Journal for Immunotherapy of Cancer:罗成/党永军团队等发现L-5-羟基色氨酸可抑制PD-L1表达,发挥抗肿瘤效应

2022-06-30 “生物世界”公众号 “生物世界”公众号

内源代谢物具有安全性较佳、不良反应易监测、类药性高的优势,能抑制 PD-L1 表达且具有良好生物安全性的小分子代谢物,将为阻断 PD-1/PD-L1 信号、激活抗肿瘤免疫提供新的策略和思路。

PD-1/PD-L1 免疫检查点疗法在临床肿瘤治疗中取得了突破性进展,部分患者得到了长期生存获益,但其响应率仅10%-25%,且在使用后会出现获得性耐药问题。此外,因抗体类药物自身局限性所导致的剂量安全性和副作用等问题进一步限制了免疫检查点疗法在临床上的应用。

内源代谢物具有安全性较佳、不良反应易监测、类药性高的优势,能抑制 PD-L1 表达且具有良好生物安全性的小分子代谢物,将为阻断 PD-1/PD-L1 信号、激活抗肿瘤免疫提供新的策略和思路。

近日,中国科学院上海药物研究所罗成团队联合重庆医科大学党永军团队等,在 Journal for Immunotherapy of Cancer 期刊发表了题为:L-5-hydroxytryptophan promotes antitumor immunity by inhibiting PD-L1 inducible expression 的研究论文。

该研究建立了检测肿瘤细胞表面 PD-L1 表达的高通量流式筛选体系,对小分子代谢物库进行筛选,发现色氨酸代谢通路中的代谢物 L-5-羟基色氨酸可抑制干扰素-γ(IFN-γ)诱导的 PD-L1 表达,并激活 T 细胞抗肿瘤免疫反应,发挥抗肿瘤效应。

在这项研究中,研究团队基于高通量筛选发现,L-5-羟基色氨酸可抑制 IFN-γ 诱导的 PD-L1 转录表达。通过对色氨酸代谢通路上 L-5-羟基色氨可转化生成的其他代谢产物进行评价,研究发现它们均不影响 IFN-γ 诱导的 PD-L1 表达,表明 L-5-羟基色氨酸通过自身调控 PD-L1诱 导性表达。

结合转录组分析,进一步实验研究发现,L-5-羟基色氨酸可下调 IFN-γ 诱导的受体酪氨酸激酶(RTK)配体的转录表达,进而阻断下游 RTK 受体/MEK/ERK/c-JUN 信号通路的磷酸化级联转导,抑制 IFN-γ 诱导的 PD-L1 转录激活。

在小鼠同系肿瘤模型上,腹腔注射100mg/kg的 L-5-羟基色氨酸,降低了瘤体内肿瘤细胞、树突状细胞以及巨噬细胞表面 PD-L1 表达,并具有显着且安全的抗肿瘤药效。通过比较 L-5-羟基色氨酸在免疫完整和免疫缺陷小鼠上的药效,以及在 PD-L1 野生型和敲除型肿瘤中的抗肿瘤药效,研究发现 L-5-羟基色氨酸主要通过抑制肿瘤细胞 PD-L1 表达,增加肿瘤组织中的效应 T 细胞数量并活化效应 T 细胞,发挥显着的抗肿瘤效应。

L-5-羟基色氨酸在体内发挥抗肿瘤效应。(A) L-5-羟基色氨酸在体内下调肿瘤细胞PD-L1表达;(B)L-5-羟基色氨酸提高瘤体内效应T细胞数量和活性;(C)L-5-羟基色氨酸延缓肿瘤生长、延长荷瘤小鼠生存时间;(D)L-5-羟基色氨酸联用PD-1抗体的抗肿瘤效应更为显着。

研究进一步评估了 L-5-羟基色氨酸的临床转化意义,发现 L-5-羟基色氨酸联用 PD-1 抗体具有更为显着的抗肿瘤作用。

L-5-羟基色氨酸在部分欧美国家作为膳食补充品用于缓解抑郁症状,鉴于肿瘤病人常伴有较高比例的抑郁并发症状,团队建立慢性社交障碍-肿瘤模型,在此基础上开展药效评价,发现 L-5-羟基色氨酸具有抗肿瘤和抗抑郁双重功效,提示L-5-羟基色氨酸在肿瘤免疫治疗中的独特优势。

总的来说,该项研究揭示了 L-5-羟基色氨酸抑制 PD-L1 表达、激活抗肿瘤免疫的重要作用,表明了 L-5-羟基色氨酸在肿瘤免疫治疗,特别是在伴随发生慢性社交障碍的肿瘤治疗中的潜在临床应用价值。

 

原始出处:

Jing Huang, et al. L-5-hydroxytryptophan promotes antitumor immunity by inhibiting PD-L1 inducible expression. Journal for Immunotherapy of Cancer, 2022.

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    2022-07-01 smartjoy
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    2022-06-30 1209e435m98(暂无昵称)

    学习了,谢谢分享

    0

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    2022-06-30 医鸣惊人

    认真学习了

    0

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    2022-06-30 yangchou

    好文章,谢谢分享。

    0

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