BACKGROUND Faced with limited and inadequate treatment options for patients with advanced gastric cancer or gastroesophageal junction cancer(GC/GEJC), researchers have turned toward, with the support of promising clin...BACKGROUND Faced with limited and inadequate treatment options for patients with advanced gastric cancer or gastroesophageal junction cancer(GC/GEJC), researchers have turned toward, with the support of promising clinical trials, anti-PD-1/anti-PD-L1 antibody therapy. But there are also different clinical trial results. To better assess its efficacy and safety, we integrated data from 13 eligible studies for a systematic review and meta-analysis.AIM To comprehensively evaluate the efficacy and safety of anti-PD-1/anti-PD-L1 antibody therapy in the treatment of advanced GC/GEJC patients.METHODS PubMed, Web of Science, Cochrane Library,and EMBASE databases were searched to identify eligible articles with outcomes including objective response rate(ORR), disease control rate(DCR), overall survival(OS), progression-free survival(PFS), and adverse events(AEs) of anti-PD-1/anti-PD-L1 antibody therapy.RESULTS Our study encompassed a total of 13 trials totaling 1618 patients. The outcomes showed a pooled ORR and DCR of 15%(95% confidence interval [CI]: 14%-18%) and 40%(95%CI: 33%-46%), respectively. The pooled 6-mo OS and PFS were 54%(95%CI: 45%-64%) and 26%(95%CI: 20%-32%), respectively, and the 12-mo OS and PFS were 42%(95%CI: 21%-62%) and 11%(95%CI: 8%-13%), respectively. In addition, the incidence of any-grade AEs and grade ≥ 3 AEs was 64%(95%CI: 54%-73%) and 18%(95%CI: 16%-20%), respectively. Most importantly, PD-L1 positive patients exhibited a higher ORR rate than PD-L1 negative patients(odds ratio = 2.54, 95%CI: 1.56-4.15).CONCLUSION Anti-PD-1/anti-PD-L1 antibody therapy has shown promising anti-tumor efficacy with manageable AEs in advanced GC/GEJC patients, with PD-L1 overexpressing patients exhibiting a higher ORR. What is more, the clinical efficacy of anti-PD-1/PD-L1 combined with traditional chemotherapy drugs is even better, although the occurrence of AEs still causes considerate concerns.展开更多
Objective:Therapy for hepatocellular carcinoma(HCC)is a major challenge,and targeted therapies provide only a modest benefit in terms of overall survival.Treatment with antibodies to programmed cell death protein 1(PD...Objective:Therapy for hepatocellular carcinoma(HCC)is a major challenge,and targeted therapies provide only a modest benefit in terms of overall survival.Treatment with antibodies to programmed cell death protein 1(PD-1)/PD-L1 can restore the functions of tumor-infiltrating T cells in HCC and has shown clinical efficacy in 20%of patients with advanced HCC.Novel approaches are urgently needed to treat HCC and to augment the efficacy of immunotherapy.Methods:Tumor-bearing mice were treated with Agrocybe aegerita galectin(AAGL)alone or in combination with anti-PD-1,and the tumor sizes and lifespans of mice were determined.Transcriptome analysis,cytokine analysis,flow cytometry analysis of the number and proportion of immune cell subsets in the liver and spleen,and molecular and cellular analyses of tumors were used to define the underlying mechanisms.Results:AAGL significantly inhibited the growth of liver tumors in a dose-dependent manner.Furthermore,AAGL increased the expression of multiple cytokines and chemokines in tumor-bearing mouse livers;this effect was associated with the activation and migration of T cells and macrophages,in agreement with the in vitro results.Importantly,the aggregation of T cells and macrophages induced by AAGL in tumor-bearing mouse livers clearly enhanced the response to PD-1 blockade immunotherapy.Conclusions:The results showed that AAGL induced the activation and migration of lymphocytes to the liver,and that the combination of AAGL and anti-PD-1 may be a promising strategy for HCC treatment.展开更多
Photothermal therapy(PTT)has brought hope for cancer treatments,with hyperthermia-induced immunogenic cell death(ICD),which is a critical part of therapeutically induced antitumor immune responses.Limited immune stimu...Photothermal therapy(PTT)has brought hope for cancer treatments,with hyperthermia-induced immunogenic cell death(ICD),which is a critical part of therapeutically induced antitumor immune responses.Limited immune stimulation response in PTT is the primary reason for incomplete tumor ablation,therefore demonstrating urgent requirements for ICD amplifier.Herein,a sub-10 nm supramolecular nanoassembly was formed by coassembly of clinically approved aluminum adjuvant and commonly used indocyanine green(ICG)under the assistance of lignosulfonate(LS,a green and sustainable multifunctional lignin derivative)for localized photothermal-immunotherapy of breast cancer.The overall results revealed that LS-Al-ICG is capable of inducing amplified ICD,efficiently eliciting solid immune responses through dendritic cells(DCs)activation and cytotoxic T-cell responses initiation for tumor killing.Moreover,anti-PD-1 therapy blocked the PD-1 pathway and led to remarkable anti-tumor efficacy against laser-irradiated primary tumors and distant tumors by potentiating systemic tumor specific T cell immunity.The results of this study demonstrate a handy and extensible approach for engineering green natural lignin nanoparticles for cancer immunotherapy,which shows promise for delivering other therapeutics in biomedical applications.展开更多
BACKGROUND Extranodal natural killer/T cell lymphoma,nasal type(ENKL) is a highly aggressive malignancy characterized by its association with Epstein-Barr virus(EBV) and extranodal involvement,which shows a poor clini...BACKGROUND Extranodal natural killer/T cell lymphoma,nasal type(ENKL) is a highly aggressive malignancy characterized by its association with Epstein-Barr virus(EBV) and extranodal involvement,which shows a poor clinical outcome.Although L-asparaginase-based chemotherapy has improved the response rates of relapsed/refractory(R/R) ENKL,relapse occurs in up to 50% of patients with disseminated disease.CASE SUMMARY Immune evasion has emerged as a critical pathway for survival in ENKL and may be effectuated via STAT3-driven upregulation of programmed cell death ligand 1(PD-L1) or other molecular pathways.Anti-PD-1 is effective for R/R ENKL with EBV-driven upregulation of PD-L1 expression.Anti-PD-1 combined with decitabine showed positive preliminary results in a patient with R/R ENKL and resistance to anti-PD-1.CONCLUSION The treatment experience,in this case,demonstrated the potential ability of decitabine combined with PD-1 inhibitor to treat R/R ENKL,thus providing a new treatment strategy for this tumor.展开更多
Background:Glioblastoma(GBM)is largely refractory to antibodies against programmed cell death 1(anti-PD-1)therapy.Fully understanding the cellular heterogeneity and immune adaptations in response to anti-PD-1 therapy ...Background:Glioblastoma(GBM)is largely refractory to antibodies against programmed cell death 1(anti-PD-1)therapy.Fully understanding the cellular heterogeneity and immune adaptations in response to anti-PD-1 therapy is necessary to design more effective immunotherapies for GBM.This study aimed to dissect the molecular mechanisms of specific immunosuppressive subpopulations to drive anti-PD-1 resistance in GBM.Methods:We systematically analysed single-cell RNA sequencing and spatial transcriptomics data from GBM tissues receiving anti-PD-1 therapy to characterize the microenvironment alterations.The biological functions of a novel circular RNA(circRNA)were validated both in vitro and in vivo.Mechanically,co-immunoprecipitation,RNA immunoprecipitation and pull-down assays were conducted.Results:Mesenchymal GBM(MES-GBM)cells,which were associated with a poor prognosis,and secreted phosphoprotein 1(SPP1)+myeloid-derived macrophages(SPP1+MDMs),a unique subpopulation of MDMs with complex functions,preferentially accumulated in non-responders to anti-PD-1 therapy,indicating that MES-GBM cells and SPP1+MDMs were the main anti-PD-1-resistant cell subpopulations.Functionally,we determined that circular RNA succinate dehydrogenase complex assembly factor 2(circSDHAF2),which was positively associated with the abundance of these two anti-PD-1-resistant cell subpopulations,facilitated the formation of a regional MES-GBM and SPP1+MDM cell interaction loop,resulting in a spatially specific adaptive immunosuppressive microenvironment.Mechanically,we found that circSDHAF2 promoted MES-GBM cell formation by stabilizing the integrin alpha 5(ITGA5)protein through N-glycosylation.Meanwhile,the N-glycosylation of the ITGA5 protein facilitated its translocation into exosomes and subsequent delivery to MDMs to induce the formation of SPP1+MDMs,which in turn maintained the MESGBM cell status and induced T-cell dysfunction via the SPP1-ITGA5 pathway,ultimately promoting GBM immune escape.Importantly,our findings demonstrated that antibody-mediated ITGA5 blockade enhanced anti-PD-1-mediated antitumor immunity.Conclusions:This work elucidated the potential tissue adaptation mechanism of intratumoral dynamic interactions between MES-GBM cells,MDMs and T cells in anti-PD-1 non-responders and identified the therapeutic potential of targeting ITGA5 to reduce anti-PD-1 resistance in GBM.展开更多
The immunosuppressive tumor microenvironment(TME)undermines the efficacy of many cancer therapies.This study investigated the immunomodulatory and anti-tumor activity of Azvudine(FNC),alone or in combination with anti...The immunosuppressive tumor microenvironment(TME)undermines the efficacy of many cancer therapies.This study investigated the immunomodulatory and anti-tumor activity of Azvudine(FNC),alone or in combination with anti-PD-1 blockade.We established syngeneic tumor models in immunocompetent mice.Single-cell RNA sequencing,flow cytometry,and immunological assays were employed to analyze immune cell reconstitution and functional changes following FNC administration.FNC demonstrated dose-and time-dependent tumor inhibition.It significantly expanded memory T cells,natural killer(NK)cells,and CD8+cytotoxic T lymphocytes,while reducing the abundance of myeloid-derived suppressor cells(MDSCs).Flow cytometry confirmed these immunological shifts,showing enhanced infiltration of effector immune cells within the TME.Moreover,FNC induced hallmark features of immunogenic cell death(ICD),including the release of damage-associated molecular patterns such as high-mobility group box 1(HMGB1)and calreticulin.When combined with anti-PD-1 therapy,FNC produced a synergistic anti-tumor effect,leading to durable tumor remission in all treated mice.FNC remodels the TME by mitigating immunosuppression and amplifying anti-tumor immunity,offering a promising strategy to augment existing immunotherapies.Further clinical evaluation is warranted to ascertain the translational potential of FNC in diverse oncologic settings.展开更多
Although the combination of chemotherapy and immunotherapy can improve the treatment of breast cancer,traditional drugs are highly toxic because they do not specifically target tumors.In this study,we developed a self...Although the combination of chemotherapy and immunotherapy can improve the treatment of breast cancer,traditional drugs are highly toxic because they do not specifically target tumors.In this study,we developed a self-driving bacteria/nanoparticle biohybrid called Bif@PDA-aPD1/DOX-Lip by attaching polydopamine(PDA)coated doxorubicin(DOX)liposomes and the immune checkpoint inhibitor anti-programmed cell death protein 1 antibody(aPD-1)to Bifidobacterium infantis(B.infantis,Bif).Using the homing abilities of bacteria,Bif@PDA-aPD1/DOX-Lip could actively accumulate in tumor tissue,releasing DOX and aPD-1 in the acidic environment to have a synergistic anti-tumor effect.Results show that the concentration of DOX in tumors of the Bif@PDA-aPD1/DOX-Lip group was 6.31 times higher than in the free DOX group.The combination of DOX and aPD-1 not only killed tumor cells but also promoted immune normalization by maturing dendritic cells(DCs),increasing M1 macrophage ratio,and enhancing infiltration of CD8^(+) and CD4^(+)T cells in tumors and spleen.Therefore,Bif@PDA-aPD1/DOX-Lip therapy significantly inhibited tumor growth and increased the average survival time of mice to over 80 days.The Bif@PDA-aPD1/DOX-Lip biomotors offer a highly effective method for enhancing chemo-immunotherapy in solid tumors.展开更多
本文通过建立肿瘤免疫微环境多尺度数学模型,结合小鼠实验数据,探讨了前列腺素E2受体4亚型(Prostaglandin E2 Receptor 4,EP4)拮抗剂MF-766和抗程序性细胞死亡蛋白1(Anti-programmed Cell Death Protein 1,Anti-PD-1)联合治疗对肿瘤免...本文通过建立肿瘤免疫微环境多尺度数学模型,结合小鼠实验数据,探讨了前列腺素E2受体4亚型(Prostaglandin E2 Receptor 4,EP4)拮抗剂MF-766和抗程序性细胞死亡蛋白1(Anti-programmed Cell Death Protein 1,Anti-PD-1)联合治疗对肿瘤免疫微环境及肿瘤生长的调控机制。模型定量分析了免疫抑制细胞、效应性免疫细胞以及细胞因子的动态变化,揭示了联合治疗在降低髓源性抑制细胞(Myeloid-derived Suppressor Cells,MDSCs)浓度和增强效应性免疫细胞功能中的协同作用。实验验证表明,模型能够准确描述肿瘤体积的动态变化及药物的免疫调节效应,并揭示了药物剂量与用药间隔对治疗效果的非线性影响。基于此模型的模拟结果,本文不仅加深了对肿瘤转移机制的理解,还为优化免疫治疗的剂量和用药策略提供了理论依据,为精准治疗的设计与推进奠定了坚实基础。展开更多
Owing to incurable castration-resistant prostate cancer(CRPC)ultimately developing after treating with androgen deprivation therapy(ADT),it is vital to devise new therapeutic strategies to treat CRPC.Treatments that t...Owing to incurable castration-resistant prostate cancer(CRPC)ultimately developing after treating with androgen deprivation therapy(ADT),it is vital to devise new therapeutic strategies to treat CRPC.Treatments that target programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for human cancers with clinical benefit.However,many patients,especially prostate cancer,fail to respond to anti-PD-1/PD-L1 treatment,so it is an urgent need to seek a support strategy for improving the traditional PD-1/PD-L1 targeting immunotherapy.In the present study,analyzing the data from our prostate cancer tissue microarray,we found that PD-L1 expression was positively correlated with the expression of heterogeneous nuclear ribonucleoprotein L(Hn RNP L).Hence,we further investigated the potential role of Hn RNP L on the PD-L1 expression,the sensitivity of cancer cells to T-cell killing and the synergistic effect with anti-PD-1 therapy in CRPC.Indeed,Hn RNP L knockdown effectively decreased PD-L1 expression and recovered the sensitivity of cancer cells to T-cell killing in vitro and in vivo,on the contrary,Hn RNP L overexpression led to the opposite effect in CRPC cells.In addition,consistent with the previous study,we revealed that ferroptosis played a critical role in T-cell-induced cancer cell death,and Hn RNP L promoted the cancer immune escape partly through targeting YY1/PD-L1 axis and inhibiting ferroptosis in CRPC cells.Furthermore,Hn RNP L knockdown enhanced antitumor immunity by recruiting infiltrating CD8^(+)T cells and synergized with anti-PD-1 therapy in CRPC tumors.This study provided biological evidence that Hn RNP L knockdown might be a novel therapeutic agent in PD-L1/PD-1 blockade strategy that enhanced anti-tumor immune response in CRPC.展开更多
Background The efficacy of anti-programmed cell death protein 1(PD-1)immunotherapy in various cancers,including gastric cancer(GC),needs to be potentiated by more effective targeting to enhance therapeutic efficacy or...Background The efficacy of anti-programmed cell death protein 1(PD-1)immunotherapy in various cancers,including gastric cancer(GC),needs to be potentiated by more effective targeting to enhance therapeutic efficacy or identifying accurate biomarkers to predict clinical responses.Here,we attempted to identify molecules predicting or/and promoting anti-PD-1 therapeutic response in advanced GC(AGC).Methods The transcriptome of AGC tissues from patients with different clinical responses to anti-PD-1 immunotherapy and GC cells was analyzed by RNA sequencing.The protein and mRNA levels of the major facilitator superfamily domain containing 2A(MFSD2A)in GC cells were assessed via quantitative real-time polymerase chain reaction,Western blotting,and immunohistochemistry.Additionally,the regulation of anti-PD-1 response by MFSD2A was studied in tumor-bearing mice.Cytometry by Time-of-Flight,multiple immunohistochemistry,and flow cytometry assays were used to explore immunological responses.The effects of MFSD2A on lipid metabolism in mice cancer tissue and GC cells was detected by metabolomics.Results Higher expression of MFSD2A in tumor tissues of AGC patients was associated with better response to anti-PD-1 immunotherapy.Moreover,MFSD2A expression was lower in GC tissues compared to adjacent normal tissues,and its expression was inversely correlated with GC stage.The overexpression of MFSD2A in GC cells enhanced the efficacy of anti-PD-1 immunotherapy in vivo by reprogramming the tumor microenvironment(TME),characterized by increased CD8+T cell activation and reduced its exhaustion.MFSD2A inhibited transforming growth factorβ1(TGFβ1)release from GC cells by suppressing cyclooxygenase 2(COX2)-prostaglandin synthesis,which consequently reprogrammed TME to promote anti-tumor T cell activation.Conclusions MFSD2A potentially serves as a predictive biomarker for anti-PD-1 immunotherapy response in AGC patients.MFSD2A may be a promising therapeutic target to potentiate the efficacy of anti-PD-1 immunotherapy by reprogramming the TME to promote T cells activation.展开更多
Background:Several programmed cell death ligand 1(PD-L1)/programmed cell death protein 1(PD-1)antibodies have been approved for cancer treatmentworldwide.Their pharmacokinetic and pharmacodynamic characteristics have ...Background:Several programmed cell death ligand 1(PD-L1)/programmed cell death protein 1(PD-1)antibodies have been approved for cancer treatmentworldwide.Their pharmacokinetic and pharmacodynamic characteristics have been reported mainly in western countries,but related data in Chinese patients are limited.This study was conducted to investigate the safety,efficacy,pharmacokinetics,and pharmacodynamics of an anti-PD-1 antibody,toripalimab,in Chinese patients.Methods:A single-center phase I study was conducted in Sun Yat-sen University Cancer Center.Eligible patients were adults with histologically confirmed,treatment-refractory,advanced,solitary malignant tumors.Toripalimab was intravenously infused every 2 weeks in dose-escalating cohorts at 0.3mg/kg,1 mg/kg,3 mg/kg,10 mg/kg,and 240 mg.The study followed standard 3+3 design.Results:Between 15th March 2016 and 27th September 2016,25 patients were enrolled,of whom 3(12.0%),7(28.0%),6(24.0%),6(24.0%),3(12.0%)received 0.3 mg/kg,1 mg/kg,3 mg/kg,10 mg/kg,and 240 mg toripalimab,respectively.After a median follow-up time of 5.0 months(range:1.5-19.8 months),we observed that the commonest treatment-related adverse events(TRAEs)were fatigue(64.0%)and rash(24.0%).No grade 3 or higher TRAEs were observed.No dose-limiting toxicity,treatment-related serious adverse events(SAEs),or treatment-related death occurred.Objective response ratewas 12.5%.The half-life of toripalimabwas 150-222 h after a single dose infusion.Most patients,including those from the 0.3 mg/kg group,maintained complete PD-1 receptor occupancy(>80%)on activated T cells since receiving the first dose of toripalimab.Conclusions:Toripalimab is a promising anti-PD-1 antibody,which was well tolerated and demonstrated anti-tumor activity in treatment-refractory advanced solitary malignant tumors.Further exploration in various tumors and combination therapies is warranted.展开更多
Background:Radiation(IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment(TME).Wee1,a cell cycle regulator,can eliminate G2/M arrest by phosphorylating cyclin-de...Background:Radiation(IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment(TME).Wee1,a cell cycle regulator,can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1(CDK1).Meanwhile,programed death-1/programed death ligand-1(PD-1/PDL-1)blockade is closely related to TME.This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody(anti-PD-1 Ab)on radiosensitization of hepatoma.Methods:The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide(MTT)assay on human and mouse hepatoma cells HepG2,Hepa1-6,and H22.The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro.A hepatoma subcutaneous xenograft mice model was constructed on Balb/c mice,which were divided into control group,IR group,AZD1775 group,IR+AZD1775 group,IR+anti-PD-1 Ab group,and the IR+AZD1775+anti-PD-1 Ab group.Cytotoxic CD8^(+)T cells in TME were analyzed by flow cytometry.Results:Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro.AZD1775 exhibited antitumor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced DNA damage.AZD1775 treatment also reduced the proportion of PD-1^(+)/CD8^(+)T cells in the spleen of hepatoma subcutaneous xenograft mice.Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferonγ(IFNγ)^(+)or Ki67^(+)CD8 T cells and decreasing the levels of CD8^(+)Tregs cells in the tumor and spleen of the hepatoma mice model,indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγexpression,enhancing CD8^(+)T cells proliferation,and weakening CD8^(+)T cells depletion.Conclusions:This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced DNA damage and improving cytotoxic CD8^(+)T cells in TME.展开更多
Background:Nivolumab and pembrolizumab—two monoclonal antibodies that block human programmed cell death-1(PD-1)—have been successfully used to treat patients with multiple advanced malignancies.The histologic patter...Background:Nivolumab and pembrolizumab—two monoclonal antibodies that block human programmed cell death-1(PD-1)—have been successfully used to treat patients with multiple advanced malignancies.The histologic patterns of hepatic toxicity induced by anti-PD-1 treatment have not been well studied and the aim of this study was to explore them.Methods:Eight patients with advanced malignancies who were treated with either nivolumab or pembrolizumab were identified from five institutions.These patients had no history of underlying liver disease and a viral hepatitis panel was negative in all patients.Results:Seven of eight patients exhibited mild to moderate gastrointestinal symptoms such as abdominal pain,fatigue,nausea,vomiting,and jaundice after anti-PD-1 treatment.Significant elevations in liver-chemistry tests were detected in all patients.Six cases(6/8)demonstrated an acute lobular hepatitis pattern of histologic injury.The remaining two cases showed different histologic patterns of injury:steatohepatitis with mild cholestasis(1/8)and pure acute cholestatic injury(1/8).No case showed typical features of autoimmune hepatitis.The liver function recovered in all eight cases after cessation of anti-PD-1 agents and with immunosuppressive therapy.Conclusions:Our study suggests that screening patients for abnormal liver-function tests prior to anti-PD-1 therapy as well as periodic monitoring of liver-function tests are necessary to prevent severe liver injury.Rather than causing classical autoimmune hepatitis,PD-1 inhibitors appear to produce an immune-mediated nonspecific acute hepatitis.Drug cessation,without steroid therapy,may therefore be sufficient in some patients.展开更多
The effect of anti-programmed cell death 1(anti-PD-1)immunotherapy is limited in patients with hepatocellular carcinoma(HCC).Yes-associated protein 1(YAP1)expression increased in liver tumor cells in early HCC,and Akk...The effect of anti-programmed cell death 1(anti-PD-1)immunotherapy is limited in patients with hepatocellular carcinoma(HCC).Yes-associated protein 1(YAP1)expression increased in liver tumor cells in early HCC,and Akkermansia muciniphila abundance decreased in the colon.The response to anti-PD-1 treatment is associated with A.muciniphila abundance in many tumors.However,the interaction between A.muciniphila abundance and YAP1 expression remains unclear in HCC.Here,anti-PD-1 treatment decreased A.muciniphila abundance in the colon,but increased YAP1 expression in the tumor cells by mice with liver tumors in situ.Mechanistically,hepatocyte-specific Yap1 knockout(Yap1^(LKO))maintained bile acid homeostasis in the liver,resulting in an increased abundance of A.muciniphila in the colon.Yap1 knockout enhanced anti-PD-1 efficacy.Therefore,YAP1 inhibition is a potential target for increasing A.muciniphila abundance to promote anti-PD-1 efficacy in liver tumors.Dihydroartemisinin(DHA),acting as YAP1 inhibitor,increased A.muciniphila abundance to sensitize anti-PD-1 therapy.A.muciniphila by gavage increased the number and activation of CD8^(+)T cells in liver tumor niches during DHA treatment or combination with anti-PD-1.Our findings suggested that the combination anti-PD-1 with DHA is an effective strategy for liver tumor treatment.展开更多
Background:Tyrosine kinase inhibitors(TKIs)and anti-PD-1 antibodies in combination provide survival benefits for patients with unresectable hepatocellular carcinoma(uHCC).However,the tool used to determine which patie...Background:Tyrosine kinase inhibitors(TKIs)and anti-PD-1 antibodies in combination provide survival benefits for patients with unresectable hepatocellular carcinoma(uHCC).However,the tool used to determine which patients likely benefit most from this treatment strategy has not been reported.We sought to develop a prognostic scoring system based on tumor burden score(TBS)and alpha-fetoprotein(AFP)to predict the long-term prognosis of uHCC treated with TKIs and anti-PD-1 antibodies.Methods:Data on patients with uHCC treated with TKIs and anti-PD-1 antibodies from multiple centers were collected.The prognostic accuracy of TBS,AFP,Barcelona Clinic Liver Cancer(BCLC),and CTA(Combined TBS and AFP)for 2-year progression-free survival(PFS)and overall survival(OS)was evaluated.Results:Overall,278 patients with uHCC treated with TKIs and anti-PD-1 antibodies were enrolled,including 48 BCLC-B and 230 BCLC-C HCC patients.CTA(AUC?0.721 and 0.683)outperformed TBS(AUC?0.680 and 0.621),AFP(AUC?0.606 and 0.594),and BCLC staging(AUC?0.551 and 0.555)in predicting PFS and OS.The 2-year PFS and OS for low CTA(low TBS/low AFP)were 65.7%and 94.4%,respectively,which were significantly higher than 21.6%and 44.9%(p<0.001 and p?0.002),respectively,for intermediate CTA(low TBS/high AFP or high TBS/low AFP)and 8.7%and 12.1%(both p<0.001),respectively,for high CTA(high TBS/high AFP).Multivariable Cox regression analysis indicated that CTA grading was an independent prognostic factor for PFS and OS(referent:low CTA;intermediate CTA,HR 2.87 and 7.17;high CTA,HR 5.52 and 10.31,respectively).Conclusions:CTA grading is an accurate tool for stratifying the prognosis of uHCC treated with TKIs and anti-PD-1 antibodies and may help determine which patients may benefit more from this treatment strategy.展开更多
Aim:Circular RNAs(circRNAs)have been found to be involved in tumor progression,but their role in colorectal cancer(CRC)immune escape remains to be elucidated.Methods:circRNAs differentially expressed in responsive and...Aim:Circular RNAs(circRNAs)have been found to be involved in tumor progression,but their role in colorectal cancer(CRC)immune escape remains to be elucidated.Methods:circRNAs differentially expressed in responsive and resistant CRC tissues to programmed cell death 1(PD-1)antibody therapy were identified by microarray analysis.The clinical and pathological significance of circNCOA3 was validated in a separate cohort of CRC samples.The function of circNCOA3 was explored experimentally.RNA immunoprecipitation and luciferase activity assays were conducted to identify downstream targets of circNCOA3.Results:The circNCOA3 was markedly overexpressed in CRC samples resistant to PD-1 blockade.circNCOA3 expression was significantly correlated with adverse tumor phenotypes and poor outcomes in CRC patients.Knockdown of circNCOA3 expression markedly suppressed the proliferative and invasive capability of CRC cells.Moreover,knockdown of circNCOA3 increased the proportion of CD8^(+)T cells while decreasing the proportion of myeloid-derived suppressor cells(MDSCs).Knockdown of circNCOA3 inhibited tumor growth and increased the sensitivity to PD-1 antibody treatment in mouse tumor models.Further studies revealed that circNCOA3 acted as a competing endogenous RNA(ceRNA)for miR-203a-3p.1 to influence the level of CXCL1.Conclusion:Our findings indicate that circNCOA3 might be useful as a potential biomarker to predict the efficacy and prognosis of CRC patients treated with anti-PD-1 therapy.展开更多
基金Beijing Hospitals Authority Ascent Plan,No. DFL20190803Capital Science and Technology Leading Talent Training Project,No. Z191100006119017+1 种基金National Nature and Science Foundation of China,No. 81773778China Postdoctoral Science Foundation,No. 2019M650775。
文摘BACKGROUND Faced with limited and inadequate treatment options for patients with advanced gastric cancer or gastroesophageal junction cancer(GC/GEJC), researchers have turned toward, with the support of promising clinical trials, anti-PD-1/anti-PD-L1 antibody therapy. But there are also different clinical trial results. To better assess its efficacy and safety, we integrated data from 13 eligible studies for a systematic review and meta-analysis.AIM To comprehensively evaluate the efficacy and safety of anti-PD-1/anti-PD-L1 antibody therapy in the treatment of advanced GC/GEJC patients.METHODS PubMed, Web of Science, Cochrane Library,and EMBASE databases were searched to identify eligible articles with outcomes including objective response rate(ORR), disease control rate(DCR), overall survival(OS), progression-free survival(PFS), and adverse events(AEs) of anti-PD-1/anti-PD-L1 antibody therapy.RESULTS Our study encompassed a total of 13 trials totaling 1618 patients. The outcomes showed a pooled ORR and DCR of 15%(95% confidence interval [CI]: 14%-18%) and 40%(95%CI: 33%-46%), respectively. The pooled 6-mo OS and PFS were 54%(95%CI: 45%-64%) and 26%(95%CI: 20%-32%), respectively, and the 12-mo OS and PFS were 42%(95%CI: 21%-62%) and 11%(95%CI: 8%-13%), respectively. In addition, the incidence of any-grade AEs and grade ≥ 3 AEs was 64%(95%CI: 54%-73%) and 18%(95%CI: 16%-20%), respectively. Most importantly, PD-L1 positive patients exhibited a higher ORR rate than PD-L1 negative patients(odds ratio = 2.54, 95%CI: 1.56-4.15).CONCLUSION Anti-PD-1/anti-PD-L1 antibody therapy has shown promising anti-tumor efficacy with manageable AEs in advanced GC/GEJC patients, with PD-L1 overexpressing patients exhibiting a higher ORR. What is more, the clinical efficacy of anti-PD-1/PD-L1 combined with traditional chemotherapy drugs is even better, although the occurrence of AEs still causes considerate concerns.
基金This work was supported by the National Natural Science Foundation of China(Grant No.81670531)Hubei Key Laboratory of Edible Wild Plants Conservation and Utilization(Grant No.EWPL201804).
文摘Objective:Therapy for hepatocellular carcinoma(HCC)is a major challenge,and targeted therapies provide only a modest benefit in terms of overall survival.Treatment with antibodies to programmed cell death protein 1(PD-1)/PD-L1 can restore the functions of tumor-infiltrating T cells in HCC and has shown clinical efficacy in 20%of patients with advanced HCC.Novel approaches are urgently needed to treat HCC and to augment the efficacy of immunotherapy.Methods:Tumor-bearing mice were treated with Agrocybe aegerita galectin(AAGL)alone or in combination with anti-PD-1,and the tumor sizes and lifespans of mice were determined.Transcriptome analysis,cytokine analysis,flow cytometry analysis of the number and proportion of immune cell subsets in the liver and spleen,and molecular and cellular analyses of tumors were used to define the underlying mechanisms.Results:AAGL significantly inhibited the growth of liver tumors in a dose-dependent manner.Furthermore,AAGL increased the expression of multiple cytokines and chemokines in tumor-bearing mouse livers;this effect was associated with the activation and migration of T cells and macrophages,in agreement with the in vitro results.Importantly,the aggregation of T cells and macrophages induced by AAGL in tumor-bearing mouse livers clearly enhanced the response to PD-1 blockade immunotherapy.Conclusions:The results showed that AAGL induced the activation and migration of lymphocytes to the liver,and that the combination of AAGL and anti-PD-1 may be a promising strategy for HCC treatment.
基金supported by the National Natural Science Foundation of China (No. 82074027, No. 81873014, No. 82104405, No. 81873018, No.82174096)Natural Science Foundation of Zhejiang Province (No. LZ21H280001)
文摘Photothermal therapy(PTT)has brought hope for cancer treatments,with hyperthermia-induced immunogenic cell death(ICD),which is a critical part of therapeutically induced antitumor immune responses.Limited immune stimulation response in PTT is the primary reason for incomplete tumor ablation,therefore demonstrating urgent requirements for ICD amplifier.Herein,a sub-10 nm supramolecular nanoassembly was formed by coassembly of clinically approved aluminum adjuvant and commonly used indocyanine green(ICG)under the assistance of lignosulfonate(LS,a green and sustainable multifunctional lignin derivative)for localized photothermal-immunotherapy of breast cancer.The overall results revealed that LS-Al-ICG is capable of inducing amplified ICD,efficiently eliciting solid immune responses through dendritic cells(DCs)activation and cytotoxic T-cell responses initiation for tumor killing.Moreover,anti-PD-1 therapy blocked the PD-1 pathway and led to remarkable anti-tumor efficacy against laser-irradiated primary tumors and distant tumors by potentiating systemic tumor specific T cell immunity.The results of this study demonstrate a handy and extensible approach for engineering green natural lignin nanoparticles for cancer immunotherapy,which shows promise for delivering other therapeutics in biomedical applications.
基金Supported by the Medical Health Science and Technology Project of Zhejiang Province Health Commission,No.2020376298。
文摘BACKGROUND Extranodal natural killer/T cell lymphoma,nasal type(ENKL) is a highly aggressive malignancy characterized by its association with Epstein-Barr virus(EBV) and extranodal involvement,which shows a poor clinical outcome.Although L-asparaginase-based chemotherapy has improved the response rates of relapsed/refractory(R/R) ENKL,relapse occurs in up to 50% of patients with disseminated disease.CASE SUMMARY Immune evasion has emerged as a critical pathway for survival in ENKL and may be effectuated via STAT3-driven upregulation of programmed cell death ligand 1(PD-L1) or other molecular pathways.Anti-PD-1 is effective for R/R ENKL with EBV-driven upregulation of PD-L1 expression.Anti-PD-1 combined with decitabine showed positive preliminary results in a patient with R/R ENKL and resistance to anti-PD-1.CONCLUSION The treatment experience,in this case,demonstrated the potential ability of decitabine combined with PD-1 inhibitor to treat R/R ENKL,thus providing a new treatment strategy for this tumor.
基金supported by grants from the National Natural Science Foundation of China(No.82473403,82273286,82273195)the Fundamental Research Funds for the Central Universities(2022JC019)+3 种基金Jinan Science and Technology Bureau of Shandong Province(2021GXRC029)Natural Science Foundation of Shandong Province of China(ZR2021LSW025,ZR2023LZL004)Taishan Pandeng Scholar Program of Shandong Province(tspd20210322)Youth Taishan Scholar Program of Shandong Province(tsqn202211316).
文摘Background:Glioblastoma(GBM)is largely refractory to antibodies against programmed cell death 1(anti-PD-1)therapy.Fully understanding the cellular heterogeneity and immune adaptations in response to anti-PD-1 therapy is necessary to design more effective immunotherapies for GBM.This study aimed to dissect the molecular mechanisms of specific immunosuppressive subpopulations to drive anti-PD-1 resistance in GBM.Methods:We systematically analysed single-cell RNA sequencing and spatial transcriptomics data from GBM tissues receiving anti-PD-1 therapy to characterize the microenvironment alterations.The biological functions of a novel circular RNA(circRNA)were validated both in vitro and in vivo.Mechanically,co-immunoprecipitation,RNA immunoprecipitation and pull-down assays were conducted.Results:Mesenchymal GBM(MES-GBM)cells,which were associated with a poor prognosis,and secreted phosphoprotein 1(SPP1)+myeloid-derived macrophages(SPP1+MDMs),a unique subpopulation of MDMs with complex functions,preferentially accumulated in non-responders to anti-PD-1 therapy,indicating that MES-GBM cells and SPP1+MDMs were the main anti-PD-1-resistant cell subpopulations.Functionally,we determined that circular RNA succinate dehydrogenase complex assembly factor 2(circSDHAF2),which was positively associated with the abundance of these two anti-PD-1-resistant cell subpopulations,facilitated the formation of a regional MES-GBM and SPP1+MDM cell interaction loop,resulting in a spatially specific adaptive immunosuppressive microenvironment.Mechanically,we found that circSDHAF2 promoted MES-GBM cell formation by stabilizing the integrin alpha 5(ITGA5)protein through N-glycosylation.Meanwhile,the N-glycosylation of the ITGA5 protein facilitated its translocation into exosomes and subsequent delivery to MDMs to induce the formation of SPP1+MDMs,which in turn maintained the MESGBM cell status and induced T-cell dysfunction via the SPP1-ITGA5 pathway,ultimately promoting GBM immune escape.Importantly,our findings demonstrated that antibody-mediated ITGA5 blockade enhanced anti-PD-1-mediated antitumor immunity.Conclusions:This work elucidated the potential tissue adaptation mechanism of intratumoral dynamic interactions between MES-GBM cells,MDMs and T cells in anti-PD-1 non-responders and identified the therapeutic potential of targeting ITGA5 to reduce anti-PD-1 resistance in GBM.
文摘The immunosuppressive tumor microenvironment(TME)undermines the efficacy of many cancer therapies.This study investigated the immunomodulatory and anti-tumor activity of Azvudine(FNC),alone or in combination with anti-PD-1 blockade.We established syngeneic tumor models in immunocompetent mice.Single-cell RNA sequencing,flow cytometry,and immunological assays were employed to analyze immune cell reconstitution and functional changes following FNC administration.FNC demonstrated dose-and time-dependent tumor inhibition.It significantly expanded memory T cells,natural killer(NK)cells,and CD8+cytotoxic T lymphocytes,while reducing the abundance of myeloid-derived suppressor cells(MDSCs).Flow cytometry confirmed these immunological shifts,showing enhanced infiltration of effector immune cells within the TME.Moreover,FNC induced hallmark features of immunogenic cell death(ICD),including the release of damage-associated molecular patterns such as high-mobility group box 1(HMGB1)and calreticulin.When combined with anti-PD-1 therapy,FNC produced a synergistic anti-tumor effect,leading to durable tumor remission in all treated mice.FNC remodels the TME by mitigating immunosuppression and amplifying anti-tumor immunity,offering a promising strategy to augment existing immunotherapies.Further clinical evaluation is warranted to ascertain the translational potential of FNC in diverse oncologic settings.
基金supported by the Science and Technology Strategic Cooperation Programs of Luzhou Municipal People's Government and Southwest Medical University(No.2024LZXNYDJ017)the Project Program of the Science and Technology Department of Sichuan Province(No.2025zNSFSC0679)the Project Program of Chongqing Science and Technology Bureau(No.cstc2020jcyjmsxmX1037).
文摘Although the combination of chemotherapy and immunotherapy can improve the treatment of breast cancer,traditional drugs are highly toxic because they do not specifically target tumors.In this study,we developed a self-driving bacteria/nanoparticle biohybrid called Bif@PDA-aPD1/DOX-Lip by attaching polydopamine(PDA)coated doxorubicin(DOX)liposomes and the immune checkpoint inhibitor anti-programmed cell death protein 1 antibody(aPD-1)to Bifidobacterium infantis(B.infantis,Bif).Using the homing abilities of bacteria,Bif@PDA-aPD1/DOX-Lip could actively accumulate in tumor tissue,releasing DOX and aPD-1 in the acidic environment to have a synergistic anti-tumor effect.Results show that the concentration of DOX in tumors of the Bif@PDA-aPD1/DOX-Lip group was 6.31 times higher than in the free DOX group.The combination of DOX and aPD-1 not only killed tumor cells but also promoted immune normalization by maturing dendritic cells(DCs),increasing M1 macrophage ratio,and enhancing infiltration of CD8^(+) and CD4^(+)T cells in tumors and spleen.Therefore,Bif@PDA-aPD1/DOX-Lip therapy significantly inhibited tumor growth and increased the average survival time of mice to over 80 days.The Bif@PDA-aPD1/DOX-Lip biomotors offer a highly effective method for enhancing chemo-immunotherapy in solid tumors.
文摘本文通过建立肿瘤免疫微环境多尺度数学模型,结合小鼠实验数据,探讨了前列腺素E2受体4亚型(Prostaglandin E2 Receptor 4,EP4)拮抗剂MF-766和抗程序性细胞死亡蛋白1(Anti-programmed Cell Death Protein 1,Anti-PD-1)联合治疗对肿瘤免疫微环境及肿瘤生长的调控机制。模型定量分析了免疫抑制细胞、效应性免疫细胞以及细胞因子的动态变化,揭示了联合治疗在降低髓源性抑制细胞(Myeloid-derived Suppressor Cells,MDSCs)浓度和增强效应性免疫细胞功能中的协同作用。实验验证表明,模型能够准确描述肿瘤体积的动态变化及药物的免疫调节效应,并揭示了药物剂量与用药间隔对治疗效果的非线性影响。基于此模型的模拟结果,本文不仅加深了对肿瘤转移机制的理解,还为优化免疫治疗的剂量和用药策略提供了理论依据,为精准治疗的设计与推进奠定了坚实基础。
基金supported by the National Natural Science Foundation of China(Grant No.81773277)Science and Technology Program of Guangzhou,China(Grant No.201803010014)+3 种基金Guangdong Basic and Applied Basic Research Foundation(Grant Nos.2020A1515110922 and 2019A1515110033,China)China Postdoctoral Science Foundation funded project(Grant Nos.2018M643126 and 2019M662865)Distinguished Young Talents in Higher Education Foundation of Guangdong Province(Grant No.2019KQNCX115,China)Achievement Cultivation and Clinical Transformation Application Cultivation Projects of the First Affiliated Hospital of Guangzhou Medical University(Grant No.ZH201908,China)。
文摘Owing to incurable castration-resistant prostate cancer(CRPC)ultimately developing after treating with androgen deprivation therapy(ADT),it is vital to devise new therapeutic strategies to treat CRPC.Treatments that target programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for human cancers with clinical benefit.However,many patients,especially prostate cancer,fail to respond to anti-PD-1/PD-L1 treatment,so it is an urgent need to seek a support strategy for improving the traditional PD-1/PD-L1 targeting immunotherapy.In the present study,analyzing the data from our prostate cancer tissue microarray,we found that PD-L1 expression was positively correlated with the expression of heterogeneous nuclear ribonucleoprotein L(Hn RNP L).Hence,we further investigated the potential role of Hn RNP L on the PD-L1 expression,the sensitivity of cancer cells to T-cell killing and the synergistic effect with anti-PD-1 therapy in CRPC.Indeed,Hn RNP L knockdown effectively decreased PD-L1 expression and recovered the sensitivity of cancer cells to T-cell killing in vitro and in vivo,on the contrary,Hn RNP L overexpression led to the opposite effect in CRPC cells.In addition,consistent with the previous study,we revealed that ferroptosis played a critical role in T-cell-induced cancer cell death,and Hn RNP L promoted the cancer immune escape partly through targeting YY1/PD-L1 axis and inhibiting ferroptosis in CRPC cells.Furthermore,Hn RNP L knockdown enhanced antitumor immunity by recruiting infiltrating CD8^(+)T cells and synergized with anti-PD-1 therapy in CRPC tumors.This study provided biological evidence that Hn RNP L knockdown might be a novel therapeutic agent in PD-L1/PD-1 blockade strategy that enhanced anti-tumor immune response in CRPC.
基金the CAMS Innovation Fund for Medical Sciences,Grant/Award Numbers:2022-I2M-2-004,2021-I2M-1-074National Natural Science Foundation of China,Grant/Award Numbers:82001677,82102921,82388201+1 种基金Fundamental Research Funds for the Central Universities,Grant/Award Number:3332021075Jiangsu Innovative and Entrepreneurial Talent Programme,Grant/Award Number:2020-30084。
文摘Background The efficacy of anti-programmed cell death protein 1(PD-1)immunotherapy in various cancers,including gastric cancer(GC),needs to be potentiated by more effective targeting to enhance therapeutic efficacy or identifying accurate biomarkers to predict clinical responses.Here,we attempted to identify molecules predicting or/and promoting anti-PD-1 therapeutic response in advanced GC(AGC).Methods The transcriptome of AGC tissues from patients with different clinical responses to anti-PD-1 immunotherapy and GC cells was analyzed by RNA sequencing.The protein and mRNA levels of the major facilitator superfamily domain containing 2A(MFSD2A)in GC cells were assessed via quantitative real-time polymerase chain reaction,Western blotting,and immunohistochemistry.Additionally,the regulation of anti-PD-1 response by MFSD2A was studied in tumor-bearing mice.Cytometry by Time-of-Flight,multiple immunohistochemistry,and flow cytometry assays were used to explore immunological responses.The effects of MFSD2A on lipid metabolism in mice cancer tissue and GC cells was detected by metabolomics.Results Higher expression of MFSD2A in tumor tissues of AGC patients was associated with better response to anti-PD-1 immunotherapy.Moreover,MFSD2A expression was lower in GC tissues compared to adjacent normal tissues,and its expression was inversely correlated with GC stage.The overexpression of MFSD2A in GC cells enhanced the efficacy of anti-PD-1 immunotherapy in vivo by reprogramming the tumor microenvironment(TME),characterized by increased CD8+T cell activation and reduced its exhaustion.MFSD2A inhibited transforming growth factorβ1(TGFβ1)release from GC cells by suppressing cyclooxygenase 2(COX2)-prostaglandin synthesis,which consequently reprogrammed TME to promote anti-tumor T cell activation.Conclusions MFSD2A potentially serves as a predictive biomarker for anti-PD-1 immunotherapy response in AGC patients.MFSD2A may be a promising therapeutic target to potentiate the efficacy of anti-PD-1 immunotherapy by reprogramming the TME to promote T cells activation.
基金sponsored by Shanghai Junshi Biosciences Co.,Ltd.and supported,in part,by National Key R&D Program of China(2018YFC1313300)Science and Technology Program of Guangdong(2019B020227002)+5 种基金CAMS Innovation Fund for Medical Sciences(2019-I2M-5-036)National Natural Science Foundation of China(81930065)Natural Science Foundation of Guangdong Province(2014A030312015)Science and Technology Program of Guangdong(2019B020227002)Science and Technology Program of Guangzhou(201904020046,201803040019,201704020228)Guangdong Basic and Applied Basic Research Foundation(2019A1515110171).
文摘Background:Several programmed cell death ligand 1(PD-L1)/programmed cell death protein 1(PD-1)antibodies have been approved for cancer treatmentworldwide.Their pharmacokinetic and pharmacodynamic characteristics have been reported mainly in western countries,but related data in Chinese patients are limited.This study was conducted to investigate the safety,efficacy,pharmacokinetics,and pharmacodynamics of an anti-PD-1 antibody,toripalimab,in Chinese patients.Methods:A single-center phase I study was conducted in Sun Yat-sen University Cancer Center.Eligible patients were adults with histologically confirmed,treatment-refractory,advanced,solitary malignant tumors.Toripalimab was intravenously infused every 2 weeks in dose-escalating cohorts at 0.3mg/kg,1 mg/kg,3 mg/kg,10 mg/kg,and 240 mg.The study followed standard 3+3 design.Results:Between 15th March 2016 and 27th September 2016,25 patients were enrolled,of whom 3(12.0%),7(28.0%),6(24.0%),6(24.0%),3(12.0%)received 0.3 mg/kg,1 mg/kg,3 mg/kg,10 mg/kg,and 240 mg toripalimab,respectively.After a median follow-up time of 5.0 months(range:1.5-19.8 months),we observed that the commonest treatment-related adverse events(TRAEs)were fatigue(64.0%)and rash(24.0%).No grade 3 or higher TRAEs were observed.No dose-limiting toxicity,treatment-related serious adverse events(SAEs),or treatment-related death occurred.Objective response ratewas 12.5%.The half-life of toripalimabwas 150-222 h after a single dose infusion.Most patients,including those from the 0.3 mg/kg group,maintained complete PD-1 receptor occupancy(>80%)on activated T cells since receiving the first dose of toripalimab.Conclusions:Toripalimab is a promising anti-PD-1 antibody,which was well tolerated and demonstrated anti-tumor activity in treatment-refractory advanced solitary malignant tumors.Further exploration in various tumors and combination therapies is warranted.
基金supported by grants from the Science and Technology Department of Jilin Province(No.YDZJ202201ZYTS590)the National Natural Science Foundation of China(No.82173454)
文摘Background:Radiation(IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment(TME).Wee1,a cell cycle regulator,can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1(CDK1).Meanwhile,programed death-1/programed death ligand-1(PD-1/PDL-1)blockade is closely related to TME.This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody(anti-PD-1 Ab)on radiosensitization of hepatoma.Methods:The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide(MTT)assay on human and mouse hepatoma cells HepG2,Hepa1-6,and H22.The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro.A hepatoma subcutaneous xenograft mice model was constructed on Balb/c mice,which were divided into control group,IR group,AZD1775 group,IR+AZD1775 group,IR+anti-PD-1 Ab group,and the IR+AZD1775+anti-PD-1 Ab group.Cytotoxic CD8^(+)T cells in TME were analyzed by flow cytometry.Results:Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro.AZD1775 exhibited antitumor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced DNA damage.AZD1775 treatment also reduced the proportion of PD-1^(+)/CD8^(+)T cells in the spleen of hepatoma subcutaneous xenograft mice.Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferonγ(IFNγ)^(+)or Ki67^(+)CD8 T cells and decreasing the levels of CD8^(+)Tregs cells in the tumor and spleen of the hepatoma mice model,indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγexpression,enhancing CD8^(+)T cells proliferation,and weakening CD8^(+)T cells depletion.Conclusions:This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced DNA damage and improving cytotoxic CD8^(+)T cells in TME.
文摘Background:Nivolumab and pembrolizumab—two monoclonal antibodies that block human programmed cell death-1(PD-1)—have been successfully used to treat patients with multiple advanced malignancies.The histologic patterns of hepatic toxicity induced by anti-PD-1 treatment have not been well studied and the aim of this study was to explore them.Methods:Eight patients with advanced malignancies who were treated with either nivolumab or pembrolizumab were identified from five institutions.These patients had no history of underlying liver disease and a viral hepatitis panel was negative in all patients.Results:Seven of eight patients exhibited mild to moderate gastrointestinal symptoms such as abdominal pain,fatigue,nausea,vomiting,and jaundice after anti-PD-1 treatment.Significant elevations in liver-chemistry tests were detected in all patients.Six cases(6/8)demonstrated an acute lobular hepatitis pattern of histologic injury.The remaining two cases showed different histologic patterns of injury:steatohepatitis with mild cholestasis(1/8)and pure acute cholestatic injury(1/8).No case showed typical features of autoimmune hepatitis.The liver function recovered in all eight cases after cessation of anti-PD-1 agents and with immunosuppressive therapy.Conclusions:Our study suggests that screening patients for abnormal liver-function tests prior to anti-PD-1 therapy as well as periodic monitoring of liver-function tests are necessary to prevent severe liver injury.Rather than causing classical autoimmune hepatitis,PD-1 inhibitors appear to produce an immune-mediated nonspecific acute hepatitis.Drug cessation,without steroid therapy,may therefore be sufficient in some patients.
基金the National Natural Science Foundation of China(No.81873112)Science and Technology Project of Hebei Education Department(No.ZD2022120)for the economic support.
文摘The effect of anti-programmed cell death 1(anti-PD-1)immunotherapy is limited in patients with hepatocellular carcinoma(HCC).Yes-associated protein 1(YAP1)expression increased in liver tumor cells in early HCC,and Akkermansia muciniphila abundance decreased in the colon.The response to anti-PD-1 treatment is associated with A.muciniphila abundance in many tumors.However,the interaction between A.muciniphila abundance and YAP1 expression remains unclear in HCC.Here,anti-PD-1 treatment decreased A.muciniphila abundance in the colon,but increased YAP1 expression in the tumor cells by mice with liver tumors in situ.Mechanistically,hepatocyte-specific Yap1 knockout(Yap1^(LKO))maintained bile acid homeostasis in the liver,resulting in an increased abundance of A.muciniphila in the colon.Yap1 knockout enhanced anti-PD-1 efficacy.Therefore,YAP1 inhibition is a potential target for increasing A.muciniphila abundance to promote anti-PD-1 efficacy in liver tumors.Dihydroartemisinin(DHA),acting as YAP1 inhibitor,increased A.muciniphila abundance to sensitize anti-PD-1 therapy.A.muciniphila by gavage increased the number and activation of CD8^(+)T cells in liver tumor niches during DHA treatment or combination with anti-PD-1.Our findings suggested that the combination anti-PD-1 with DHA is an effective strategy for liver tumor treatment.
基金supported by the National Natural Science Foundation of China(No.62275050)the Major Research Projects for Young and Middle-aged Talent of Fujian Provincial Health Commission(No.2021ZQNZD013)+1 种基金Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors(Grant number:2020Y2013)the Scientific Foundation of Fuzhou Municipal Health Commission(Grant number:2021-S-wp1).
文摘Background:Tyrosine kinase inhibitors(TKIs)and anti-PD-1 antibodies in combination provide survival benefits for patients with unresectable hepatocellular carcinoma(uHCC).However,the tool used to determine which patients likely benefit most from this treatment strategy has not been reported.We sought to develop a prognostic scoring system based on tumor burden score(TBS)and alpha-fetoprotein(AFP)to predict the long-term prognosis of uHCC treated with TKIs and anti-PD-1 antibodies.Methods:Data on patients with uHCC treated with TKIs and anti-PD-1 antibodies from multiple centers were collected.The prognostic accuracy of TBS,AFP,Barcelona Clinic Liver Cancer(BCLC),and CTA(Combined TBS and AFP)for 2-year progression-free survival(PFS)and overall survival(OS)was evaluated.Results:Overall,278 patients with uHCC treated with TKIs and anti-PD-1 antibodies were enrolled,including 48 BCLC-B and 230 BCLC-C HCC patients.CTA(AUC?0.721 and 0.683)outperformed TBS(AUC?0.680 and 0.621),AFP(AUC?0.606 and 0.594),and BCLC staging(AUC?0.551 and 0.555)in predicting PFS and OS.The 2-year PFS and OS for low CTA(low TBS/low AFP)were 65.7%and 94.4%,respectively,which were significantly higher than 21.6%and 44.9%(p<0.001 and p?0.002),respectively,for intermediate CTA(low TBS/high AFP or high TBS/low AFP)and 8.7%and 12.1%(both p<0.001),respectively,for high CTA(high TBS/high AFP).Multivariable Cox regression analysis indicated that CTA grading was an independent prognostic factor for PFS and OS(referent:low CTA;intermediate CTA,HR 2.87 and 7.17;high CTA,HR 5.52 and 10.31,respectively).Conclusions:CTA grading is an accurate tool for stratifying the prognosis of uHCC treated with TKIs and anti-PD-1 antibodies and may help determine which patients may benefit more from this treatment strategy.
基金supported by the National Natural Science Foundation of China(No.82373376)the Natural Science Foundation of Guangdong Province(No.2023A1515030257).
文摘Aim:Circular RNAs(circRNAs)have been found to be involved in tumor progression,but their role in colorectal cancer(CRC)immune escape remains to be elucidated.Methods:circRNAs differentially expressed in responsive and resistant CRC tissues to programmed cell death 1(PD-1)antibody therapy were identified by microarray analysis.The clinical and pathological significance of circNCOA3 was validated in a separate cohort of CRC samples.The function of circNCOA3 was explored experimentally.RNA immunoprecipitation and luciferase activity assays were conducted to identify downstream targets of circNCOA3.Results:The circNCOA3 was markedly overexpressed in CRC samples resistant to PD-1 blockade.circNCOA3 expression was significantly correlated with adverse tumor phenotypes and poor outcomes in CRC patients.Knockdown of circNCOA3 expression markedly suppressed the proliferative and invasive capability of CRC cells.Moreover,knockdown of circNCOA3 increased the proportion of CD8^(+)T cells while decreasing the proportion of myeloid-derived suppressor cells(MDSCs).Knockdown of circNCOA3 inhibited tumor growth and increased the sensitivity to PD-1 antibody treatment in mouse tumor models.Further studies revealed that circNCOA3 acted as a competing endogenous RNA(ceRNA)for miR-203a-3p.1 to influence the level of CXCL1.Conclusion:Our findings indicate that circNCOA3 might be useful as a potential biomarker to predict the efficacy and prognosis of CRC patients treated with anti-PD-1 therapy.
