OBJECTIVE To evaluate whether the IDO1 inhibitor 1-methyl-L-tryptophan(1-MT)combine calcium influx inhibitor carboxyamidotriazole(CAI)could further enhance the suppression of programmed death 1(PD-1)in CD8^+T cells an...OBJECTIVE To evaluate whether the IDO1 inhibitor 1-methyl-L-tryptophan(1-MT)combine calcium influx inhibitor carboxyamidotriazole(CAI)could further enhance the suppression of programmed death 1(PD-1)in CD8^+T cells and investigate the curative effect of the combined use.METHODS CD8^+T cells were isolated from normal mice spleen by negative selection using magnetic cell separation.The isolated CD8^+T cells were cultured in RPMI 1640 medium containing 10%FBS and 100 U·mL^(-1)IL-2 and activated by the addition of anti-CD3 and anti-CD28(1 g·L^(-1) each mabs).CD8^+T cells were pretreated for 48 h with drug and the fluo-3 as a marker of intracellular calcium concentration was detected by flow cytometry.The calcineurin(Ca N)levels were assayed with ELISA in CD8^+T cells after 48 h incubation with 10μm CAI.The nuclear translocations of NFAT and AHR were detected by immunofluorescent staining after 48 h of drug treatment.The expression of PD-1 in CD8^+T cells was analyzed by flow cytometry.RESULTS Intracellular fluorescent intensity was markedly debase due to CAI treatment(P<0.01).Meanwhile,the changes of CaN content had a resembled correlation(P<0.01).Immunofluorescence experiment showed that after combination therapy the transfer of NFAT and AHR in nuclear substantially reduced.Flow cytometry revealed that after the combination caused a significant decrease in PD-1 expression in CD8^+T cells.CONCLUSION CAI and 1-MT could inhibit markedly the expression of PD-1 in CD8^+T cells by inhibiting the nuclear translocation of NFAT and AHR,respectively and the combination of them has synergetic effect.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
以程序性死亡蛋白-1(programmed death protein-1,PD-1)抑制剂为代表的免疫检查点抑制剂在胃癌中显示良好疗效,逐步改变晚期胃癌的治疗格局。对于程序性死亡蛋白配体-1(programmed death-ligand 1,PD-L1)高表达的患者,PD-L1单抗的治疗...以程序性死亡蛋白-1(programmed death protein-1,PD-1)抑制剂为代表的免疫检查点抑制剂在胃癌中显示良好疗效,逐步改变晚期胃癌的治疗格局。对于程序性死亡蛋白配体-1(programmed death-ligand 1,PD-L1)高表达的患者,PD-L1单抗的治疗效果更为优异,且与PD-L1蛋白表达水平呈正相关。而对于PD-L1阴性或低表达这类免疫治疗非优势人群,以PD-1单抗为基础的用药方案疗效有限,尝试双特异性抗体、ADC等不同药物的联合也是一种趋势。为了精准指导临床实践,中国抗癌协会胃癌专业委员会组织国内胃癌领域专家进行多轮讨论,系统汇总国内外最新指南和循证证据,并结合我国临床实际,从病理检测、晚期治疗以及围术期治疗3个方面制订了本专家共识,旨在提高胃癌诊治的科学性和规范性,尤其是指导基层医生对免疫治疗的选择和应用。展开更多
基金supported by National Natural Science Foundation of China(81402943)CAMS Major Collaborative Innovation Project(2016-I2M-1-011)PUMC Youth Fund(3332015168)
文摘OBJECTIVE To evaluate whether the IDO1 inhibitor 1-methyl-L-tryptophan(1-MT)combine calcium influx inhibitor carboxyamidotriazole(CAI)could further enhance the suppression of programmed death 1(PD-1)in CD8^+T cells and investigate the curative effect of the combined use.METHODS CD8^+T cells were isolated from normal mice spleen by negative selection using magnetic cell separation.The isolated CD8^+T cells were cultured in RPMI 1640 medium containing 10%FBS and 100 U·mL^(-1)IL-2 and activated by the addition of anti-CD3 and anti-CD28(1 g·L^(-1) each mabs).CD8^+T cells were pretreated for 48 h with drug and the fluo-3 as a marker of intracellular calcium concentration was detected by flow cytometry.The calcineurin(Ca N)levels were assayed with ELISA in CD8^+T cells after 48 h incubation with 10μm CAI.The nuclear translocations of NFAT and AHR were detected by immunofluorescent staining after 48 h of drug treatment.The expression of PD-1 in CD8^+T cells was analyzed by flow cytometry.RESULTS Intracellular fluorescent intensity was markedly debase due to CAI treatment(P<0.01).Meanwhile,the changes of CaN content had a resembled correlation(P<0.01).Immunofluorescence experiment showed that after combination therapy the transfer of NFAT and AHR in nuclear substantially reduced.Flow cytometry revealed that after the combination caused a significant decrease in PD-1 expression in CD8^+T cells.CONCLUSION CAI and 1-MT could inhibit markedly the expression of PD-1 in CD8^+T cells by inhibiting the nuclear translocation of NFAT and AHR,respectively and the combination of them has synergetic effect.
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。
文摘以程序性死亡蛋白-1(programmed death protein-1,PD-1)抑制剂为代表的免疫检查点抑制剂在胃癌中显示良好疗效,逐步改变晚期胃癌的治疗格局。对于程序性死亡蛋白配体-1(programmed death-ligand 1,PD-L1)高表达的患者,PD-L1单抗的治疗效果更为优异,且与PD-L1蛋白表达水平呈正相关。而对于PD-L1阴性或低表达这类免疫治疗非优势人群,以PD-1单抗为基础的用药方案疗效有限,尝试双特异性抗体、ADC等不同药物的联合也是一种趋势。为了精准指导临床实践,中国抗癌协会胃癌专业委员会组织国内胃癌领域专家进行多轮讨论,系统汇总国内外最新指南和循证证据,并结合我国临床实际,从病理检测、晚期治疗以及围术期治疗3个方面制订了本专家共识,旨在提高胃癌诊治的科学性和规范性,尤其是指导基层医生对免疫治疗的选择和应用。
