and 13.9 mo obtained for the two groups,respectively(P =0.028,HR =0.573,95%CI:0.347-0.945).These findings indicated a 42.7% decrease in the risk of death.In addition,we found that clinical stage and application of EAAL immunotherapy wereindependent prognostic factors for gastric cancer patients.Indeed,the OS in stage Ⅲc and Ⅳ patients that had received surgery was prolonged after EAAL immunotherapy(P < 0.05).Importantly,in vitro induction and proliferation of EAAL were easy and biologically safe.CONCLUSION:Overall,EAAL adoptive immunotherapy might prolong the OS in gastric cancer patients.
文摘Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells(LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic tumor-cell variants and the suppression of the active immune response. Despitethe introduction of new reagents and new therapeutic approaches, no treatment strategies have been able to definitively eradicate LSCs. However, recent adoptive immunotherapy in cancer is expected to revolutionize our way to fight against this disease, by redirecting the immune system in order to eliminate relapse issues. Initially described at the onset of the 90's, chimeric antigen receptors(CARs) are recombinant receptors transferred in various T cell subsets, providing specific antigens binding in a non-major histocompatibility complex restricted manner, and effective on a large variety of human leukocyte antigen-divers cell populations. Once transferred, engineered T cells act like an expanding "living drug" specifically targeting the tumor-associated antigen, and ensure long-term antitumor memory. Over the last decades, substantial improvements have been made in CARs design. CAR T cells have finally reached the clinical practice and first clinical trials have shown promising results. In acute lymphoblastic leukemia, high rate of complete and prolonged clinical responses have been observed after anti-CD19 CAR T cell therapy, with specific but manageable adverse events. In this review, our goal was to describe CAR structures and functions, and to summarize recent data regarding pre-clinical studies and clinical trials in acute leukemia.
文摘Background: The importance of immunotherapy in cancer treatment has been increased owing to its non-toxicity and application to personalized medicine. However, precise estimation indices of immunotherapy have yet to be established. To determine effective evaluation indices of immunotherapy for cancer treatment, we analyzed the CD4/CD8 ratio under various conditions in clinical patients with advanced cancer. Patients and Methods: Thirty-four patients who underwent one course of adoptive activated immunotherapy with or without additional conventional chemotherapy were enrolled. Before and after one course of immunotherapy, changes in the CD4/CD8 ratio were estimated by flow cytometry. Results: All patients showed a tendency toward a decrease in the CD4/CD8 ratio during a 3-month period after one course of adoptive activated T lymphocyte immunotherapy. Patients who had undergone prior surgery showed a remarkable increase in CD8 T cell number. Thus, adoptive activated T lymphocyte immunotherapy improves immunological ability against cancer invasion. The Eastern Cooperative Oncology Group’s performance status during one course of immunotherapy was significantly improved in the antecedent surgery group, with no evidence of improved PS in the non-antecedent surgery group. Patients with an increased CD4/CD8 ratio (n = 6) may have a worse outcome during adoptive activated T lymphocyte immunotherapy even with an additional course of immunotherapy. Improved actuarial survival rate of patients in the antecedent surgery group showed significant long-term benefit compared to those in the non-antecedent surgery group (p = 0.0298), as previously reported. Conclusion: The CD4/CD8 ratio is a significant indicator of outcome of adoptive activated T lymphocyte immunotherapy.
基金supported by a grant from National Natural Science Foundation of China(No.30901481,81372752,81472411)Wu-Jie Ping Medical Foundation(320.6750.13261)
文摘In recent years, immunotherapy has been gradually established as the fourth frequently adopted antitumor therapy, following surgery, chemotherapy and radiotherapy, for advanced urologic malignancies with an improved understanding of theoretical basis, such as molecular biology and immunology. Thereinto, adoptive cellular immunotherapy （ACI） has become one of the hotspots, which comprises a variety of treatment approaches, such as TIL, CIK cell, ~＇~ T cell, CAR-engineered T cell and Allogeneie stem cell transplantation （alloSCT）. Although preclinical efficacy has been demonstrated remarkably, clinical trials could not consistently show the benefit due to multi-factors in complex immnnosuppressive microenvironment in vivo compared to that of in vitro. Here we review some timely aspects of ACI for advanced urologic malignancies, and describe the current status and limitation of immunotherapy from the cellular level. It＇s our expectation to provide prompting consideration of novel combinatorial ACI strategies and a resurgence of interest in ACI for advanced urologic malignancies.
文摘The infused stem cell autograft in autologous stem cell transplantation(ASCT)has been viewed mainly as hematologic rescue from the myelosuppressive side effect of conditioning regimens.However,recent reports have shown that the immune effector cells collected at the same time as the stem cells can produce an autologous graft-versus-tumor effect,similar to the graft-versus-tumor effect seen in allogeneic stem cell transplantation without the detrimental effects of graftversus-host disease.In this article,we review the different immune effector cells collected and infused from the stem cell autograft and their association with clinical outcome post-ASCT,suggesting that ASCT can be viewed not only as a therapeutic maneuver to recover bone marrow function after deliver high-dose chemotherapy,but also as an adoptive immunotherapeutic intervention capable of eradicating residual tumor cells in patients with cancer.
文摘T lymphocytes,the main participants of cellular immunity,can express a variety of surface molecules and form different lymphocyte subsets under the induction of different factors to play the functions of immune regulation and immune killing.Studies have shown that platelets play a crucial role in maintaining the stable differentiation of lymphocytes and the balance in immunomodulation.Therefore,it is necessary to study the effect of platelets on lymphocytes in vitro to better understand the role of platelets in the immune system and broaden the application of adoptive immunotherapy.Methods:Cell counting and microscopic observation were used to detect the effect of activated platelets on lymphocyte proliferation in vitro;Flow cytometry was used to detect whether changes in platelet activity affect the proportion of lymphocyte subpopulations in vitro,and to detect differences in the expression of granzyme B;lactate dehydrogenase assay(LDH)was used to determine the difference in lymphocyte killing activity caused by platelet activity in vitro.Results:This was the first to promote lymphocyte proliferation through the expression or release of certain molecules in vitro,demonstrating that platelet activation is one of the key factors.Secondly,activated platelets or inactivated platelets promoted lymphocyte subset differentiation by enhancing the proportion of CD3+CD8+T lymphocytes(CTL cells)but had a slight effect on the proportion of CD3+CD4+T(Th cells)and CD4+CD25+T lymphocytes(Treg cells).Then,it was found that either activated platelets or inactivated platelets down-regulated the proportion of natural killer(NK)T lymphocytes,while activated platelets significantly enhance the proportion of NK lymphocytes.Therefore,by further detecting the killing activity of PBMCs treated with platelets,it was found that activated platelets promoted the extensive anti-tumor activity of lymphocytes and significantly increased the expression of granzyme B.Conclusion:Our results suggest that activated platelets promote lymphocyte proliferation,optimize lymphocyte subpopulation ratio,and promote cytotoxic effect of lymphocytes in vitro,which may provide a new strategy for optimizing the adoptive immunotherapy culture system and improving its efficacy.
基金Supported by The National Natural Science Foundation of China,No.30872176,30950022 and 30972703grants of Jiangsu Province and Soochow University Medical Development Foundation,No.EE126765
文摘AIM:To analyze the correlation between cytokineinduced killer(CIK)cells adoptive immunotherapy and cancer-related death in gastric cancer patients.METHODS:One hundred and fifty-six gastric cancer patients after operation at the Third Affiliated Hospital of Soochow University were enrolled in this study.Their clinical data including demographic characteristics,operation time,tumor size,pathological type and staging,tumor metastasis,outcome of chemotherapy or CIK cells adoptive immunotherapy,survival time or time of death were collected with a standard structured questionnaire.Kaplan-Meier method was used to estimate the median survival time,and the 2-and 5-year survival rates.Hazard risk(HR)and 95%confidence interval(95%CI)of CIK cells adoptive immunotherapy for gastric cancer were calculated using the two-stage time-dependent covariates Cox model.RESULTS:The survival time of gastric cancer patients was longer after CIK cells adoptive immunotherapy than after chemotherapy(χ2=10.907,P=0.001).The median survival time of gastric cancer patients was also longer after CIK cells adoptive immunotherapy than after chemotherapy(49 mo vs 27 mo,P<0.05).The 2-and 5-year survival rates of gastric cancer patients were significantly higher after CIK cells adoptive immunotherapy than after chemotherapy(73.5%vs 52.6%,40.4%vs 23.9%,P<0.05).A significant difference was observed in the survival curve for patients who received CIK cells adoptive immunotherapy(0,1-10,11-25,and over 25 frequencies)(χ2=14.534,P=0.002).The frequencies of CIK cells adoptive immunotherapy were significantly related with the decreasing risk of death in gastric cancer patients after adjustment for sex and age of the patients,tumor stage and relapse(HR=0.54,95%CI:0.36-0.80)when the first stage Cox model was used to define the subjects who remained alive beyond 36 mo as survivors.However,no correlation was observed between the frequencies of death in CIK cells adoptive immunotherapy and the risk of gastric cancer patients(HR=1.09,95%CI:0.63-0.89)when the second stage Cox model was used to define the subjects who survived for more than 36 mo as survivors.CONCLUSION:The survival time of the gastric cancer patients treated with chemotherapy combined with CIK cells adoptive immunotherapy is significantly longer than that of the patients treated with chemotherapy alone and increasing the frequency of CIK cells adoptive immunotherapy seems to benefit patients more.
文摘Induction of tumor-specific cellular immune responseis very important in the cancer therapy. In this study,we used tumor antigen obtained by thaw of melanomacells to pulse M-CSF or/and IFN-γ gene-modificdmacrophages before in viro infusion. Tumor membraneantigens could be phagocytosed by macrophages inculture. Antigen processing and mcxlulation of thepresentation can be achieved before macrophageinjection. The tumor antigens will be processedintracellularly by macrophages and thereafter
基金supported by grants from the National Natural Science Foundation of China (No.224-30872981)Guangdong Province Natural Science Foundation (No.10151008901000156)
文摘Establishing Epstein-Barr virus (EBV)-specific cytolytic T lymphocytes (EBV-CTLs) from peripheral blood mononuclear cells (PBMCs) for adoptive immunotherapy has been reported in EBV-associated malignancies including Hodgkin's lymphoma and nasopharyngeal carcinoma (NPC). In the current study,we performed ex vivo expansion of tumor-infiltrating lymphocytes (TILs) obtained from NPC biopsy specimens with a rapid expansion protocol using anti-CD3 monoclonal antibody (OKT3), recombinant human interleukin (IL)-2, and irradiated PBMCs from healthy donors to initiate the growth of TILs. Young TIL cultures comprised of more than 90% of CD3+T cells, a variable percentage of CD3+CD8+and CD3+CD4+T cells, and less than 10% of CD3-CD16+natural killer cells, a similar phenotype of EBV-CTL cultures from PBMCs. Interestingly, TIL cultures secreted high levels of the Th1 cytokines, interferon gamma (IFNγ) and tumor necrosis factor-alpha (TNF-α), and low levels of the Th2 cytokines, IL-4 and IL-10. Moreover, young TILs could recognize autologous EBV-transformed B lymphoblast cell lines, but not autologous EBV-negative blast cells or allogeneic EBV-negative tumor cells. Taken together, these data suggest that ex vivo expansion of TILs from NPC biopsy tissue is an appealing alternative method to establish T cell-based immunotherapy for NPC.
基金supported by Key Research and Development Plan of Hunan Province(2024DK2006)the Fundamental Research Funds for the Central Universities of Central South University(1053320221769)+2 种基金Hunan Provincial Respiratory Disease Rehabilitation and Nursing Engineering Research Center Innovation Capacity Building Project(No.202012)the Zhangjiajie Science and Technology Development Key Special Project(No.202304)the National Key Clinical Specialty Major Scientific Research Project(No.20230382).
文摘Background:Glioblastoma(GBM)prognosis has seen little improvement over the past two decades.While immunotherapy has revolutionized cancer treatment,its impact on GBM remains limited.To characterize the evolving research landscape and identify future directions in GBM immunotherapy,we conducted a comprehensive bibliometric review.Methods:All literature related to immunotherapy in GBM from 1999 to 2024 was collected from the Web of Science Core Collection.CtieSpace and VOSviewer were used to conduct bibliometric analysis and visualize the data.Results:Bibliometric analysis identified 5038 publications authored by 23,335 researchers from 4699 institutions across 96 countries/regions,published in 945 journals.The United States produced the highest number of publications,while Switzerland achieved the highest average citation rate.Duke University led in institutional output and citations.John H Sampson was the most productive author,and Roger Stupp was the most cited.Frontiers in Immunology published the most papers,while Clinical Cancer Research was the most cited journal.Research focus centered on adoptive T cell therapy,particularly chimeric antigen receptor(CAR)-T cells with 572 dedicated publications.Within CAR-T research for GBM,the University of Pennsylvania was the leading institution,Frontiers in Immunology the predominant journal,and Christine E Brown(City of Hope National Medical Center)was the most prolific and cited author.Conclusions:There has been a growing interest in GBM immunotherapy over past decades.The United States is the dominant contributor.CAR-T therapy represents the primary research focus.Emerging strategies like chimeric antigen receptor-modified natural killer(CAR-NK)cells,chimeric antigen receptor-engineered macrophages(CAR-M),and cytomegalovirus-specific T cell receptor(CMV-TCR)T cells are gaining prominence,aiming to address limitations in antigen recognition inherent to CAR-T therapy for GBM.
文摘Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance.This study aims to collect the most recent information on melanoma immunotherapy,discuss potential strategies to overcome resistance to immunotherapy,and identify areas that require further analysis.Methods:To achieve this goal,scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed.The databases were searched using the following terms:“melanoma”,“immunotherapy”,“Immune Checkpoint Blockade”,and“immunoresistance”.Results:The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1(TBK-1),fecal microbiota transplant(FMT),Toll-like Receptor 9(TLR9),lipid nanoparticles(LNPs)containing a stimulator of an interferon gene agonist(STING),BRAF inhibitors,Lymphocyte Activation Gene(LAG-3),T-Cell Immunoglobulin and ITIM Domain(TIGIT),and oncolytic viruses(OVs)as potential methods to enhance melanoma sensitivity to ICB.Discussion:To optimize immunotherapy,further research is needed to determine the detailed mechanisms of action,safety profiles,tolerability,and precise patient selection criteria for methods capable of overcoming melanoma’s immunoresistance.
基金funded by the National Natural Science Foundation of China(Grant Nos.82204517 to T.Z.and 82404756 to J.Z.)the Science and Technology Program in Medicine and Health of Zhejiang Province(Grant No.2023KY726 to T.Z.).
文摘Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regulation is not fully understood.The study aimed to elucidate the function of E-twenty-six variant 4(ETV4)in tumor immune evasion and its potential as a predictive biomarker for immunotherapy in melanoma.Methods:The expression patterns of ETS family TFs were analyzed in melanoma and hepatocellular carcinoma(HCC).Single-cell RNA sequencing(scRNA-seq)was used to dissect the cellular expression and function of ETV4 in the tumor microenvironment.Functional studies and murine models were employed to investigate the role of ETV4 in T cell-mediated tumor killing and tumor growth.The correlation between ETV4 expression level and patient responsiveness to programmed cell death protein 1(PD-1)blockade therapy was evaluated.Results:TFs in the ETS family were found to effectively stratify melanoma and HCC patients into prognostic subgroups.In melanoma,the polyoma enhancer activator 3(PEA3)subfamily,particularly ETV4 and ETV5,showed a negative correlation with immune infiltration.scRNA-seq analysis showed that ETV4 is preferentially expressed in melanoma cells and involves in mediating tumor-immunocyte interactions.Functional studies demonstrated that ETV4 impairs T cell-mediated tumor killing by transcriptionally upregulating programmed death-ligand 1(PD-L1).In immunocompetent murine models,ETV4 downregulation significantly suppressed tumor growth.Furthermore,high ETV4 expression correlated with poor responses to anti-PD-1 therapy.Conclusion:Our findings identify ETV4 as a key transcriptional regulator of immune evasion in melanoma by controlling PD-L1 expression.ETV4 may act as a predictive biomarker for immunotherapy outcomes.
基金supported by the Nature Science Foundation of Liaoning Province,Nos.2022-MS-211,2021-MS-064,and 2024-MS-048(all to YC).
文摘Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.
基金supported by the National Natural Science Foundation of China(82472842 and 82473350)and Wuxi Double-Hundred Talent Fund Project(BJ2023075).
文摘Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune checkpoint-T cell”axis.Collagen not only constitutes a mechanical barrier that distinguishes between the periphery and core of solid tumors but also systematically remodels the orientation of metabolism,vasculature,and immune cell phenotypic plasticity through its spatial density,fiber arrangement,and crosslinking patterns(F igure 1)[1,2].Abundant evidence suggests that over-accumulated types I and III collagen drive CD8+T cell exhaustion,NK cell functional inhibition,and tumor-associated macrophage polarization through ligand-receptor networks involving LAIR-1,DDR2,andβ1/β3 integrins[3-6].Mechanistically,collagen engagement of LAIR-1 delivers inhibitory signals in effector lymphocytes,promoting dysfunctional or exhausted states[7-9].In parallel,collagen-β1/β3 integrin signaling activates mechanotransduction pathways(e.g.,FAK/SRC),reducing T-cell motility and immune-tumor contact,while DDR2 activation supports matrix-remodeling programs that limit lymphocyte trafficking.
基金funded by the Research,Development,and Innovation Authority(RDIA)—Kingdom of Saudi Arabia(Grant No.13292-psu-2023-PSNU-R-3-1-EF-).
文摘Colorectal cancer is the third most diagnosed cancer worldwide,and immune checkpoint inhibitors have shown promising therapeutic outcomes in selected patient groups.This study performed a comprehensive analysis of multi-omics data from The Cancer Genome Atlas colorectal adenocarcinoma cohort(TCGA-COADREAD),accessed through cBioPortal,to develop machine learning models for predicting progression-free survival(PFS)following immunotherapy.The dataset included clinical variables,genomic alterations in Kirsten Rat Sarcoma Viral Oncogene Homolog(KRAS),B-Raf Proto-Oncogene(BRAF),and Neuroblastoma RAS Viral Oncogene Homolog(NRAS),microsatellite instability(MSI)status,tumor mutation burden(TMB),and expression of immune checkpoint genes.Kaplan–Meier analysis showed that KRAS mutations were significantly associated with reduced PFS,while BRAF and NRAS mutations had no significant impact.MSI-high tumors exhibited elevated TMB and increased immune checkpoint expression,reflecting their immunologically active phenotype.We developed both survival and classification models,with the Extra Trees classifier achieving the best performance(accuracy=0.86,precision=0.67,recall=0.70,F1-score=0.68,AUC=0.84).These findings highlight the potential of combining genomic and immune biomarkers with machine learning to improve patient stratification and guide personalized immunotherapy decisions.An interactive web application was also developed to enable clinicians to input patient-specific molecular and clinical data and visualize individualized PFS predictions,supporting timely,data-driven treatment planning.
基金supported by the National Natural Science Foundation of China(82441036)Ganzhou Municipal Science and Technology Project(2022-RC1342)+3 种基金Guangdong Basic and Applied Basic Research Foundation(2022B1515130004)Key-Area Research and Development Program of Guangdong Province(2019B020234003)Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Cancer(2020B121201004)Open Project Fund Project of Guangdong Academy of Medical Sciences(YKY-KF202210).
文摘Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CRC)and melanoma.Methods:A combination of in vitro and in vivo approaches was employed.Cell proliferation,apoptosis,migration,and invasion were assessed using Cell Counting Kit-8(CCK-8),colony formation,ATP viability,Western blotting,flow cytometry,wound-healing and Transwell assays.Subcutaneous,lung metastases,and Azoxymethane/Dextran Sulfate Sodium Salt(AOM/DSS)-induced colitis-associated CRC models were established to examine antitumor efficacy and safety.The functional role of mercury ions was validated using structural analogues.Mechanistic studies included RNA sequencing,Western blot,and immunohistochemical analysis of CD8^(+)T cell infiltration.The synergistic effect with programmed cell death protein 1(PD-1)antibody therapy was also evaluated.Results:Thimerosal potently inhibited tumor growth(with IC50 values ranging from 0.1 to 1μM in vitro)and significantly prolonged survival without overt toxicity in vivo.Mechanistically,mercury ions were identified as critical functional sites mediating Thimerosal’s antitumor effects.Specifically,Thimerosal inhibited the phosphorylation of Janus kinase 1(JAK1)and signal transducer and activator of transcription 3(STAT3).Furthermore,it enhanced the infiltration of CD8^(+)T cells into the tumor microenvironment and synergistically augmented the efficacy of anti-PD-1 therapy.Conclusion:Thimerosal exerts dual antitumor roles by direct JAK1/STAT3 inhibition and immune modulation via CD8^(+)T cell recruitment.It represents a promising repurposed drug and immunotherapeutic adjuvant for CRC and melanoma.
文摘Despite existing curative options like surgical removal,tissue destruction techniques,and liver transplantation for early-stage hepatocellular carcinoma(HCC),the rising incidence and mortality rates of this global health burden necessitate continuous exploration of novel therapeutic strategies.This review critically assesses the dynamic treatment panorama for HCC,focusing specifically on the burgeoning role of immunotherapy in two key contexts:early-stage HCC and downstaging advanced HCC to facilitate liver transplant candidacy.It delves into the unique immunobiology of the liver and HCC,highlighting tumor-mediated immune evasion mechanisms.Analyzing the diverse immunothera-peutic approaches including checkpoint inhibitors,cytokine modulators,vaccines,oncolytic viruses,antigen-targeting antibodies,and adoptive cell therapy,this review acknowledges the limitations of current diagnostic markers alpha-fetoprotein and glypican-3 and emphasizes the need for novel biomarkers for patient selection and treatment monitoring.Exploring the rationale for neoadjuvant and adjuvant immunotherapy in early-stage HCC,current research is actively exploring the safety and effectiveness of diverse immunothera-peutic approaches through ongoing clinical trials.The review further explores the potential benefits and challenges of combining immunotherapy and liver transplant,highlighting the need for careful patient selection,meticulous monitoring,and novel strategies to mitigate post-transplant complications.Finally,this review delves into the latest findings from the clinical research landscape and future directions in HCC management,paving the way for optimizing treatment strategies and improving long-term survival rates for patients with this challenging malignancy.
基金supported by the Inner Mongolia Autonomous Region Science and Technology Plan Project (No.2022YFSH0055)Public Hospital Scientific Research Joint Fund Project (No.2023GLLH0106)The Start-up Fund for Doctoral Scientific Research of Inner Mongolia Autonomous Region People's Hospital(No.2024BS04)
文摘Colorectal cancer(CRC)is a digestive tract malignancy with the highest global incidence and mortality rate.In China,the number of patients with colorectal cancer has been increasing annually.In 2020,the numbers of new cases and cancer deaths were 560,000 and 290,000,respectively,ranking second among new cancer cases and fifth among cancer deaths in China.Treatment of colorectal cancer involves a combined regimen of surgery supplemented with radiotherapy,chemotherapy,targeted therapy,and immunotherapy.This article comprehensively analyzed the classification and function of natural killer(NK)cells,their development and metabolic processes,expression and effector mechanisms,their effects on colorectal cancer,and the development prospects of using NK cells to treat colorectal cancer.Here,we comprehensively review preclinical and clinical investigations exploring the therapeutic effects and mechanisms of NK cell-based immunotherapy against CRC.This approach not only leverages NK cells’unique abilities to recognize and eliminate tumor cells but also overcomes the immunosuppressive tumor microenvironment in advanced CRC,providing a promising strategy for future therapeutic development.
基金Supported by the Natural Science Foundation of the Science and Technology Commission of Shanghai Municipality,China,No.23ZR1458300Key Discipline Project of Shanghai Municipal Health System,China,No.2024ZDXK0004+1 种基金Doctoral Innovation Talent Base Project for Diagnosis and Treatment of Chronic Liver Diseases,China,No.RCJD2021B02Pujiang Project of Shanghai Magnolia Talent Plan,China,No.24PJD098.
文摘Colorectal cancer(CRC)is the third most common cancer worldwide and remains a major treatment challenge,particularly in advanced and metastatic stages.Current standard treatments have limited efficacy,underscoring the urgent need for innovative strategies.Adoptive cell therapy(ACT),which involves in vitro expansion or genetic engineering of immune cells,is a promising approach to bolster anti-tumor immune responses.Key ACT modalities include chimeric antigen receptor(CAR)T cells,tumor-infiltrating lymphocytes(TILs),and T cell receptor(TCR)-engineered T cells.CAR-T cell therapy has shown success in hematological malignancies but faces significant challenges in solid tumors like CRC.These challenges include antigen heterogeneity,an immunosuppressive tumor microenvironment,on-target off-tumor toxicity,among other factors.To address these limitations,combinatorial approaches,such as immune checkpoint inhibitors,cytokines,and advanced gene-editing tools like CRISPR/Cas9,are being actively explored.These strategies aim to enhance CAR-T cell specificity,improve resistance to immunosuppressive signals,and optimize in vivo functionality.This review summarizes ACT approaches for CRC,with a focus on CAR-T therapy.It briefly introduces TILs and TCR-T cells,while emphasizing the major challenges faced by CAR-T therapy in solid tumors and discusses potential strategies to improve therapeutic outcomes.
基金supported by the Natural Scientific Foundation of Zhejiang Province,China(Grant No.LTGY23H160007).
文摘Objective:Immune checkpoint inhibitors(ICIs)have demonstrated substantial efficacy in patients with advanced non-small cell lung cancer(NSCLC).However,the optimal duration of ICI therapy remains unclear,and limited real-world data are available.The aim of this study was to evaluate the relationship between ICI therapy duration and overall survival(OS)in patients who achieved varying best overall response(BOR)during ICI treatment,and to compare patients treated for 6 to 18 months vs.at least 18 months.Methods:This retrospective cohort study included adult patients diagnosed with advanced NSCLC who received ICI therapy at the Zhejiang Cancer Hospital between 2017 and 2022.Data collection ended on May 1,2024,and statistical analysis was performed between May and June 2024.Results:Using strict entry criteria,we screened 487 patients with advanced NSCLC and identified 134 eligible patients.Among these patients,the median durations of immunotherapy and follow-up were 24.57 months and 43.60 months,respectively.The objective response rate(ORR)was 58.2%,and the median progression-free survival(PFS)was 10.6 months.Median OS was not reached.At the last follow-up,54 patients had no disease progression,and 118 patients remained alive.Patients treated with ICI therapy for≥18 months had superior survival to those treated for 6 to 18 months(P=0.039).Further analysis revealed that the survival benefit was associated with BOR during ICI therapy.Specifically,patients achieving complete response/partial response(CR/PR)who received≥18 months of ICI therapy had a trend toward longer median OS than those treated for 6 to 18 months,but the difference did not reach statistical significance(P=0.177).Patients with stable disease(SD)who received≥18 months of ICI therapy had a statistically longer median OS than those treated for 6 to 18 months(P=0.019).Among patients treated with ICIs for≥18 months,24 continued with ICI-based therapy and achieved a median PFS2 of 6.67 months,an ORR of 33.3%,and a disease control rate(DCR)of 83.3%.Conclusions:This study provides real-world evidence and novel insights into the need for continuing ICI therapy beyond 18 months in patients with advanced NSCLC who do not exhibit progressive disease.For patients achieving SD during ICI therapy,a treatment duration of at least 18 months appears appropriate.For patients achieving CR/PR,treatment decisions should be individualized according to patient-specific circumstances.However,owing to the retrospective study design,potential selection bias and confounding factors might have influenced the results.Therefore,our findings require further validation in prospective clinical studies.
