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
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
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
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 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
Intestinal flora affects the maturation of the host immune system,serves as a biomarker and efficacy predictor in the immunotherapy of several cancers,and has an important role in the development of colorectal cancer(...Intestinal flora affects the maturation of the host immune system,serves as a biomarker and efficacy predictor in the immunotherapy of several cancers,and has an important role in the development of colorectal cancer(CRC).Anti-PD-1/PD-L1 antibodies have shown satisfactory results in MSI-H/d MMR CRC but performed poorly in patients with MSS/p MMR CRC.In recent years an increasing number of studies have shown that intestinal flora has an important impact on anti-PD-1/PD-L1 antibody efficacy in CRC patients.Preclinical and clinical evidence have suggested that anti-PD-1/PD-L1 antibody efficacy can be improved by altering the composition of the intestinal flora in CRC.Herein,we summarize the studies related to the influence of intestinal flora on anti-PD-1/PD-L1 antibody efficacy in CRC and discuss the potential underlying mechanism(s).We have focused on the impact of the intestinal flora on the efficacy and safety of anti-PD-1/PD-L1 antibodies in CRC and how to better utilize the intestinal flora as an adjuvant to improve the efficacy of anti-PD-1/PD-L1 antibodies.In addition,we have provided a basis for the potential of the intestinal flora as a new treatment modality and indicator for determining patient prognosis.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
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
目的:通过对比免疫相关不良反应(irAE)发生前后血常规中主要指标的变化,为鉴别诊断irAE及感染性炎症提供新依据。方法:回顾性分析201例2018年8月至2022年6月在河南省肿瘤医院接受抗PD-1抗体治疗后出现irAE的肿瘤患者的临床资料,包括抗P...目的:通过对比免疫相关不良反应(irAE)发生前后血常规中主要指标的变化,为鉴别诊断irAE及感染性炎症提供新依据。方法:回顾性分析201例2018年8月至2022年6月在河南省肿瘤医院接受抗PD-1抗体治疗后出现irAE的肿瘤患者的临床资料,包括抗PD-1抗体治疗前、发生irAE前及irAE后血常规的主要指标,采用配对t检验分析治疗前后血常规指标值的统计学差异。采用定性变量的配对χ^(2)检验分析治疗前后血常规指标值的阳性率(高于正常值的比例)的统计学差异。结果:从201例患者中观察到了258次irAE,其中27例(13.4%)患者发生了2种及以上类型的irAE,214次(82.94%)irAE未引起发热;irAE发生后与抗PD-1抗体治疗前相比,白细胞计数(t=1.087,P=0.278)、中性粒细胞计数(t=0.959,P=0.338)及中性粒细胞百分比(t=0.817,P=0.414)未见明显升高,且三指标高于正常值的病例数分别为28 vs 38(χ^(2)=1.737,P=0.187)、32 vs 44(χ^(2)=2.222,P=0.136)、45 vs 55(χ^(2)=1.240,P=0.265),差异均无统计学意义。结论:irAE发生后患者外周血白细胞计数、中性粒细胞计数及中性粒细胞百分比无明显变化,这对鉴别诊断感染性炎症可能具有参考意义。展开更多
1文献来源Adusumilli PS,Zauderer MG,Rivière I,et al.A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease,in combination with the anti-PD-1 agent pembrolizum...1文献来源Adusumilli PS,Zauderer MG,Rivière I,et al.A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease,in combination with the anti-PD-1 agent pembrolizumab[J].Cancer Discov,2021,11(11):2748-2763.2证据水平1b。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supported by grants from National Cancer Center Climbing Fund(Grant No.NCC201916B03)Provincial-ministerial Co-construction Project of Henan Province Science and Technology Key Point Tackling Plan(Grant No.SBGJ202102064)Henan Provincial Scientific and Technological Project(Grant Nos.222102310363 and 222102310677)。
文摘Intestinal flora affects the maturation of the host immune system,serves as a biomarker and efficacy predictor in the immunotherapy of several cancers,and has an important role in the development of colorectal cancer(CRC).Anti-PD-1/PD-L1 antibodies have shown satisfactory results in MSI-H/d MMR CRC but performed poorly in patients with MSS/p MMR CRC.In recent years an increasing number of studies have shown that intestinal flora has an important impact on anti-PD-1/PD-L1 antibody efficacy in CRC patients.Preclinical and clinical evidence have suggested that anti-PD-1/PD-L1 antibody efficacy can be improved by altering the composition of the intestinal flora in CRC.Herein,we summarize the studies related to the influence of intestinal flora on anti-PD-1/PD-L1 antibody efficacy in CRC and discuss the potential underlying mechanism(s).We have focused on the impact of the intestinal flora on the efficacy and safety of anti-PD-1/PD-L1 antibodies in CRC and how to better utilize the intestinal flora as an adjuvant to improve the efficacy of anti-PD-1/PD-L1 antibodies.In addition,we have provided a basis for the potential of the intestinal flora as a new treatment modality and indicator for determining patient prognosis.
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 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.
文摘目的:通过对比免疫相关不良反应(irAE)发生前后血常规中主要指标的变化,为鉴别诊断irAE及感染性炎症提供新依据。方法:回顾性分析201例2018年8月至2022年6月在河南省肿瘤医院接受抗PD-1抗体治疗后出现irAE的肿瘤患者的临床资料,包括抗PD-1抗体治疗前、发生irAE前及irAE后血常规的主要指标,采用配对t检验分析治疗前后血常规指标值的统计学差异。采用定性变量的配对χ^(2)检验分析治疗前后血常规指标值的阳性率(高于正常值的比例)的统计学差异。结果:从201例患者中观察到了258次irAE,其中27例(13.4%)患者发生了2种及以上类型的irAE,214次(82.94%)irAE未引起发热;irAE发生后与抗PD-1抗体治疗前相比,白细胞计数(t=1.087,P=0.278)、中性粒细胞计数(t=0.959,P=0.338)及中性粒细胞百分比(t=0.817,P=0.414)未见明显升高,且三指标高于正常值的病例数分别为28 vs 38(χ^(2)=1.737,P=0.187)、32 vs 44(χ^(2)=2.222,P=0.136)、45 vs 55(χ^(2)=1.240,P=0.265),差异均无统计学意义。结论:irAE发生后患者外周血白细胞计数、中性粒细胞计数及中性粒细胞百分比无明显变化,这对鉴别诊断感染性炎症可能具有参考意义。
文摘1文献来源Adusumilli PS,Zauderer MG,Rivière I,et al.A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease,in combination with the anti-PD-1 agent pembrolizumab[J].Cancer Discov,2021,11(11):2748-2763.2证据水平1b。
