Chen Yueyue, Shen Xuqing, Tang Yingying, Weng Yawen, Yang Wenjuan, Liu Mingzhu, Xu Dapeng, Shi Juanjuan, Yang Xiaotong, Yu Feier, Xu Junyi, Zhang Zhengyan, Lu Ping, Sun Yongwei, Xue Jing, Niu Ningning
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cancer Lett. 2023 May 28;562:216153. doi: 10.1016/j.canlet.2023.216153. Epub 2023 Apr 5.
IFNγ signaling is mainly mediated through the activation of the canonical JAK-STAT signaling pathway, transcription factors, and epigenetic modifications. The activation of IFNγ signaling pathway may provide a novel option for tumor immunotherapy, but the outcomes remain controversial. In fact, recent studies suggest that the resistance to IFNγ-dependent immunotherapies is commonly derived from the tumor cell-intrinsic heterogeneity, the molecular mechanism of which remains elusive. Therefore, elucidating the tumor cell-intrinsic heterogeneity in response to IFNγ would be beneficial to improve the efficacy of immunotherapy. Here, we first delineated the epigenetic redistribution and transcriptome alteration in response to IFNγ stimulation, and demonstrated that ectopic gain of H3K4me3 and H3K27Ac at the promoter region mainly contributed to the enhancement of IFNγ-mediated transcriptional activity of interferon-stimulated genes (ISGs). Furthermore, we found that the cellular heterogeneity of PD-L1 expression in response to IFNγ was mainly attributed to cell-intrinsic H3K27me3 levels. Enhancement of H3K27me3 by GSK-J4 limited PD-L1 tumor growth by salvaging the intratumoral cytotoxicity of CD8 T cells, which may provide therapeutic strategies to overcome immune escape and resistance to IFNγ-based immunotherapies in pancreatic cancer.
IFNγ信号主要通过经典的JAK-STAT信号通路、转录因子和表观遗传修饰的激活来介导。IFNγ信号通路的激活可能为肿瘤免疫治疗提供一种新的选择，但结果仍存在争议。事实上，最近的研究表明，对IFNγ依赖性免疫疗法的耐药性通常源于肿瘤细胞内在的异质性，其分子机制仍不清楚。因此，阐明肿瘤细胞对IFNγ反应的内在异质性将有助于提高免疫治疗的疗效。在这里，我们首先描绘了对IFNγ刺激的表观遗传重分布和转录组改变，并证明启动子区域H3K4me3和H3K27Ac的异位增加主要有助于增强IFNγ介导的干扰素刺激基因（ISGs）的转录活性。此外，我们发现响应IFNγ时PD-L1表达的细胞异质性主要归因于细胞内在的H3K27me3水平。GSK-J4增强H3K27me3通过挽救肿瘤内CD8 T细胞的细胞毒性来限制PD-L1肿瘤生长，这可能为克服胰腺癌中的免疫逃逸和对基于IFNγ的免疫疗法的耐药性提供治疗策略。
