目的探讨Galectin-9、FGL1在三阴型乳腺癌(triple-negative breast cancer,TNBC)中的表达及意义,分析两者在TNBC治疗中的临床应用价值。方法收集2016年1月~2019年12月台州市中心医院(台州学院附属医院)收治的108例TNBC和108例非TNBC。观...目的探讨Galectin-9、FGL1在三阴型乳腺癌(triple-negative breast cancer,TNBC)中的表达及意义,分析两者在TNBC治疗中的临床应用价值。方法收集2016年1月~2019年12月台州市中心医院(台州学院附属医院)收治的108例TNBC和108例非TNBC。观察Galectin-9、FGL1的表达情况及免疫浸润模式,并分析两者表达与临床病理特征的关系。结果TNBC组和非TNBC组中Galectin-9、FGL1 mRNA的阳性率分别为55.55%、26.85%和47.22%、12.96%;Galectin-9在TNBC组和非TNBC组肿瘤细胞和间质肿瘤浸润淋巴细胞(tumor infiltrating lymphocyte,TIL)中的阳性率分别为50.93%、52.78%和39.81%和38.89%;FGL1在TNBC组和非TNBC组肿瘤细胞和间质TIL中的阳性率分别为27.78%、30.56%和14.81%和13.89%。TNBC组和非TNBC组中Galectin-9、FGL1的表达差异均有统计学意义(P<0.05)。TNBC肿瘤细胞与间质TIL中Galectin-9表达与患者年龄、肿瘤直径和肿瘤分化程度无关(P>0.05),与组织学分级和淋巴结转移有关(P<0.05);TNBC肿瘤细胞与间质TIL中FGL1表达与患者年龄和肿瘤分化程度无关(P>0.05),与肿瘤直径、组织学分级和淋巴结转移有关(P<0.05)。Galectin-9和FGL1在TNBC浸润性导管癌和非TNBC浸润性导管癌中的表达差异有统计学意义(P<0.05)。结论Galectin-9和FGL1在TNBC中高表达,两者可能是TNBC有效的免疫治疗靶点,有望在TNBC免疫治疗中发挥作用。展开更多
Protein arginine methyltransferase 5(PRMT5)acts as an oncogene in liver cancer,yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined.Here,we demonstrat...Protein arginine methyltransferase 5(PRMT5)acts as an oncogene in liver cancer,yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined.Here,we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8^(+)T-cell-mediated antitumor immunity both in vivo and in vitro.Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule,fibrinogen-like protein 1(FGL1).Mechanistically,PRMT5 catalyzed symmetric dimethylation of transcription factor 12(TCF12)at arginine 554(R554),prompting the binding of TCF12 to FGL1 promoter region,which transcriptionally activated FGL1 in tumor cells.Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression,which promoted CD8^(+)T-cell-mediated antitumor immunity.Notably,combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice.Collectively,our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.展开更多
Aside from antibodies,peptides show great potential as immune checkpoint inhibitors(ICIs)due to several advantages,such as better tumor penetration and lower cost.Lymphocyte-activation gene 3(LAG-3)is an immune checkp...Aside from antibodies,peptides show great potential as immune checkpoint inhibitors(ICIs)due to several advantages,such as better tumor penetration and lower cost.Lymphocyte-activation gene 3(LAG-3)is an immune checkpoint which can induce T cell dysfunction through interaction with its soluble ligand fibrinogen like protein-1(FGL1).Here,we found that LAG-3 expression was higher than programmed cell death protein 1(PD-1)in multiple human cancers by TCGA databases,and successfully identified a LAG-3 binding peptide LFP-6 by phage display bio-panning,which specifically blocks the interaction of LAG-3/FGL1 but not LAG-3/MHC-II.Subsequently,D-amino acids were introduced to substitute the N-and C-terminus of LFP-6 to obtain the proteolysis-resistant peptide LFP-D1,which restores T cell function in vitro and inhibits tumor growth in vivo.Further,a bispecific peptide LFOP targeting both PD-1/PD-L1 and LAG-3/FGL1 was designed by conjugating LFP-D1 with PD-1/PD-L1blocking peptide OPBP-1(8-12),which activates T cell with enhanced proliferation and IFN-γ production.More importantly,LFOP combined with radiotherapy significantly improve the T cell infiltration in tumor and elevate systemic antitumor immune response.In conclusion,we developed a novel peptide blocking LAG-3/FGL1 which can restore T cell function,and the bispecific peptide synergizes with radiotherapy to further enhance the antitumor immune response.展开更多
目的:免疫检查点抑制剂在多种实体肿瘤中疗效显著,但是在子宫内膜癌中尚未大规模应用。研究表明程序性死亡蛋白1(programmed death protein-1, PD-1)/程序性死亡蛋白配体1 (programmed death protein-ligand 1, PD-L1)在POLE突变型、微...目的:免疫检查点抑制剂在多种实体肿瘤中疗效显著,但是在子宫内膜癌中尚未大规模应用。研究表明程序性死亡蛋白1(programmed death protein-1, PD-1)/程序性死亡蛋白配体1 (programmed death protein-ligand 1, PD-L1)在POLE突变型、微卫星不稳定型(microsatellite instability,MSI)子宫内膜癌中表达升高,而其他免疫检查点分子的表达情况并不清楚。本研究旨在全面分析多种免疫检查点分子在子宫内膜癌中的表达及临床意义。方法:通过分析TCGA数据库中最新子宫内膜癌数据,比较多种免疫检查点分子与病理类型、分子亚型、患者预后的关系。结果:采用外显子及RNA测序数据对子宫内膜癌进行分子分型,分型结果与以往研究一致性较高。免疫抑制分子PD-1/PD-L1、CTLA-4/CD80和LAG-3在POLE突变型、MSI型子宫内膜癌中高表达。FGL1作为LAG-3配体,在MSI型和无特异性分子变异(NSMP)亚型中高表达。受体分子PD-1、CTLA-4、TIM-3、LAG-3高表达与患者总生存期延长相关。FGL1高表达与总生存及无复发生存延长显著相关,其他配体分子与预后相关性无统计学意义。FGL1在子宫内膜样癌中显著高表达,而在浆液性/混合型癌中表达较低。FGL1与多种淋巴细胞、巨噬细胞丰度无显著相关性,提示该基因可能主要表达于癌细胞。此外,FGL1高表达肿瘤中肿瘤突变负荷显著升高。结论:除PD-1/PD-L1外,其他免疫检查点分子(如LAG-3/FGL1)也在子宫内膜癌中异常表达,这为该类疾病的免疫治疗提供了新思路。展开更多
目的研究纤维蛋白原样蛋白1(fibrinogen-like protein 1,FGL1)在乳腺癌组织中的表达情况并探讨其临床意义。方法收集行手术治疗乳腺癌患者癌组织及配对的癌旁组织标本16对,采用免疫组织化学检测标本中FGL1的表达水平,采用生物信息学分析...目的研究纤维蛋白原样蛋白1(fibrinogen-like protein 1,FGL1)在乳腺癌组织中的表达情况并探讨其临床意义。方法收集行手术治疗乳腺癌患者癌组织及配对的癌旁组织标本16对,采用免疫组织化学检测标本中FGL1的表达水平,采用生物信息学分析FGL1表达水平与乳腺癌患者预后的关系。结果与乳腺癌癌旁组织相比,FGL1在乳腺癌组织中的表达降低,差异具有统计学意义(P<0.05);FGL1的表达水平与预后相关,且表达水平越高,预后越好。结论FGL1在乳腺癌中低表达,与乳腺癌的临床预后相关,可能是乳腺癌新的潜在的预后分子及治疗靶点。展开更多
Three previously undescribed cytochalasins,named xylariasins A‒C(1‒3),together with six known ones(4‒9)were iso-lated from Xylaria sp.CFL5,an endophytic fungus of Cephalotaxus fortunei.The chemical structures of all n...Three previously undescribed cytochalasins,named xylariasins A‒C(1‒3),together with six known ones(4‒9)were iso-lated from Xylaria sp.CFL5,an endophytic fungus of Cephalotaxus fortunei.The chemical structures of all new compounds were elucidated on the basis of extensive spectroscopic data analyses and electronic circular dichroism calculation,as well as optical rotation calculation.Biological activities of compounds 1,4‒9 were evaluated,including cytotoxic,LAG3/MHC II binding inhibition and LAG3/FGL1 binding inhibition activities.Compounds 6 and 9 possessed cytotoxicity against AGS cells at 5μM,with inhibition rates of 94%and 64%,respectively.In addition,all tested isolates,except compound 6,exhibited obvious inhibitory activity against the interaction of both LAG3/MHC II and LAG3/FGL1.Compounds 1,5,7,and 8 inhibited LAG3/MHC II with IC50 values ranging from 2.37 to 4.74μM.Meanwhile,the IC50 values of compounds 1,7,and 8 against LAG3/FGL1 were 11.78,4.39,and 7.45μM,respectively.展开更多
Partial hepatectomy is a first-line treatment for hepatocellular carcinoma.Within 2 weeks following partial hepatectomy,specific molecular pathways are activated to promote liver regeneration.Nevertheless,residual mic...Partial hepatectomy is a first-line treatment for hepatocellular carcinoma.Within 2 weeks following partial hepatectomy,specific molecular pathways are activated to promote liver regeneration.Nevertheless,residual microtumors may also exploit these pathways to reappear and metastasize.Therapeutically targeting molecules that are differentially regulated between normal cells and malignancies,such as fibrinogen-like protein 1(FGL1),appears to be an effective approach.The potential functions of FGL1 in both regenerative and malignant cells are discussed within the ambit of this review.While FGL1 is normally elevated in regenerative hepatocytes,it is normally downregulated in malignant cells.Hepatectomy does indeed upregulate FGL1 by increasing the release of transcription factors that promote FGL1,including HNF-1α and STAT3,and inflammatory effectors,such as TGF-β and IL6.This,in turn,stimulates certain proliferative pathways,including EGFR/Src/ERK.Hepatectomy alters the phase transition of highly differentiated hepatocytes from G0 to G1,thereby transforming susceptible cells into cancerous ones.Activation of the PI3K/Akt/mTOR pathway by FGL1 allele loss on chromosome 8,a tumor suppressor area,may also cause hepatocellular carcinoma.Interestingly,FGL1 is specifically expressed in the liver via HNF-1α histone acetylase activity,which triggers lipid metabolic reprogramming in malignancies.FGL1 might also be involved in other carcinogenesis processes such as hypoxia,epithelial-mesenchymal transition,immunosuppression,and sorafenib-mediated drug resistance.This study highlights a research gap in these disciplines and the necessity for additional research on FGL1 function in the described processes.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82372818 to Xiaodong Zhang,82103066 to Guang Yang,82302887 to Hongfeng Yuan,82303210 to Yufei Wang)The China Postdoctoral Science Foundation(No.2022M712389 to Hongfeng Yuan,No.2023M732624 to Yufei Wang,No.2023M742621 to Lina Zhao)+1 种基金Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-009A to W.Lu,China)“14th Five-Year Plan”Tumor Prevention and Treatment Research Project of Tianjin Medical University Cancer Institute and Hospital(No.YZ-03,China).
文摘Protein arginine methyltransferase 5(PRMT5)acts as an oncogene in liver cancer,yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined.Here,we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8^(+)T-cell-mediated antitumor immunity both in vivo and in vitro.Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule,fibrinogen-like protein 1(FGL1).Mechanistically,PRMT5 catalyzed symmetric dimethylation of transcription factor 12(TCF12)at arginine 554(R554),prompting the binding of TCF12 to FGL1 promoter region,which transcriptionally activated FGL1 in tumor cells.Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression,which promoted CD8^(+)T-cell-mediated antitumor immunity.Notably,combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice.Collectively,our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.
基金supported by the grants from National Science Foundation of China(U20A20369)“Pearl River Talent Plan”Innovation and Entrepreneurship Team Project of Guangdong Province(2019ZT08Y464,China)+2 种基金Guangdong Basic and Applied Basic Research Foundation(2022B1515120085,China)Shenzhen Science and Technology Program(KQTD20190929173853397,China)Henan Provincial Key R&D and Promotion Special(Scientific Problem Tackling)(222102310344,China)。
文摘Aside from antibodies,peptides show great potential as immune checkpoint inhibitors(ICIs)due to several advantages,such as better tumor penetration and lower cost.Lymphocyte-activation gene 3(LAG-3)is an immune checkpoint which can induce T cell dysfunction through interaction with its soluble ligand fibrinogen like protein-1(FGL1).Here,we found that LAG-3 expression was higher than programmed cell death protein 1(PD-1)in multiple human cancers by TCGA databases,and successfully identified a LAG-3 binding peptide LFP-6 by phage display bio-panning,which specifically blocks the interaction of LAG-3/FGL1 but not LAG-3/MHC-II.Subsequently,D-amino acids were introduced to substitute the N-and C-terminus of LFP-6 to obtain the proteolysis-resistant peptide LFP-D1,which restores T cell function in vitro and inhibits tumor growth in vivo.Further,a bispecific peptide LFOP targeting both PD-1/PD-L1 and LAG-3/FGL1 was designed by conjugating LFP-D1 with PD-1/PD-L1blocking peptide OPBP-1(8-12),which activates T cell with enhanced proliferation and IFN-γ production.More importantly,LFOP combined with radiotherapy significantly improve the T cell infiltration in tumor and elevate systemic antitumor immune response.In conclusion,we developed a novel peptide blocking LAG-3/FGL1 which can restore T cell function,and the bispecific peptide synergizes with radiotherapy to further enhance the antitumor immune response.
文摘目的:免疫检查点抑制剂在多种实体肿瘤中疗效显著,但是在子宫内膜癌中尚未大规模应用。研究表明程序性死亡蛋白1(programmed death protein-1, PD-1)/程序性死亡蛋白配体1 (programmed death protein-ligand 1, PD-L1)在POLE突变型、微卫星不稳定型(microsatellite instability,MSI)子宫内膜癌中表达升高,而其他免疫检查点分子的表达情况并不清楚。本研究旨在全面分析多种免疫检查点分子在子宫内膜癌中的表达及临床意义。方法:通过分析TCGA数据库中最新子宫内膜癌数据,比较多种免疫检查点分子与病理类型、分子亚型、患者预后的关系。结果:采用外显子及RNA测序数据对子宫内膜癌进行分子分型,分型结果与以往研究一致性较高。免疫抑制分子PD-1/PD-L1、CTLA-4/CD80和LAG-3在POLE突变型、MSI型子宫内膜癌中高表达。FGL1作为LAG-3配体,在MSI型和无特异性分子变异(NSMP)亚型中高表达。受体分子PD-1、CTLA-4、TIM-3、LAG-3高表达与患者总生存期延长相关。FGL1高表达与总生存及无复发生存延长显著相关,其他配体分子与预后相关性无统计学意义。FGL1在子宫内膜样癌中显著高表达,而在浆液性/混合型癌中表达较低。FGL1与多种淋巴细胞、巨噬细胞丰度无显著相关性,提示该基因可能主要表达于癌细胞。此外,FGL1高表达肿瘤中肿瘤突变负荷显著升高。结论:除PD-1/PD-L1外,其他免疫检查点分子(如LAG-3/FGL1)也在子宫内膜癌中异常表达,这为该类疾病的免疫治疗提供了新思路。
文摘目的研究纤维蛋白原样蛋白1(fibrinogen-like protein 1,FGL1)在乳腺癌组织中的表达情况并探讨其临床意义。方法收集行手术治疗乳腺癌患者癌组织及配对的癌旁组织标本16对,采用免疫组织化学检测标本中FGL1的表达水平,采用生物信息学分析FGL1表达水平与乳腺癌患者预后的关系。结果与乳腺癌癌旁组织相比,FGL1在乳腺癌组织中的表达降低,差异具有统计学意义(P<0.05);FGL1的表达水平与预后相关,且表达水平越高,预后越好。结论FGL1在乳腺癌中低表达,与乳腺癌的临床预后相关,可能是乳腺癌新的潜在的预后分子及治疗靶点。
基金supported financially by the National Natural Science Foundation of China(No.21778027)the Natural Science Foundation of Gansu Province(No.18JR4RA003).
文摘Three previously undescribed cytochalasins,named xylariasins A‒C(1‒3),together with six known ones(4‒9)were iso-lated from Xylaria sp.CFL5,an endophytic fungus of Cephalotaxus fortunei.The chemical structures of all new compounds were elucidated on the basis of extensive spectroscopic data analyses and electronic circular dichroism calculation,as well as optical rotation calculation.Biological activities of compounds 1,4‒9 were evaluated,including cytotoxic,LAG3/MHC II binding inhibition and LAG3/FGL1 binding inhibition activities.Compounds 6 and 9 possessed cytotoxicity against AGS cells at 5μM,with inhibition rates of 94%and 64%,respectively.In addition,all tested isolates,except compound 6,exhibited obvious inhibitory activity against the interaction of both LAG3/MHC II and LAG3/FGL1.Compounds 1,5,7,and 8 inhibited LAG3/MHC II with IC50 values ranging from 2.37 to 4.74μM.Meanwhile,the IC50 values of compounds 1,7,and 8 against LAG3/FGL1 were 11.78,4.39,and 7.45μM,respectively.
基金supported by the Doctoral Research Fund of Hubei University of Science and Technology,with project number Q201810.
文摘Partial hepatectomy is a first-line treatment for hepatocellular carcinoma.Within 2 weeks following partial hepatectomy,specific molecular pathways are activated to promote liver regeneration.Nevertheless,residual microtumors may also exploit these pathways to reappear and metastasize.Therapeutically targeting molecules that are differentially regulated between normal cells and malignancies,such as fibrinogen-like protein 1(FGL1),appears to be an effective approach.The potential functions of FGL1 in both regenerative and malignant cells are discussed within the ambit of this review.While FGL1 is normally elevated in regenerative hepatocytes,it is normally downregulated in malignant cells.Hepatectomy does indeed upregulate FGL1 by increasing the release of transcription factors that promote FGL1,including HNF-1α and STAT3,and inflammatory effectors,such as TGF-β and IL6.This,in turn,stimulates certain proliferative pathways,including EGFR/Src/ERK.Hepatectomy alters the phase transition of highly differentiated hepatocytes from G0 to G1,thereby transforming susceptible cells into cancerous ones.Activation of the PI3K/Akt/mTOR pathway by FGL1 allele loss on chromosome 8,a tumor suppressor area,may also cause hepatocellular carcinoma.Interestingly,FGL1 is specifically expressed in the liver via HNF-1α histone acetylase activity,which triggers lipid metabolic reprogramming in malignancies.FGL1 might also be involved in other carcinogenesis processes such as hypoxia,epithelial-mesenchymal transition,immunosuppression,and sorafenib-mediated drug resistance.This study highlights a research gap in these disciplines and the necessity for additional research on FGL1 function in the described processes.
