2025年4月5日,上海交通大学医学院附属新华医院检验科郑英霞教授团队在权威期刊Journal for Immunotherapy of Cancer发表题目为“PRMT5 deficiency in myeloid cells reprograms macrophages to enhance antitumor immunity and synerg...2025年4月5日,上海交通大学医学院附属新华医院检验科郑英霞教授团队在权威期刊Journal for Immunotherapy of Cancer发表题目为“PRMT5 deficiency in myeloid cells reprograms macrophages to enhance antitumor immunity and synergizes with anti-PD-L1 therapy”的研究论文。该研究揭示了蛋白精氨酸甲基转移酶5(protein arginine methyltransferase 5,PRMT5)通过STAT6-PPARγ途径调节脂质代谢,促进单核巨噬细胞的迁移和分化,促进巨噬细胞向M2型极化。在小鼠髓系细胞中特异性敲除Prmt5(Prmt5 cKO)并进行肿瘤模型构建,发现在敲除鼠中肿瘤相关巨噬细胞发生重编程,抗肿瘤活性增强,抑制肿瘤进展并显著增强抗程序性死亡受体配体1(programmed death-ligand 1,PD-L1)的免疫治疗效果。该研究结果提示靶向髓系细胞中的PRMT5有望为癌症免疫治疗提供一种新的方法。展开更多
Background:The dysregulation of Isocitrate dehydrogenase(IDH)and the subsequent production of 2-Hydroxyglutrate(2HG)may alter the expression of epigenetic proteins in Grade 4 astrocytoma.The interplay mechanism betwee...Background:The dysregulation of Isocitrate dehydrogenase(IDH)and the subsequent production of 2-Hydroxyglutrate(2HG)may alter the expression of epigenetic proteins in Grade 4 astrocytoma.The interplay mechanism between IDH,O-6-methylguanine-DNA methyltransferase(MGMT)-promoter methylation,and protein methyltransferase proteins-5(PRMT5)activity,with tumor progression has never been described.Methods:A retrospective cohort of 34 patients with G4 astrocytoma is classified into IDH-mutant and IDH-wildtype tumors.Both groups were tested for MGMT-promoter methylation and PRMT5 through methylation-specific and gene expression PCR analysis.Inter-cohort statistical significance was evaluated.Results:Both IDH-mutant WHO grade 4 astrocytomas(n=22,64.7%)and IDH-wildtype glioblastomas(n=12,35.3%)had upregulated PRMT5 gene expression except in one case.Out of the 22 IDH-mutant tumors,10(45.5%)tumors showed MGMT-promoter methylation and 12(54.5%)tumors had unmethylated MGMT.All IDH-wildtype tumors had unmethylated MGMT.There was a statistically significant relationship between MGMT-promoter methylation and IDH in G4 astrocytoma(p-value=0.006).Statistically significant differences in progression-free survival(PFS)were also observed among all G4 astrocytomas that expressed PRMT5 and received either temozolomide(TMZ)or TMZ plus other chemotherapies,regardless of their IDH or MGMT-methylation status(p-value=0.0014).Specifically,IDH-mutant tumors that had upregulated PRMT5 activity and MGMT-promoter methylation,who received only TMZ,have exhibited longer PFS.Conclusions:The relationship between PRMT5,MGMT-promoter,and IDH is not tridirectional.However,accumulation of D2-hydroxyglutarate(2-HG),which partially activates 2-OG-dependent deoxygenase,may not affect their activities.In IDH-wildtype glioblastomas,the 2HG-2OG pathway is typically inactive,leading to PRMT5 upregulation.TMZ alone,compared to TMZ-plus,can increase PFS in upregulated PRMT5 tumors.Thus,using a PRMT5 inhibitor in G4 astrocytomas may help in tumor regression.展开更多
文摘2025年4月5日,上海交通大学医学院附属新华医院检验科郑英霞教授团队在权威期刊Journal for Immunotherapy of Cancer发表题目为“PRMT5 deficiency in myeloid cells reprograms macrophages to enhance antitumor immunity and synergizes with anti-PD-L1 therapy”的研究论文。该研究揭示了蛋白精氨酸甲基转移酶5(protein arginine methyltransferase 5,PRMT5)通过STAT6-PPARγ途径调节脂质代谢,促进单核巨噬细胞的迁移和分化,促进巨噬细胞向M2型极化。在小鼠髓系细胞中特异性敲除Prmt5(Prmt5 cKO)并进行肿瘤模型构建,发现在敲除鼠中肿瘤相关巨噬细胞发生重编程,抗肿瘤活性增强,抑制肿瘤进展并显著增强抗程序性死亡受体配体1(programmed death-ligand 1,PD-L1)的免疫治疗效果。该研究结果提示靶向髓系细胞中的PRMT5有望为癌症免疫治疗提供一种新的方法。
文摘Background:The dysregulation of Isocitrate dehydrogenase(IDH)and the subsequent production of 2-Hydroxyglutrate(2HG)may alter the expression of epigenetic proteins in Grade 4 astrocytoma.The interplay mechanism between IDH,O-6-methylguanine-DNA methyltransferase(MGMT)-promoter methylation,and protein methyltransferase proteins-5(PRMT5)activity,with tumor progression has never been described.Methods:A retrospective cohort of 34 patients with G4 astrocytoma is classified into IDH-mutant and IDH-wildtype tumors.Both groups were tested for MGMT-promoter methylation and PRMT5 through methylation-specific and gene expression PCR analysis.Inter-cohort statistical significance was evaluated.Results:Both IDH-mutant WHO grade 4 astrocytomas(n=22,64.7%)and IDH-wildtype glioblastomas(n=12,35.3%)had upregulated PRMT5 gene expression except in one case.Out of the 22 IDH-mutant tumors,10(45.5%)tumors showed MGMT-promoter methylation and 12(54.5%)tumors had unmethylated MGMT.All IDH-wildtype tumors had unmethylated MGMT.There was a statistically significant relationship between MGMT-promoter methylation and IDH in G4 astrocytoma(p-value=0.006).Statistically significant differences in progression-free survival(PFS)were also observed among all G4 astrocytomas that expressed PRMT5 and received either temozolomide(TMZ)or TMZ plus other chemotherapies,regardless of their IDH or MGMT-methylation status(p-value=0.0014).Specifically,IDH-mutant tumors that had upregulated PRMT5 activity and MGMT-promoter methylation,who received only TMZ,have exhibited longer PFS.Conclusions:The relationship between PRMT5,MGMT-promoter,and IDH is not tridirectional.However,accumulation of D2-hydroxyglutarate(2-HG),which partially activates 2-OG-dependent deoxygenase,may not affect their activities.In IDH-wildtype glioblastomas,the 2HG-2OG pathway is typically inactive,leading to PRMT5 upregulation.TMZ alone,compared to TMZ-plus,can increase PFS in upregulated PRMT5 tumors.Thus,using a PRMT5 inhibitor in G4 astrocytomas may help in tumor regression.
