Circadian Regulator CLOCK Drives Immunosuppression in Glioblastoma.
Circadian Regulator CLOCK Drives Immunosuppression in Glioblastoma.
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DOI：
10.1158/2326-6066.cir-21-0559
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发表时间：
2022-06-03
影响因子：
10.1
通讯作者：
Chen, Peiwen
中科院分区：
文献类型：
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作者：
Xuan, Wenjing;Hsu, Wen-Hao;Khan, Fatima;Dunterman, Madeline;Pang, Lizhi;Wainwright, Derek A.;Ahmed, Atique U.;Heimberger, Amy B.;Lesniak, Maciej S.;Chen, Peiwen
肿瘤干细胞与肿瘤微环境(TME)之间的共生相互作用对肿瘤的发展至关重要。然而，胶质母细胞瘤(GBM)这种共生的分子机制仍然是个谜。在这里，我们表明，在胶质瘤干细胞(GSCs)中，昼夜节律运动输出周期Kaput(Clock)及其异二聚体伙伴脑和肌肉Arnt-like 1(BMAL1)驱动GBM中的免疫抑制。综合分析转录组图谱、单细胞RNA测序和TCGA数据集的数据，再加上功能研究，确定豆蛋白(LGMN)是GSCs中CLOCK-BMAL1复合体的直接转录靶标。此外，时钟定向的类嗅球蛋白3(OLFML3)通过低氧诱导因子1-α(HIF1α)信号上调GSCLGMN。因此，LGMN通过上调CD162促进小胶质细胞向GBM TME的渗透，并将渗透的小胶质细胞极化为免疫抑制表型。在GBM小鼠模型中，抑制Clock-OLFML3-HIF1α-LGMN-CD162轴可减少肿瘤内免疫抑制的小胶质细胞，增加CD8+T细胞的侵袭、激活和细胞毒作用，并与抗PD1治疗协同作用。在人的GBM中，时钟调节的LGMN信号与小胶质细胞的丰度和预后不良呈正相关。总之，这些发现揭示了时钟-OLFML3-HIF1α-LGMN轴是控制小胶质细胞生物学和免疫抑制的分子开关，从而揭示了基底膜患者潜在的新的治疗靶点。
The symbiotic interactions between cancer stem cells and the tumor microenvironment (TME) are critical for tumor progression. However, the molecular mechanism underlying this symbiosis in glioblastoma (GBM) remains enigmatic. Here, we show that circadian locomotor output cycles kaput (CLOCK) and its heterodimeric partner brain and muscle ARNT-like 1 (BMAL1) in glioma stem cells (GSCs) drive immunosuppression in GBM. Integrated analyses of the data from transcriptome profiling, single-cell RNA sequencing, and TCGA datasets, coupled with functional studies, identified legumain (LGMN) as a direct transcriptional target of the CLOCK–BMAL1 complex in GSCs. Moreover, CLOCK-directed olfactomedin-like 3 (OLFML3) upregulates LGMN in GSCs via hypoxia-inducible factor 1-alpha (HIF1α) signaling. Consequently, LGMN promotes microglial infiltration into the GBM TME via upregulating CD162 and polarizes infiltrating microglia towards an immune-suppressive phenotype. In GBM mouse models, inhibition of the CLOCK–OLFML3–HIF1α–LGMN–CD162 axis reduces intratumoral immune-suppressive microglia, increases CD8+ T-cell infiltration, activation and cytotoxicity, and synergizes with anti-PD1 therapy. In human GBM, the CLOCK-regulated LGMN signaling correlates positively with microglial abundance and poor prognosis. Together, these findings uncover the CLOCK–OLFML3–HIF1α–LGMN axis as a molecular switch that controls microglial biology and immunosuppression, thus revealing potential new therapeutic targets for GBM patients.