Objective:Well-defined germ-line mutations in thePTCH1 gene are associated with syndromic multiple basal cell carcinomas(BCCs).Here,we used whole exome sequencing(WES)to identify the role of patched-1 in patients with...Objective:Well-defined germ-line mutations in thePTCH1 gene are associated with syndromic multiple basal cell carcinomas(BCCs).Here,we used whole exome sequencing(WES)to identify the role of patched-1 in patients with multiple,unusually large BCCs.Methods:A 72-year old patient presenting with numerous BCCs progressing to large ulcerating lesions was enrolled.WES was used to identify the pathogenic gene locus.Results:Genetic work-up by WES identified a homozygousPTCH1 nonsense mutation in the tumor tissue but not present in her blood cells or in non-lesional skin.In addition,heterozygous missense mutations were identified in three cancer-associated genes(EPHB2,RET,andGALNT12)in blood cells as well as in lesional and non-lesional skin.We also tested systemic immune therapy as a potentially beneficial approach to treat patients with numerous large BCCs on scatted areas of involvement.A rapid and sustained response to nivolumab was noted,suggesting that it is an efficacious drug for long-term therapeutic outcome.Conclusion:PTCH1,EPHB2,RET,andGALNT12 may potentially contribute to the synergistic oncogene driven malignant transformation manifesting as multiple,unusually large BCCs.展开更多
Chimeric antigen receptor T(CAR-T)cells have emerged as novel and promising immune therapies for the treatment of multiple types of cancer in patients with hematological malignancies.There are several key components c...Chimeric antigen receptor T(CAR-T)cells have emerged as novel and promising immune therapies for the treatment of multiple types of cancer in patients with hematological malignancies.There are several key components critical for development and application of CAR-T therapy.First,the design of CAR vectors can considerably affect several aspects of the physiological functions of these T cells.Moreover,despite the wide use of g-retrovirus and lentivirus in mediating gene transfer into T cells,optimal CAR delivery systems are also being developed and evaluated.In addition,several classes of mouse models have been used to evaluate the efficacies of CART cells;however,each model has its own limitations.Clinically,although surprising complete remission(CR)rates were observed in acute lymphoblastic leukemia(ALL),lymphoma,and multiple myeloma(MM),there is still a lack of specific targets for acute myeloid leukemia(AML).Leukemia relapse remains a major challenge,and its mechanism is presently under investigation.Cytokine release syndrome(CRS)and neurotoxicity are life-threatening adverse effects that need to be carefully treated.Several factors that compromise the activities of anti-solid cancer CAR-T cells have been recognized,and further improvements targeting these factors are the focus of the development of novel CAR-T cells.Overcoming the current hurdles will lead to optimal responses of CAR-T cells,thus paving the way for their wide clinical application.展开更多
Follicular lymphoma(FL)is the most common indolent B-cell lymphoma(BCL)globally.Recently,its incidence has increased in Europe,the United States,and Asia,with the number of gastrointestinal FL cases expected to increa...Follicular lymphoma(FL)is the most common indolent B-cell lymphoma(BCL)globally.Recently,its incidence has increased in Europe,the United States,and Asia,with the number of gastrointestinal FL cases expected to increase.Genetic abnormalities related to t(14;18)translocation,BCL2 overexpression,NF-κB pathway-related factors,histone acetylases,and histone methyltransferases cause FL and enhance its proliferation.Meanwhile,microRNAs are commonly used in diagnosing FL and predicting patient prognosis.Many clinical trials on novel therapeutics targeting these genetic abnormalities and immunomodulatory mechanisms have been conducted,resulting in a marked improvement in therapeutic outcomes for FL.Although developing these innovative therapeutic agents targeting specific genetic mutations and immune pathways has provided hope for curative options,FL treatment has become more complex,requiring combinatorial therapeutic regimens.However,optimal treatment combinations have not yet been achieved,highlighting the importance of a complete understanding regarding the pathogenesis of gastrointestinal FL.Accordingly,this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations.Moreover,the results of clinical trials are summarized,with a particular focus on treating nodal and gastrointestinal FLs.展开更多
As a rapidly progressing field in oncology,the adoptive transfer of T cells that have been genetically modified with chimeric antigen receptors(CARs)has shown striking efficacy in the management of hematological malig...As a rapidly progressing field in oncology,the adoptive transfer of T cells that have been genetically modified with chimeric antigen receptors(CARs)has shown striking efficacy in the management of hematological malignancies and has been reported in a number of clinical trials.of note,CAR T cell therapy has shown extraordinary potential,especially in relapsed/refractory patients.However,there are still challenges regarding the further development of this strategy,spanning from engineering and manufacturing issues,to limited applications,to accompanying toxicities.In this review,we will summarize the general knowledge of this novel method,including receptor composition,applications,adverse events and challenges.Additionally,we will propose several comprehensive recommendations.展开更多
Prostate cancers(PCa)have been reported to actively suppress antitumor immune responses by creating an immune-suppressive microenvironment.There is mounting evidence that PCas may undergo an‘‘Epithelial Immune Cell-...Prostate cancers(PCa)have been reported to actively suppress antitumor immune responses by creating an immune-suppressive microenvironment.There is mounting evidence that PCas may undergo an‘‘Epithelial Immune Cell-like Transition’’(EIT)by expressing molecules conventionally associated with immune cells(e.g.,a variety of cytokines/receptors,immune transcription factors,Ig motifs,and immune checkpoint molecules),which subsequently results in the suppression of anti-cancer immune activity within the tumor microenvironment.Recent progress within the field of immune therapy has underscored the importance of immune checkpoint molecules in cancer development,thus leading to the development of novel immunotherapeutic approaches.Here,we review the expression of select immune checkpoint molecules in PCa epithelial and associated immune cells,with particular emphasis on clinical data supporting the concept of an EIT-mediated phenotype in PCa.Furthermore,we summarize current advances in anti-immune checkpoint therapies,and provide perspectives on their potential applicability.展开更多
Approximately 20%-30%of patients with acute necrotizing pancreatitis develop infected pancreatic necrosis(IPN),a highly morbid and potentially lethal complication.Early identification of patients at high risk of IPN m...Approximately 20%-30%of patients with acute necrotizing pancreatitis develop infected pancreatic necrosis(IPN),a highly morbid and potentially lethal complication.Early identification of patients at high risk of IPN may facilitate appropriate preventive measures to improve clinical outcomes.In the past two decades,several markers and predictive tools have been proposed and evaluated for this purpose.Conventional biomarkers like C-reactive protein,procalcitonin,lymphocyte count,interleukin-6,and interleukin-8,and newly developed biomarkers like angiopoietin-2 all showed significant association with IPN.On the other hand,scoring systems like the Acute Physiology and Chronic Health Evaluation II and Pancreatitis Activity Scoring System have also been tested,and the results showed that they may provide better accuracy.For early prevention of IPN,several new therapies were tested,including early enteral nutrition,anti-biotics,probiotics,immune enhancement,etc.,but the results varied.Taken together,several evidence-supported predictive markers and scoring systems are readily available for predicting IPN.However,effective treatments to reduce the incidence of IPN are still lacking apart from early enteral nutrition.In this editorial,we summarize evidence concerning early prediction and prevention of IPN,providing insights into future practice and study design.A more homo-geneous patient population with reliable risk-stratification tools may help find effective treatments to reduce the risk of IPN,thereby achieving individualized treatment.展开更多
Tumor-associated macrophages(TAMs)are emerging as targets for tumor therapy because of their primary role in promoting tumor progression.Several studies have been conducted to target TAMs by reducing their infiltratio...Tumor-associated macrophages(TAMs)are emerging as targets for tumor therapy because of their primary role in promoting tumor progression.Several studies have been conducted to target TAMs by reducing their infiltration,depleting their numbers,and reversing their phenotypes to suppress tumor progression,leading to the development of drugs in preclinical and clinical trials.However,the heterogeneous characteristics of TAMs,including their ontogenetic and functional heterogeneity,limit their targeting.Therefore,in-depth exploration of the heterogeneity of TAMs,combined with immune checkpoint therapy or other therapeutic modalities could improve the efficiency of tumor treatment.This review focuses on the heterogeneous ontogeny and function of TAMs,as well as the current development of tumor therapies targeting TAMs and combination strategies.展开更多
The difficulty of early diagnosis,high tumor heterogeneity,and high recurrence and metastasis rates lead to an unsatisfactory treatment status for hepatocellular carcinoma(HCC).HCC is a typical inflammation-driven tum...The difficulty of early diagnosis,high tumor heterogeneity,and high recurrence and metastasis rates lead to an unsatisfactory treatment status for hepatocellular carcinoma(HCC).HCC is a typical inflammation-driven tumor.Chronic inflammation allows nascent tumors to escape immunosurveillance.Chemokines are small,soluble,secreted proteins that can regulate the activation and trafficking of immune cells during inflammation.Several studies have shown that various chemokines with overarching functions disrupt the immune microenvironment during the initiation and progression of HCC.The dysregulated chemokine network in HCC contributes to multiple malignant processes,including angiogenesis,tumor proliferation,migration,invasion,tumor low response,and resistance to immune therapy.Here,we summarize the current studies focusing on the role of chemokines and their receptors in the HCC immune microenvironment,highlighting potential translational therapeutic uses for modulating the chemokine system in HCC.展开更多
Objective:DNA damage response(DDR)genes have low mutation rates,which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor(ICI)treatment.Thus,a systemic analysis of multip...Objective:DNA damage response(DDR)genes have low mutation rates,which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor(ICI)treatment.Thus,a systemic analysis of multiple DDR genes is needed to identify potential biomarkers of ICI efficacy.Methods:A total of 39,631 patients with mutation data were selected from the cBioPortal database.A total of 155 patients with mutation data were obtained from the Fudan University Shanghai Cancer Center(FUSCC).A total of 1,660 patients from the MSK-IMPACT cohort who underwent ICI treatment were selected for survival analysis.A total of 249 patients who underwent ICI treatment from the Dana-Farber Cancer Institute(DFCI)cohort were obtained from a published dataset.The Cancer Genome Atlas(TCGA)level 3 RNA-Seq version 2 RSEM data for gastric cancer were downloaded from cBioPortal.Results:Six MMR and 30 DDR genes were included in this study.Six MMR and 20 DDR gene mutations were found to predict the therapeutic efficacy of ICI,and most of them predicted the therapeutic efficacy of ICI,in a manner dependent on TMB,except for 4 combined DDR gene mutations,which were associated with the therapeutic efficacy of ICI independently of the TMB.Single MMR/DDR genes showed low mutation rates;however,the mutation rate of all the MMR/DDR genes associated with the therapeutic efficacy of ICI was relatively high,reaching 10%–30%in several cancer types.Conclusions:Coanalysis of multiple MMR/DDR mutations aids in selecting patients who are potential candidates for immunotherapy.展开更多
BACKGROUND Gut microbiome(GM)composition and diversity have recently been studied as a biomarker of response to immune checkpoint blockade therapy(ICB)and of ICBrelated colitis.AIM To conduct a systematic review on th...BACKGROUND Gut microbiome(GM)composition and diversity have recently been studied as a biomarker of response to immune checkpoint blockade therapy(ICB)and of ICBrelated colitis.AIM To conduct a systematic review on the role of GM composition and diversity in predicting response and colitis in patients with melanoma treated with ICB.METHODS The review protocol was registered in PROSPERO:CRD42021228018.From a total of 300 studies,nine studies met inclusion criteria.Two studies were phase I clinical trials,while the remainder were prospective observational studies.All but one study has moderate risk of bias.In addition,we conducted a relevant search by Reference Citation Analysis(RCA)(https://www.referencecitationanalysis.com).RESULTS Fecal samples enriched in Firmicutes phylum were associated with good response to ICB,whereas the Bacteroidales family was associated with poor response to ICB.Samples with greater GM diversity were associated with more favorable response to ICB[hazard ratio(HR)=3.57,95%confidence interval=1.02-12.52,P<0.05].Fecal samples with a higher abundance in Firmicutes were more susceptible to ICB-related colitis(P<0.01)whereas samples enriched in Bacteroidetes were more resistant to ICB-related colitis(P<0.05).Overall,there was limited concordance in the organisms in the GM identified to be associated with response to ICB,and studies evaluating GM diversity showed conflicting results.CONCLUSION This highlights the need for further prospective studies to confirm whether the GM could be used as a biomarker and potential intervention to modulate ICB response in melanoma patients.展开更多
Immune therapy based on programmed death-ligand 1(PD-L1)is widely used to treat human tumors.The current strategies to improve immune checkpoint blockade therapy fail in rescuing increased expression of PD-L1 in tumor...Immune therapy based on programmed death-ligand 1(PD-L1)is widely used to treat human tumors.The current strategies to improve immune checkpoint blockade therapy fail in rescuing increased expression of PD-L1 in tumor issues.Here,we for the first time synthesized the metal-organic framework(MOF)nanocrystals of rare-earth element dysprosium(Dy)coordinated with tetrakis(4-carboxyphenyl)porphyrin(TCPP),which show well-defined two-dimensional morphologies.The MOF nanocrystals of Dy-TCPP could apparently reduce PD-L1 expression in tumor cells both in vitro and in vivo,and therefore display effective tumor treatment through immune therapy without any immune checkpoint inhibitor drugs.Considering the sensitivity of TCPP ligand toward ultrasound,the prepared Dy-TCPP can also realize sonodynamic therapy(SDT)besides immune therapy.In addition,the Dy-TCPP nanocrystals can efficiently obtain T_(2)-weight magnetic resonance imaging(MRI)of tumor sites.Our study provides the Dy-TCPP nanocrystals as promising diagnostic MRI-guided platforms for the combined treatment on tumors with SDT and immune therapy.Moreover,this strategy succeeds in reducing the elevated expression of PD-L1 in tumor cells,which might serve as a novel avenue for tumor immunotherapy in future.展开更多
Alzheimer’s disease(AD) is an age-related neurodegenerative disease characterized by progressive cognitive defects. The role of the central immune system dominated by microglia in the progression of AD has been exten...Alzheimer’s disease(AD) is an age-related neurodegenerative disease characterized by progressive cognitive defects. The role of the central immune system dominated by microglia in the progression of AD has been extensively investigated. However, little is known about the peripheral immune system in AD pathogenesis.Recently, with the discovery of the meningeal lymphatic vessels and glymphatic system, the roles of the acquired immunity in the maintenance of central homeostasis and neurodegenerative diseases have attracted an increasing attention. The T cells not only regulate the function of neurons, astrocytes, microglia, oligodendrocytes and brain microvascular endothelial cells, but also participate in the clearance of β-amyloid(Aβ) plaques. Apart from producing antibodies to bind Aβ peptides, the B cells affect Aβ-related cascades via a variety of antibodyindependent mechanisms. This review systemically summarizes the recent progress in understanding pathophysiological roles of the T cells and B cells in AD.展开更多
BACKGROUND The majority of clinical trials of first-line systemic treatments for hepatocellular carcinoma(HCC)used placebo or sorafenib as comparators,and there are limited data providing a cross comparison of treatme...BACKGROUND The majority of clinical trials of first-line systemic treatments for hepatocellular carcinoma(HCC)used placebo or sorafenib as comparators,and there are limited data providing a cross comparison of treatments in this setting,especially for newly-approved immune checkpoint inhibitor and vascular endothelial growth factor inhibitor combination treatments.AIM To systematically review and compare response rates,survival outcomes,and safety of first-line systemic therapies for advanced hepatocellular carcinoma.METHODS We searched PubMed,Science Direct,the Cochrane Database,Excerpta Medica Database,and abstracts from the American Society of Clinical Oncology 2020 annual congress.Eligible studies were randomized controlled trials of systemic therapy enrolling adults with advanced/unresectable HCC.Risk of bias was assessed with the Cochrane risk of bias tool for randomized controlled trials.A network meta-analysis was used to synthesize data and perform direct and indirect comparisons between treatments.P value,a frequentist analog to the surface under the cumulative ranking curve,was used to rank treatments.RESULTS In total,1398 articles were screened and 27 included.Treatments compared were atezolizumab plus bevacizumab,brivanib,donafenib,dovitinib,FOLFOX4,lenvatinib,linifanib,nintedanib,nivolumab,sorafenib,sunitinib,vandetanib,11 sorafenib combination therapies,and three other combination therapies.For overall response rate,lenvatinib ranked 1/19,followed by atezolizumab plus bevacizumab and nivolumab.For progression-free survival(PFS),atezolizumab+bevacizumab was ranked 1/15,followed by lenvatinib.With the exception of atezolizumab+bevacizumab[hazard ratios(HR)PFS=0.90;95%confidence interval(CI):0.64-1.25],the estimated HRs for PFS for all included treatments vs lenvatinib were>1;however,the associated 95%CI passed through unity for bevacizumab plus erlotinib,linifanib,and FOLFOX4.For overall survival,atezolizumab plus bevacizumab was ranked 1/25,followed by vandetanib 100 mg/d and donafinib,with lenvatinib ranked 6/25.Atezolizumab+bevacizumab was associated with a lower risk of death vs lenvatinib(HRos=0.63;95%CI:0.44-0.89),while the HR for overall survival for most other treatments vs lenvatinib had associated 95%CIs that passed through unity.Vandetanib 300 mg/d and 100 mg/d were ranked 1/13 and 2/13,respectively,for the lowest incidence of treatment terminations due to adverse events,followed by sorafenib(5/13),lenvatinib(10/13),and atezolizumab+bevacizumab(13/13).CONCLUSION There is not one single first-line treatment for advanced HCC associated with superior outcomes across all outcome measurements.Therefore,first-line systemic treatment should be selected based on individualized treatment goals.展开更多
With the development and introduction of immune checkpoint inhibitors(ICIs)in cancer patients,immune-related side effects have increasingly attracted attention.However,the risks of immune-related renal toxicity are po...With the development and introduction of immune checkpoint inhibitors(ICIs)in cancer patients,immune-related side effects have increasingly attracted attention.However,the risks of immune-related renal toxicity are poorly characterized.In this study,we performed a network meta-analysis(NMA)of ICI-related randomized clinical trials(RCTs)to elucidate the comparative risk of acute kidney injury(AKI)in cancer patients receiving different ICIs.We also sought to identify other factors potentially affecting the risk of AKI.PubMed and EMBASE were searched for peer-reviewed trial reports published between January 2000 and May 2021.Eligible studies were RCTs studying ICIs in cancer patients and reporting AKI data.We performed a frequentist NMA to evaluate the risk ratios for grade 1-5 and grade 3-5 AKI between the treatment groups.We also assessed the absolute incidence of AKI in the ICI-containing arm using traditional direct meta-analysis.Once significant heterogeneity was detected in a traditional direct meta-analysis,multivariable meta-regression analysis was applied to identify factors that significantly affected the absolute incidence of AKI.A total of 85 RCTs were included in this study.In the NMA for the risk of grade 1-5 and 3-5 AKI,ipilimumab showed a significantly higher risk than avelumab and durvalumab,whereas 1 mg/kg nivolumab plus 3 mg/kg ipilimumab(N1I3)showed a significantly higher risk than other groups.In terms of treatment ranking,durvalumab±low-dose tremelimumab and avelumab were consistently among the top three safest treatments for grade 1-5 or 3-5 AKI,whereas N1I3,ipilimumab and tremelimumab were consistently among the top three treatments with the highest risk for grade 1-5 or 3-5 AKI.Compared with other cancers,renal cell carcinoma and urothelial carcinoma showed a significantly higher risk of AKI.The incidence of AKI was significantly higher with ICI+chemotherapy than with ICI monotherapy.In this NMA involving largescale up-to-date ICI trials,we demonstrated the comparative safety of existing ICI drugs for grade 1-5 and grade 3-5 AKI.Based on data from the ICI arms of these trials,we also revealed several potential risk factors for immune-related AKI,including tumor type and treatment paradigm.展开更多
Even though the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is related to SARS-CoV and Middle East respiratory syndrome coronavirus(MERS-CoV),identifying effective and safe therapeutic strategies remain...Even though the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is related to SARS-CoV and Middle East respiratory syndrome coronavirus(MERS-CoV),identifying effective and safe therapeutic strategies remains challenging.In search of finding effective treatments to eradicate the virus and improve disease symptoms,scientists are exploring possible therapies such as anti-viral,anti-malaria,immune therapy,and hormone treatments.However,the efficacy of these treatments was not validated on either SARS-CoV or MERS-CoV.In this study,we have reviewed synthetic evidence achieved through systematic and meta-analysis of therapeutics specific for SARS-CoV-2 and observed that the use of the above-mentioned therapies had no clinical benefits in coronavirus disease 2019 patients and,conversely,displayed side effects.展开更多
Objective:To explore immunotherapy effectiveness of the CD4^(+)CD25^(+) regulatory T cells for treating female mouse with recurrent spontaneous abortion(RSA)by animal experiments.Methods:Mononuclear lymphocytes were i...Objective:To explore immunotherapy effectiveness of the CD4^(+)CD25^(+) regulatory T cells for treating female mouse with recurrent spontaneous abortion(RSA)by animal experiments.Methods:Mononuclear lymphocytes were isolated from the blood(instead of cord blood)of new-born baby of KunMing Bai mouse or BALB/c male mouse with normal birth ability(as unrelated third party blood source)by density gradient centrifuga-tion method.The CD4^(+)CD25^(+) regulatory T cells were selected by magnetic-activated cell sorting from mononuclear cells of cord blood cells.CBA/J female mouse copulated with DBA/2J male mouse was utilized as RSA animal model.Pregnant RSA mice were injected different types of lymphocytes through tail vein.Independent sample t-test was used to analyze the data from each group.Results:The proportion of CD4^(+)CD25^(+)T cells in CD4^(+)T cells was(17.49±0.60)%in CD4^(+)CD25^(+) regulatory T cells injection group,which was statistical significant higher than that of mononuclear lymphocyte injection group(14.68±0.83)%,sterile PBS group(9.54±0.85)%or no injection group(9.28±0.68)%(p<.05,t-value was 4.754,13.242 and 15.621,respec-tively).The Foxp3 relative protein expression level of CD4^(+)CD25^(+) regulatory T cells injected group was 5.85±0.45,which was also significant higher than that of mononuclear lymphocyte injection(2.86±0.54),sterile PBS group(1.08±0.16)or no injection group(1.00±0.00)(p<.05,t-value was 7.276,17.227 and 18.635,respectively).Finally,two times of CD4^(+)CD25^(+)T cell injected group at the 4 th and 8 th day had well effect for RSA mouse,and embryo sorption rate was(4.92±0.08)%,which significant lower than that of two times of mononuclear lymphocyte injected group(13.07±0.06)%,sterile PBS group(23.11±0.12)%,or no injection group(25.47±0.11)%(p<.05,t-value was-2.603,-4.012 and-4.700,respectively).Conclusions:Pregnant mouse with RSA injected CD4^(+)CD25^(+)T cells several times for immunotherapy can get better effec-tiveness than that of pregnant mouse injected traditional mononuclear cells.展开更多
Interferon-gamma (IFNγ) is a pleiotropic cytokine implicated in tumor immune surveillance, with its antiproliferative, pro-apoptotic, and immune-provoking effects. Regarding the antitumor effects of IFNγ, IFNγ-depe...Interferon-gamma (IFNγ) is a pleiotropic cytokine implicated in tumor immune surveillance, with its antiproliferative, pro-apoptotic, and immune-provoking effects. Regarding the antitumor effects of IFNγ, IFNγ-dependent therapies have been proposed and have undergone many clinical trials for various cancer types but the outcomes were not satisfactory. Recent studies have suggested that cancer cells develop immune evasion strategies to escape from IFNγ-dependent immunosurveillance by various mechanisms. In this review, we summarize recent advances in the effects and molecular mechanisms of IFNγ on target cells, as well as potential immune escape mechanisms of tumor cells. Furthermore, we discuss how to target IFNγ signaling and overcome immune evasion to provide promising therapeutic strategies for the treatment of patients with cancer.展开更多
The incidence of gastric cancer ranks 4th in malignant tumors,and the mortality rate ranks 3rd in malignant tumors.Most patients with gastric cancer are already at the advanced stage when diagnosed.Although chemothera...The incidence of gastric cancer ranks 4th in malignant tumors,and the mortality rate ranks 3rd in malignant tumors.Most patients with gastric cancer are already at the advanced stage when diagnosed.Although chemotherapy is the main treatment for patients with advanced gastric cancer,it can extend the overall survival.But adverse reactions are more prominent.With the rise of targeted therapy,the molecular mechanism of gastric cancer occurrence and development continues to develop,and molecular targeted therapy of gastric cancer has gradually emerged.The current targets for gastric cancer mainly include endothelial growth factor receptor,HER2,vascular endothelium growth factor,vascular endothelium growth factor receptor,mammalian rapamycin receptor,hepatocellular growth factor,et al.,but the clinical efficacy is still not satisfactory.At present,most of the studies on molecular targeted drugs for gastric cancer have ended in failure.The heterogeneity between patients and the prognosis of tumors in different parts may be different.It is suggested that screening targeted drugs according to the patient's pathological characteristics and molecular typing,and individualized treatment is the inevitable way of targeted treatment of gastric cancer.展开更多
Hepatocellular carcinoma(HCC),one of the deadliest cancers all over the world,had a limited prognosis in the past.Recently,the remarkable efficacy of immune checkpoint inhibitors(ICIs)therapy has been shown in various...Hepatocellular carcinoma(HCC),one of the deadliest cancers all over the world,had a limited prognosis in the past.Recently,the remarkable efficacy of immune checkpoint inhibitors(ICIs)therapy has been shown in various solid tumors.What's more,the occurrence of HCC is associated with immune escape and therefore various ICIs have been applied to clinical trials for HCC.However,the special immune environment of the liver creates the complex tumor microenvironment(TME)of HCC,which impairs the overall survival(OS)and overall response rate(OCR)of ICIs as a monotherapy.Lately,various therapies have been used in combination with ICIs therapy to improve its clinical efficacy.Among which,radiotherapy is widely concerned because of its unique immunoreaction.A large number of basic and clinical studies have demonstrated that the combined radiotherapy and ICIs therapy has advantages in improving the OCR and efficacy,as compared with ICIs therapy alone.Herein,this article reviews the studies on the advantages and possible mechanisms of the combination of radiotherapy and ICIs therapy for HCC.展开更多
The blocking of the immune checkpoint pathway with antibodies,especially targeting to programmed death-1/programmed death ligand-1(PD-1/PD-L1)pathway,was currently a widely used treatment strategy in clinical practice...The blocking of the immune checkpoint pathway with antibodies,especially targeting to programmed death-1/programmed death ligand-1(PD-1/PD-L1)pathway,was currently a widely used treatment strategy in clinical practice.However,the shortcomings of PD-L1 antibodies were constantly exposed with the deepening of its research and their therapeutic effect was limited by the translocation and redistribution of intracellular PD-L1.Herein,we proposed to improve immune checkpoint blockade therapy by using liposomes-coated CaO_(2)(CaO_(2)@Lipo)nanoparticles to inhibit the de novo biosynthesis of PD-L1.CaO_(2)@Lipo would produce oxygen and reduce hypoxia-inducible factor-1α(HIF-1α)level,which then downregulated the expression of PD-L1.Our in vitro and in vivo results have confirmed CaO_(2)@Lipo promoted the degradation of HIF-1αand then downregulated the expression of PD-L1 in cancer cells for avoiding immune escape.Furthermore,to mimicking the clinical protocol of anti-PD-L1 antibodies+chemo-drugs,CaO_(2)@Lipo was combined with doxorubicin(DOX)to investigate the tumor inhibition efficiency.We found CaO_(2)@Lipo enhanced DOX-induced immunogenic cell death(ICD)effect,which then promoted the infiltration of T cells,strengthened the blocking effect,thus provided an effective means to overcome the traditional immune checkpoint blockade treatment.展开更多
基金The study was supported by NIH R01 IA143810the Department of Dermatology and Cutaneous Biology,Thomas Jefferson University Institutional funds.
文摘Objective:Well-defined germ-line mutations in thePTCH1 gene are associated with syndromic multiple basal cell carcinomas(BCCs).Here,we used whole exome sequencing(WES)to identify the role of patched-1 in patients with multiple,unusually large BCCs.Methods:A 72-year old patient presenting with numerous BCCs progressing to large ulcerating lesions was enrolled.WES was used to identify the pathogenic gene locus.Results:Genetic work-up by WES identified a homozygousPTCH1 nonsense mutation in the tumor tissue but not present in her blood cells or in non-lesional skin.In addition,heterozygous missense mutations were identified in three cancer-associated genes(EPHB2,RET,andGALNT12)in blood cells as well as in lesional and non-lesional skin.We also tested systemic immune therapy as a potentially beneficial approach to treat patients with numerous large BCCs on scatted areas of involvement.A rapid and sustained response to nivolumab was noted,suggesting that it is an efficacious drug for long-term therapeutic outcome.Conclusion:PTCH1,EPHB2,RET,andGALNT12 may potentially contribute to the synergistic oncogene driven malignant transformation manifesting as multiple,unusually large BCCs.
基金The National Major Scientific and Technological Special Project for“Significant New Drugs Development,”No.SQ2018ZX090201The Strategic Priority Research Program of the Chinese Academy of Sciences,Grant No.XDB19030205,No.XDA12050305+10 种基金Guangdong Provincial Applied Science and Technology Research&Development Program,No.2016B020237006Guangdong Special Support Program,NO.2017TX04R102Frontier and key technology innovation special grant from the Department of Science and Technology of Guangdong province,No.2015B020227003Natural Science Fund of Guangdong Province:Distinguished Young Scholars(Grant No.:2014A030306028)Doctoral Foundation,No.:2017A030310381National Natural Science Foundation of China(NSFC),No.81773301,81700156,81870121,81873847Frontier Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory,No.2018GZR110105003Science and Technology Planning Project of Guangdong Province,China(2017B030314056)Guangzhou Medical University High-level University Construction Research Startup Fund,NO.B195002004013Research Program of Hefei Institute of Stem Cell and Regenerative Medicine,No.2019YF001Guangzhou science and technology plan project,NO.201907010042,201904010473.
文摘Chimeric antigen receptor T(CAR-T)cells have emerged as novel and promising immune therapies for the treatment of multiple types of cancer in patients with hematological malignancies.There are several key components critical for development and application of CAR-T therapy.First,the design of CAR vectors can considerably affect several aspects of the physiological functions of these T cells.Moreover,despite the wide use of g-retrovirus and lentivirus in mediating gene transfer into T cells,optimal CAR delivery systems are also being developed and evaluated.In addition,several classes of mouse models have been used to evaluate the efficacies of CART cells;however,each model has its own limitations.Clinically,although surprising complete remission(CR)rates were observed in acute lymphoblastic leukemia(ALL),lymphoma,and multiple myeloma(MM),there is still a lack of specific targets for acute myeloid leukemia(AML).Leukemia relapse remains a major challenge,and its mechanism is presently under investigation.Cytokine release syndrome(CRS)and neurotoxicity are life-threatening adverse effects that need to be carefully treated.Several factors that compromise the activities of anti-solid cancer CAR-T cells have been recognized,and further improvements targeting these factors are the focus of the development of novel CAR-T cells.Overcoming the current hurdles will lead to optimal responses of CAR-T cells,thus paving the way for their wide clinical application.
文摘Follicular lymphoma(FL)is the most common indolent B-cell lymphoma(BCL)globally.Recently,its incidence has increased in Europe,the United States,and Asia,with the number of gastrointestinal FL cases expected to increase.Genetic abnormalities related to t(14;18)translocation,BCL2 overexpression,NF-κB pathway-related factors,histone acetylases,and histone methyltransferases cause FL and enhance its proliferation.Meanwhile,microRNAs are commonly used in diagnosing FL and predicting patient prognosis.Many clinical trials on novel therapeutics targeting these genetic abnormalities and immunomodulatory mechanisms have been conducted,resulting in a marked improvement in therapeutic outcomes for FL.Although developing these innovative therapeutic agents targeting specific genetic mutations and immune pathways has provided hope for curative options,FL treatment has become more complex,requiring combinatorial therapeutic regimens.However,optimal treatment combinations have not yet been achieved,highlighting the importance of a complete understanding regarding the pathogenesis of gastrointestinal FL.Accordingly,this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations.Moreover,the results of clinical trials are summarized,with a particular focus on treating nodal and gastrointestinal FLs.
基金the Key Program of the National Natural Science Foundation(NNSF)of China(No.81230052 and No.81630006).
文摘As a rapidly progressing field in oncology,the adoptive transfer of T cells that have been genetically modified with chimeric antigen receptors(CARs)has shown striking efficacy in the management of hematological malignancies and has been reported in a number of clinical trials.of note,CAR T cell therapy has shown extraordinary potential,especially in relapsed/refractory patients.However,there are still challenges regarding the further development of this strategy,spanning from engineering and manufacturing issues,to limited applications,to accompanying toxicities.In this review,we will summarize the general knowledge of this novel method,including receptor composition,applications,adverse events and challenges.Additionally,we will propose several comprehensive recommendations.
文摘Prostate cancers(PCa)have been reported to actively suppress antitumor immune responses by creating an immune-suppressive microenvironment.There is mounting evidence that PCas may undergo an‘‘Epithelial Immune Cell-like Transition’’(EIT)by expressing molecules conventionally associated with immune cells(e.g.,a variety of cytokines/receptors,immune transcription factors,Ig motifs,and immune checkpoint molecules),which subsequently results in the suppression of anti-cancer immune activity within the tumor microenvironment.Recent progress within the field of immune therapy has underscored the importance of immune checkpoint molecules in cancer development,thus leading to the development of novel immunotherapeutic approaches.Here,we review the expression of select immune checkpoint molecules in PCa epithelial and associated immune cells,with particular emphasis on clinical data supporting the concept of an EIT-mediated phenotype in PCa.Furthermore,we summarize current advances in anti-immune checkpoint therapies,and provide perspectives on their potential applicability.
文摘Approximately 20%-30%of patients with acute necrotizing pancreatitis develop infected pancreatic necrosis(IPN),a highly morbid and potentially lethal complication.Early identification of patients at high risk of IPN may facilitate appropriate preventive measures to improve clinical outcomes.In the past two decades,several markers and predictive tools have been proposed and evaluated for this purpose.Conventional biomarkers like C-reactive protein,procalcitonin,lymphocyte count,interleukin-6,and interleukin-8,and newly developed biomarkers like angiopoietin-2 all showed significant association with IPN.On the other hand,scoring systems like the Acute Physiology and Chronic Health Evaluation II and Pancreatitis Activity Scoring System have also been tested,and the results showed that they may provide better accuracy.For early prevention of IPN,several new therapies were tested,including early enteral nutrition,anti-biotics,probiotics,immune enhancement,etc.,but the results varied.Taken together,several evidence-supported predictive markers and scoring systems are readily available for predicting IPN.However,effective treatments to reduce the incidence of IPN are still lacking apart from early enteral nutrition.In this editorial,we summarize evidence concerning early prediction and prevention of IPN,providing insights into future practice and study design.A more homo-geneous patient population with reliable risk-stratification tools may help find effective treatments to reduce the risk of IPN,thereby achieving individualized treatment.
基金This work was supported by the National Natural Science Foundation of China(82003018).
文摘Tumor-associated macrophages(TAMs)are emerging as targets for tumor therapy because of their primary role in promoting tumor progression.Several studies have been conducted to target TAMs by reducing their infiltration,depleting their numbers,and reversing their phenotypes to suppress tumor progression,leading to the development of drugs in preclinical and clinical trials.However,the heterogeneous characteristics of TAMs,including their ontogenetic and functional heterogeneity,limit their targeting.Therefore,in-depth exploration of the heterogeneity of TAMs,combined with immune checkpoint therapy or other therapeutic modalities could improve the efficiency of tumor treatment.This review focuses on the heterogeneous ontogeny and function of TAMs,as well as the current development of tumor therapies targeting TAMs and combination strategies.
基金Supported by grants from the National Natural Science Foundation of China(No.81871911[W.H.],No.81772623[L.X.],and No.81972237[L.X.])the National Key Research and Development Program of China(No.2018YFC1312103[L.X.]).
文摘The difficulty of early diagnosis,high tumor heterogeneity,and high recurrence and metastasis rates lead to an unsatisfactory treatment status for hepatocellular carcinoma(HCC).HCC is a typical inflammation-driven tumor.Chronic inflammation allows nascent tumors to escape immunosurveillance.Chemokines are small,soluble,secreted proteins that can regulate the activation and trafficking of immune cells during inflammation.Several studies have shown that various chemokines with overarching functions disrupt the immune microenvironment during the initiation and progression of HCC.The dysregulated chemokine network in HCC contributes to multiple malignant processes,including angiogenesis,tumor proliferation,migration,invasion,tumor low response,and resistance to immune therapy.Here,we summarize the current studies focusing on the role of chemokines and their receptors in the HCC immune microenvironment,highlighting potential translational therapeutic uses for modulating the chemokine system in HCC.
基金This work was supported by the National Key R&D Program of China(Grant No.2018YFC1313300)the National Natural Science Foundation of China(Grant No.81572331).
文摘Objective:DNA damage response(DDR)genes have low mutation rates,which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor(ICI)treatment.Thus,a systemic analysis of multiple DDR genes is needed to identify potential biomarkers of ICI efficacy.Methods:A total of 39,631 patients with mutation data were selected from the cBioPortal database.A total of 155 patients with mutation data were obtained from the Fudan University Shanghai Cancer Center(FUSCC).A total of 1,660 patients from the MSK-IMPACT cohort who underwent ICI treatment were selected for survival analysis.A total of 249 patients who underwent ICI treatment from the Dana-Farber Cancer Institute(DFCI)cohort were obtained from a published dataset.The Cancer Genome Atlas(TCGA)level 3 RNA-Seq version 2 RSEM data for gastric cancer were downloaded from cBioPortal.Results:Six MMR and 30 DDR genes were included in this study.Six MMR and 20 DDR gene mutations were found to predict the therapeutic efficacy of ICI,and most of them predicted the therapeutic efficacy of ICI,in a manner dependent on TMB,except for 4 combined DDR gene mutations,which were associated with the therapeutic efficacy of ICI independently of the TMB.Single MMR/DDR genes showed low mutation rates;however,the mutation rate of all the MMR/DDR genes associated with the therapeutic efficacy of ICI was relatively high,reaching 10%–30%in several cancer types.Conclusions:Coanalysis of multiple MMR/DDR mutations aids in selecting patients who are potential candidates for immunotherapy.
文摘BACKGROUND Gut microbiome(GM)composition and diversity have recently been studied as a biomarker of response to immune checkpoint blockade therapy(ICB)and of ICBrelated colitis.AIM To conduct a systematic review on the role of GM composition and diversity in predicting response and colitis in patients with melanoma treated with ICB.METHODS The review protocol was registered in PROSPERO:CRD42021228018.From a total of 300 studies,nine studies met inclusion criteria.Two studies were phase I clinical trials,while the remainder were prospective observational studies.All but one study has moderate risk of bias.In addition,we conducted a relevant search by Reference Citation Analysis(RCA)(https://www.referencecitationanalysis.com).RESULTS Fecal samples enriched in Firmicutes phylum were associated with good response to ICB,whereas the Bacteroidales family was associated with poor response to ICB.Samples with greater GM diversity were associated with more favorable response to ICB[hazard ratio(HR)=3.57,95%confidence interval=1.02-12.52,P<0.05].Fecal samples with a higher abundance in Firmicutes were more susceptible to ICB-related colitis(P<0.01)whereas samples enriched in Bacteroidetes were more resistant to ICB-related colitis(P<0.05).Overall,there was limited concordance in the organisms in the GM identified to be associated with response to ICB,and studies evaluating GM diversity showed conflicting results.CONCLUSION This highlights the need for further prospective studies to confirm whether the GM could be used as a biomarker and potential intervention to modulate ICB response in melanoma patients.
基金This work was financially supported by the National Natural Science Foundation of China(No.52172096)the Foundation of CNU(No.0092255073).
文摘Immune therapy based on programmed death-ligand 1(PD-L1)is widely used to treat human tumors.The current strategies to improve immune checkpoint blockade therapy fail in rescuing increased expression of PD-L1 in tumor issues.Here,we for the first time synthesized the metal-organic framework(MOF)nanocrystals of rare-earth element dysprosium(Dy)coordinated with tetrakis(4-carboxyphenyl)porphyrin(TCPP),which show well-defined two-dimensional morphologies.The MOF nanocrystals of Dy-TCPP could apparently reduce PD-L1 expression in tumor cells both in vitro and in vivo,and therefore display effective tumor treatment through immune therapy without any immune checkpoint inhibitor drugs.Considering the sensitivity of TCPP ligand toward ultrasound,the prepared Dy-TCPP can also realize sonodynamic therapy(SDT)besides immune therapy.In addition,the Dy-TCPP nanocrystals can efficiently obtain T_(2)-weight magnetic resonance imaging(MRI)of tumor sites.Our study provides the Dy-TCPP nanocrystals as promising diagnostic MRI-guided platforms for the combined treatment on tumors with SDT and immune therapy.Moreover,this strategy succeeds in reducing the elevated expression of PD-L1 in tumor cells,which might serve as a novel avenue for tumor immunotherapy in future.
基金supported by grants from the National Natural Science Foundation of China (Grants No. 82071199 and 32100674)。
文摘Alzheimer’s disease(AD) is an age-related neurodegenerative disease characterized by progressive cognitive defects. The role of the central immune system dominated by microglia in the progression of AD has been extensively investigated. However, little is known about the peripheral immune system in AD pathogenesis.Recently, with the discovery of the meningeal lymphatic vessels and glymphatic system, the roles of the acquired immunity in the maintenance of central homeostasis and neurodegenerative diseases have attracted an increasing attention. The T cells not only regulate the function of neurons, astrocytes, microglia, oligodendrocytes and brain microvascular endothelial cells, but also participate in the clearance of β-amyloid(Aβ) plaques. Apart from producing antibodies to bind Aβ peptides, the B cells affect Aβ-related cascades via a variety of antibodyindependent mechanisms. This review systemically summarizes the recent progress in understanding pathophysiological roles of the T cells and B cells in AD.
文摘BACKGROUND The majority of clinical trials of first-line systemic treatments for hepatocellular carcinoma(HCC)used placebo or sorafenib as comparators,and there are limited data providing a cross comparison of treatments in this setting,especially for newly-approved immune checkpoint inhibitor and vascular endothelial growth factor inhibitor combination treatments.AIM To systematically review and compare response rates,survival outcomes,and safety of first-line systemic therapies for advanced hepatocellular carcinoma.METHODS We searched PubMed,Science Direct,the Cochrane Database,Excerpta Medica Database,and abstracts from the American Society of Clinical Oncology 2020 annual congress.Eligible studies were randomized controlled trials of systemic therapy enrolling adults with advanced/unresectable HCC.Risk of bias was assessed with the Cochrane risk of bias tool for randomized controlled trials.A network meta-analysis was used to synthesize data and perform direct and indirect comparisons between treatments.P value,a frequentist analog to the surface under the cumulative ranking curve,was used to rank treatments.RESULTS In total,1398 articles were screened and 27 included.Treatments compared were atezolizumab plus bevacizumab,brivanib,donafenib,dovitinib,FOLFOX4,lenvatinib,linifanib,nintedanib,nivolumab,sorafenib,sunitinib,vandetanib,11 sorafenib combination therapies,and three other combination therapies.For overall response rate,lenvatinib ranked 1/19,followed by atezolizumab plus bevacizumab and nivolumab.For progression-free survival(PFS),atezolizumab+bevacizumab was ranked 1/15,followed by lenvatinib.With the exception of atezolizumab+bevacizumab[hazard ratios(HR)PFS=0.90;95%confidence interval(CI):0.64-1.25],the estimated HRs for PFS for all included treatments vs lenvatinib were>1;however,the associated 95%CI passed through unity for bevacizumab plus erlotinib,linifanib,and FOLFOX4.For overall survival,atezolizumab plus bevacizumab was ranked 1/25,followed by vandetanib 100 mg/d and donafinib,with lenvatinib ranked 6/25.Atezolizumab+bevacizumab was associated with a lower risk of death vs lenvatinib(HRos=0.63;95%CI:0.44-0.89),while the HR for overall survival for most other treatments vs lenvatinib had associated 95%CIs that passed through unity.Vandetanib 300 mg/d and 100 mg/d were ranked 1/13 and 2/13,respectively,for the lowest incidence of treatment terminations due to adverse events,followed by sorafenib(5/13),lenvatinib(10/13),and atezolizumab+bevacizumab(13/13).CONCLUSION There is not one single first-line treatment for advanced HCC associated with superior outcomes across all outcome measurements.Therefore,first-line systemic treatment should be selected based on individualized treatment goals.
基金National Key R&D Program of China,Grant/Award Number:2020AAA0109500National Natural Science Foundation of China,Grant/Award Numbers:82030025,32100631,82003269,82122053+3 种基金Young Elite Scientists Sponsorship Program by the China Association for Science and Technology,Grant/Award Number:YESS20210056CAMS Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-067Central Research Institute Fund of Chinese Academy of Medical Sciences,Grant/Award Number:2021-PT310-001Key-Area Research and Development Program of Guangdong Province,Grant/Award Number:2021B0101420005。
文摘With the development and introduction of immune checkpoint inhibitors(ICIs)in cancer patients,immune-related side effects have increasingly attracted attention.However,the risks of immune-related renal toxicity are poorly characterized.In this study,we performed a network meta-analysis(NMA)of ICI-related randomized clinical trials(RCTs)to elucidate the comparative risk of acute kidney injury(AKI)in cancer patients receiving different ICIs.We also sought to identify other factors potentially affecting the risk of AKI.PubMed and EMBASE were searched for peer-reviewed trial reports published between January 2000 and May 2021.Eligible studies were RCTs studying ICIs in cancer patients and reporting AKI data.We performed a frequentist NMA to evaluate the risk ratios for grade 1-5 and grade 3-5 AKI between the treatment groups.We also assessed the absolute incidence of AKI in the ICI-containing arm using traditional direct meta-analysis.Once significant heterogeneity was detected in a traditional direct meta-analysis,multivariable meta-regression analysis was applied to identify factors that significantly affected the absolute incidence of AKI.A total of 85 RCTs were included in this study.In the NMA for the risk of grade 1-5 and 3-5 AKI,ipilimumab showed a significantly higher risk than avelumab and durvalumab,whereas 1 mg/kg nivolumab plus 3 mg/kg ipilimumab(N1I3)showed a significantly higher risk than other groups.In terms of treatment ranking,durvalumab±low-dose tremelimumab and avelumab were consistently among the top three safest treatments for grade 1-5 or 3-5 AKI,whereas N1I3,ipilimumab and tremelimumab were consistently among the top three treatments with the highest risk for grade 1-5 or 3-5 AKI.Compared with other cancers,renal cell carcinoma and urothelial carcinoma showed a significantly higher risk of AKI.The incidence of AKI was significantly higher with ICI+chemotherapy than with ICI monotherapy.In this NMA involving largescale up-to-date ICI trials,we demonstrated the comparative safety of existing ICI drugs for grade 1-5 and grade 3-5 AKI.Based on data from the ICI arms of these trials,we also revealed several potential risk factors for immune-related AKI,including tumor type and treatment paradigm.
文摘Even though the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is related to SARS-CoV and Middle East respiratory syndrome coronavirus(MERS-CoV),identifying effective and safe therapeutic strategies remains challenging.In search of finding effective treatments to eradicate the virus and improve disease symptoms,scientists are exploring possible therapies such as anti-viral,anti-malaria,immune therapy,and hormone treatments.However,the efficacy of these treatments was not validated on either SARS-CoV or MERS-CoV.In this study,we have reviewed synthetic evidence achieved through systematic and meta-analysis of therapeutics specific for SARS-CoV-2 and observed that the use of the above-mentioned therapies had no clinical benefits in coronavirus disease 2019 patients and,conversely,displayed side effects.
文摘Objective:To explore immunotherapy effectiveness of the CD4^(+)CD25^(+) regulatory T cells for treating female mouse with recurrent spontaneous abortion(RSA)by animal experiments.Methods:Mononuclear lymphocytes were isolated from the blood(instead of cord blood)of new-born baby of KunMing Bai mouse or BALB/c male mouse with normal birth ability(as unrelated third party blood source)by density gradient centrifuga-tion method.The CD4^(+)CD25^(+) regulatory T cells were selected by magnetic-activated cell sorting from mononuclear cells of cord blood cells.CBA/J female mouse copulated with DBA/2J male mouse was utilized as RSA animal model.Pregnant RSA mice were injected different types of lymphocytes through tail vein.Independent sample t-test was used to analyze the data from each group.Results:The proportion of CD4^(+)CD25^(+)T cells in CD4^(+)T cells was(17.49±0.60)%in CD4^(+)CD25^(+) regulatory T cells injection group,which was statistical significant higher than that of mononuclear lymphocyte injection group(14.68±0.83)%,sterile PBS group(9.54±0.85)%or no injection group(9.28±0.68)%(p<.05,t-value was 4.754,13.242 and 15.621,respec-tively).The Foxp3 relative protein expression level of CD4^(+)CD25^(+) regulatory T cells injected group was 5.85±0.45,which was also significant higher than that of mononuclear lymphocyte injection(2.86±0.54),sterile PBS group(1.08±0.16)or no injection group(1.00±0.00)(p<.05,t-value was 7.276,17.227 and 18.635,respectively).Finally,two times of CD4^(+)CD25^(+)T cell injected group at the 4 th and 8 th day had well effect for RSA mouse,and embryo sorption rate was(4.92±0.08)%,which significant lower than that of two times of mononuclear lymphocyte injected group(13.07±0.06)%,sterile PBS group(23.11±0.12)%,or no injection group(25.47±0.11)%(p<.05,t-value was-2.603,-4.012 and-4.700,respectively).Conclusions:Pregnant mouse with RSA injected CD4^(+)CD25^(+)T cells several times for immunotherapy can get better effec-tiveness than that of pregnant mouse injected traditional mononuclear cells.
基金National Natural Science Foundation of China(No. 82022049, JXNo. 82073105, NN)+1 种基金Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(No. 20161312, JX)State Key Laboratory of Oncogenes and Related Genes(KF2113, NN)。
文摘Interferon-gamma (IFNγ) is a pleiotropic cytokine implicated in tumor immune surveillance, with its antiproliferative, pro-apoptotic, and immune-provoking effects. Regarding the antitumor effects of IFNγ, IFNγ-dependent therapies have been proposed and have undergone many clinical trials for various cancer types but the outcomes were not satisfactory. Recent studies have suggested that cancer cells develop immune evasion strategies to escape from IFNγ-dependent immunosurveillance by various mechanisms. In this review, we summarize recent advances in the effects and molecular mechanisms of IFNγ on target cells, as well as potential immune escape mechanisms of tumor cells. Furthermore, we discuss how to target IFNγ signaling and overcome immune evasion to provide promising therapeutic strategies for the treatment of patients with cancer.
文摘The incidence of gastric cancer ranks 4th in malignant tumors,and the mortality rate ranks 3rd in malignant tumors.Most patients with gastric cancer are already at the advanced stage when diagnosed.Although chemotherapy is the main treatment for patients with advanced gastric cancer,it can extend the overall survival.But adverse reactions are more prominent.With the rise of targeted therapy,the molecular mechanism of gastric cancer occurrence and development continues to develop,and molecular targeted therapy of gastric cancer has gradually emerged.The current targets for gastric cancer mainly include endothelial growth factor receptor,HER2,vascular endothelium growth factor,vascular endothelium growth factor receptor,mammalian rapamycin receptor,hepatocellular growth factor,et al.,but the clinical efficacy is still not satisfactory.At present,most of the studies on molecular targeted drugs for gastric cancer have ended in failure.The heterogeneity between patients and the prognosis of tumors in different parts may be different.It is suggested that screening targeted drugs according to the patient's pathological characteristics and molecular typing,and individualized treatment is the inevitable way of targeted treatment of gastric cancer.
基金National Natural Science Foundation of China(Nos.81773226,82073476,82103483,and U1967220)Shanghai Sailing Program(20YF1459700)Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Hepatocellular carcinoma(HCC),one of the deadliest cancers all over the world,had a limited prognosis in the past.Recently,the remarkable efficacy of immune checkpoint inhibitors(ICIs)therapy has been shown in various solid tumors.What's more,the occurrence of HCC is associated with immune escape and therefore various ICIs have been applied to clinical trials for HCC.However,the special immune environment of the liver creates the complex tumor microenvironment(TME)of HCC,which impairs the overall survival(OS)and overall response rate(OCR)of ICIs as a monotherapy.Lately,various therapies have been used in combination with ICIs therapy to improve its clinical efficacy.Among which,radiotherapy is widely concerned because of its unique immunoreaction.A large number of basic and clinical studies have demonstrated that the combined radiotherapy and ICIs therapy has advantages in improving the OCR and efficacy,as compared with ICIs therapy alone.Herein,this article reviews the studies on the advantages and possible mechanisms of the combination of radiotherapy and ICIs therapy for HCC.
基金the National Natural Science Foundation of China(Nos.31971304,32271420,and 21977024)the Beijing-Tianjin-Hebei Basic Research Cooperation Project(No.19JCZDJC64100)+3 种基金Cross-disciplinary Project of Hebei University(No.DXK201916)One Hundred Talent Project of Hebei Province(No.E2018100002)Science Fund for Creative Research Groups of Nature Science Foundation of Hebei Province(No.B2021201038)Guangdong Basic and Applied Basic Research Foundation(No.2021B1515120065).
文摘The blocking of the immune checkpoint pathway with antibodies,especially targeting to programmed death-1/programmed death ligand-1(PD-1/PD-L1)pathway,was currently a widely used treatment strategy in clinical practice.However,the shortcomings of PD-L1 antibodies were constantly exposed with the deepening of its research and their therapeutic effect was limited by the translocation and redistribution of intracellular PD-L1.Herein,we proposed to improve immune checkpoint blockade therapy by using liposomes-coated CaO_(2)(CaO_(2)@Lipo)nanoparticles to inhibit the de novo biosynthesis of PD-L1.CaO_(2)@Lipo would produce oxygen and reduce hypoxia-inducible factor-1α(HIF-1α)level,which then downregulated the expression of PD-L1.Our in vitro and in vivo results have confirmed CaO_(2)@Lipo promoted the degradation of HIF-1αand then downregulated the expression of PD-L1 in cancer cells for avoiding immune escape.Furthermore,to mimicking the clinical protocol of anti-PD-L1 antibodies+chemo-drugs,CaO_(2)@Lipo was combined with doxorubicin(DOX)to investigate the tumor inhibition efficiency.We found CaO_(2)@Lipo enhanced DOX-induced immunogenic cell death(ICD)effect,which then promoted the infiltration of T cells,strengthened the blocking effect,thus provided an effective means to overcome the traditional immune checkpoint blockade treatment.
