OBJECTIVE Programmed death ligand-1(PD-L1)and indoleamine 2,3-dioxygenase 1(IDO1)are immune checkpoints which can be induced by interferon-γ(IFN-γ)in the tumor microenvironment,leading to immune escape of tumors.Myr...OBJECTIVE Programmed death ligand-1(PD-L1)and indoleamine 2,3-dioxygenase 1(IDO1)are immune checkpoints which can be induced by interferon-γ(IFN-γ)in the tumor microenvironment,leading to immune escape of tumors.Myricetin(MY)is a flavonoid distributed in many edible and medicinal plants.The aim of this study is to clarify the effect and the mechanism of MY on inhibiting IFN-γ-induced PD-L1 and IDO1 in lung cancer cells.METHODS Expressions of PD-L1 and major histocompatibility complex-I(MHC-I)were evaluated by flow cytometry and Western blotting,and the expression of IDO1 was measured by Western blotting.qRT-PCR was used to detect their mRNA levels.The function of T cells was evaluated using a co-culture system consist of lung cancer cells and the Jurkat-PD-1 T cell line that overexpressing PD-1.Molecular docking analysis,Western blotting and immunofluorescence were used for mechanism study.RESULTS MY potently inhibited IFN-γ-induced PD-L1 and IDO1 expression in human lung cancer cells,while didn't show obvious effect on the expression of MHC-I.In addition,MY restored the survival,proliferation,CD69 expression and interleukin-2(IL-2)secretion of Jurkat-PD-1 T cells suppressed by IFN-γ-treated lung cancer cells in the co-culture system.Mechanistically,IFN-γup-regulated PD-L1 and IDO1 at the transcriptional level through the JAK-STAT-IRF1 axis,which was targeted and inhibited by MY.CONCLUSION Our research revealed a new insight into the anti-tumor effects of MY which inhibited IFN-γ-induced PD-L1 and IDO1 expression,supporting the potential of MY in anti-tumor immunotherapy.展开更多
程序性细胞死亡受体1(programmed cell death 1,PD-1)单抗治疗肺腺癌可能引起罕见而严重的血液学不良反应,可出现重症贫血等表现。尽管糖皮质激素被推荐用于免疫相关不良事件的管理,但针对PD-1单抗诱发的重症贫血的治疗经验仍十分有限,...程序性细胞死亡受体1(programmed cell death 1,PD-1)单抗治疗肺腺癌可能引起罕见而严重的血液学不良反应,可出现重症贫血等表现。尽管糖皮质激素被推荐用于免疫相关不良事件的管理,但针对PD-1单抗诱发的重症贫血的治疗经验仍十分有限,其疗效和安全性尚未充分验证。本文报道了1例化疗联合PD-1单抗治疗后发生重症贫血的晚期肺腺癌患者,经过系列检查,考虑诊断炎症性贫血,经足量糖皮质激素治疗后,血红蛋白显著回升,以期为临床中这类罕见血液学毒性的识别和治疗提供新的见解。展开更多
目的:程序性死亡受体-1(programmed death-1,PD-1)相关性暴发性1型糖尿病(PD-1 associated fulminant type 1 diabetes,PFD)是少见的内科急危重症,临床特点尚不清楚。本研究分析PFD患者的临床特点,以期提升临床诊疗水平。方法:回顾性分...目的:程序性死亡受体-1(programmed death-1,PD-1)相关性暴发性1型糖尿病(PD-1 associated fulminant type 1 diabetes,PFD)是少见的内科急危重症,临床特点尚不清楚。本研究分析PFD患者的临床特点,以期提升临床诊疗水平。方法:回顾性分析中南大学湘雅二医院(以下简称我院)就诊的10例PFD患者的临床资料,结合相关文献报道的66例患者资料,分析总结其临床与免疫特征,并对不同胰岛自身抗体状态的PFD患者进行比较。结果:结合我院及文献检索数据,共报道76例PFD患者,年龄(60.9±12.1)岁,男性占60.0%,体重指数(22.1±5.2)kg/m2。76例患者中最常见的肿瘤是肺癌(43.4%)和黑色素瘤(22.4%)。PD-1相关抑制剂最常见的药物是纳武单抗(37.5%)和派姆单抗(38.9%)。82.2%的PFD患者出现糖尿病酮症酸中毒。从PD-1相关抑制剂治疗开始到血糖升高的中位发病时间为95(36.0,164.5)d,糖尿病发病前中位治疗周期为6(2.3,8.0)。26.0%(19/73)的PFD患者胰岛自身抗体阳性,阳性组的酮症酸中毒比例显著高于阴性组(100.0%vs 75.0%,P<0.05)。PD-1抑制剂治疗后的糖尿病发病时间和输注次数在抗体阳性组中均显著低于抗体阴性组(28.5 d vs 120.0 d;2周期vs 7周期,均P<0.001)。结论:启动肿瘤免疫治疗后需警惕发生PFD不良反应,胰岛自身抗体阳性PFD比阴性患者发病更快、更严重。PD-1相关抑制剂治疗前后检测胰岛自身抗体及血糖对PFD预警预测有重要价值。展开更多
基金Science and Technology Development Fund,Macao SAR(0129/2019/A3176/2017/A3)and University of Macao(MYRG2018-00165-ICMS)。
文摘OBJECTIVE Programmed death ligand-1(PD-L1)and indoleamine 2,3-dioxygenase 1(IDO1)are immune checkpoints which can be induced by interferon-γ(IFN-γ)in the tumor microenvironment,leading to immune escape of tumors.Myricetin(MY)is a flavonoid distributed in many edible and medicinal plants.The aim of this study is to clarify the effect and the mechanism of MY on inhibiting IFN-γ-induced PD-L1 and IDO1 in lung cancer cells.METHODS Expressions of PD-L1 and major histocompatibility complex-I(MHC-I)were evaluated by flow cytometry and Western blotting,and the expression of IDO1 was measured by Western blotting.qRT-PCR was used to detect their mRNA levels.The function of T cells was evaluated using a co-culture system consist of lung cancer cells and the Jurkat-PD-1 T cell line that overexpressing PD-1.Molecular docking analysis,Western blotting and immunofluorescence were used for mechanism study.RESULTS MY potently inhibited IFN-γ-induced PD-L1 and IDO1 expression in human lung cancer cells,while didn't show obvious effect on the expression of MHC-I.In addition,MY restored the survival,proliferation,CD69 expression and interleukin-2(IL-2)secretion of Jurkat-PD-1 T cells suppressed by IFN-γ-treated lung cancer cells in the co-culture system.Mechanistically,IFN-γup-regulated PD-L1 and IDO1 at the transcriptional level through the JAK-STAT-IRF1 axis,which was targeted and inhibited by MY.CONCLUSION Our research revealed a new insight into the anti-tumor effects of MY which inhibited IFN-γ-induced PD-L1 and IDO1 expression,supporting the potential of MY in anti-tumor immunotherapy.
文摘程序性细胞死亡受体1(programmed cell death 1,PD-1)单抗治疗肺腺癌可能引起罕见而严重的血液学不良反应,可出现重症贫血等表现。尽管糖皮质激素被推荐用于免疫相关不良事件的管理,但针对PD-1单抗诱发的重症贫血的治疗经验仍十分有限,其疗效和安全性尚未充分验证。本文报道了1例化疗联合PD-1单抗治疗后发生重症贫血的晚期肺腺癌患者,经过系列检查,考虑诊断炎症性贫血,经足量糖皮质激素治疗后,血红蛋白显著回升,以期为临床中这类罕见血液学毒性的识别和治疗提供新的见解。
文摘目的:程序性死亡受体-1(programmed death-1,PD-1)相关性暴发性1型糖尿病(PD-1 associated fulminant type 1 diabetes,PFD)是少见的内科急危重症,临床特点尚不清楚。本研究分析PFD患者的临床特点,以期提升临床诊疗水平。方法:回顾性分析中南大学湘雅二医院(以下简称我院)就诊的10例PFD患者的临床资料,结合相关文献报道的66例患者资料,分析总结其临床与免疫特征,并对不同胰岛自身抗体状态的PFD患者进行比较。结果:结合我院及文献检索数据,共报道76例PFD患者,年龄(60.9±12.1)岁,男性占60.0%,体重指数(22.1±5.2)kg/m2。76例患者中最常见的肿瘤是肺癌(43.4%)和黑色素瘤(22.4%)。PD-1相关抑制剂最常见的药物是纳武单抗(37.5%)和派姆单抗(38.9%)。82.2%的PFD患者出现糖尿病酮症酸中毒。从PD-1相关抑制剂治疗开始到血糖升高的中位发病时间为95(36.0,164.5)d,糖尿病发病前中位治疗周期为6(2.3,8.0)。26.0%(19/73)的PFD患者胰岛自身抗体阳性,阳性组的酮症酸中毒比例显著高于阴性组(100.0%vs 75.0%,P<0.05)。PD-1抑制剂治疗后的糖尿病发病时间和输注次数在抗体阳性组中均显著低于抗体阴性组(28.5 d vs 120.0 d;2周期vs 7周期,均P<0.001)。结论:启动肿瘤免疫治疗后需警惕发生PFD不良反应,胰岛自身抗体阳性PFD比阴性患者发病更快、更严重。PD-1相关抑制剂治疗前后检测胰岛自身抗体及血糖对PFD预警预测有重要价值。
