PD-1/PD-L1 monoclonal antibodies exhibit promising therapeutic effectiveness in multiple cancers. However, developing a simple and efficient non-antibody treatment strategy using the PD-1/PD-L1 signaling pathway still remains challenging. In this study, we developed a flow cytometry assay to screen bioactive compounds with PD-L1 inhibitory activity. A total of 409 marine natural products were screened, and sokotrasterol sulfate (SKS) was found to efficiently suppress the IFN-γ-induced PD-L1 expression. SKS sensitizes the tumor cells to antigen-specific T-cell killing in the T cell–tumor cell coculture system. Mechanistically, SKS directly targeted Janus kinase (JAK) to inhibit the downstream activation of signal transducer and activator of transcription (STAT) and the subsequent transcription of PDL1. Our findings highlight the immunological role of SKS that may act as a basis for a potential immunotherapeutic agent.

中文翻译：

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硫酸索科曲甾醇通过抑制 JAK 活性来抑制 IFN-γ 诱导的 PD-L1 表达

PD-1/PD-L1 单克隆抗体在多种癌症中表现出良好的治疗效果。然而，利用 PD-1/PD-L1 信号通路开发简单有效的非抗体治疗策略仍然具有挑战性。在这项研究中，我们开发了一种流式细胞术来筛选具有 PD-L1 抑制活性的生物活性化合物。共筛选了409种海洋天然产物，发现硫酸索科曲甾醇（SKS）可有效抑制IFN-γ诱导的PD-L1表达。 SKS 使肿瘤细胞对 T 细胞-肿瘤细胞共培养系统中抗原特异性 T 细胞杀伤敏感。从机制上来说，SKS直接靶向Janus激酶（JAK）来抑制信号转导子和转录激活子（STAT）的下游激活以及随后的PDL1转录。我们的研究结果强调了 SKS 的免疫学作用，它可以作为潜在免疫治疗剂的基础。