羟脯氨酸代谢增强 IFN-γ 诱导的 PD-L1 表达并抑制自噬流。
Hydroxyproline metabolism enhances IFN-γ-induced PD-L1 expression and inhibits autophagic flux.
机构信息
Department of Chemistry, the Scripps Research Institute, La Jolla, CA 92037, USA.
Scripps Center for Metabolomics, the Scripps Research Institute, La Jolla, CA 92037, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
出版信息
Cell Chem Biol. 2023 Sep 21;30(9):1115-1134.e10. doi: 10.1016/j.chembiol.2023.06.016. Epub 2023 Jul 18.
The immune checkpoint protein PD-L1 plays critical roles in both immune system homeostasis and tumor progression. Impaired PD-1/PD-L1 function promotes autoimmunity and PD-L1 expression within tumors promotes immune evasion. If and how changes in metabolism or defined metabolites regulate PD-L1 expression is not fully understood. Here, using a metabolomics activity screening-based approach, we have determined that hydroxyproline (Hyp) significantly and directly enhances adaptive (i.e., IFN-γ-induced) PD-L1 expression in multiple relevant myeloid and cancer cell types. Mechanistic studies reveal that Hyp acts as an inhibitor of autophagic flux, which allows it to regulate this negative feedback mechanism, thereby contributing to its overall effect on PD-L1 expression. Due to its prevalence in fibrotic tumors, these findings suggest that hydroxyproline could contribute to the establishment of an immunosuppressive tumor microenvironment and that Hyp metabolism could be targeted to pharmacologically control PD-L1 expression for the treatment of cancer or autoimmune diseases.
免疫检查点蛋白 PD-L1 在免疫系统稳态和肿瘤进展中都发挥着关键作用。PD-1/PD-L1 功能的受损会促进自身免疫，而肿瘤内 PD-L1 的表达则会促进免疫逃逸。代谢或特定代谢物如何以及是否调节 PD-L1 的表达尚不完全清楚。在这里，我们使用基于代谢组学活性筛选的方法，确定羟脯氨酸（Hyp）可显著且直接增强多种相关髓样细胞和癌细胞类型中适应性（即 IFN-γ 诱导）的 PD-L1 表达。机制研究表明，Hyp 作为自噬通量的抑制剂，使其能够调节这种负反馈机制，从而对 PD-L1 的表达产生整体影响。由于其在纤维化肿瘤中的普遍存在，这些发现表明羟脯氨酸可能有助于建立免疫抑制性肿瘤微环境，并且 Hyp 代谢可以作为一种药物靶点来控制 PD-L1 的表达，以治疗癌症或自身免疫性疾病。
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