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Targeting Nuclear LSD1 to Reprogram Cancer Cells and Reinvigorate Exhausted T Cells via a Novel LSD1-EOMES Switch

靶向核 LSD1 通过一种新的 LSD1-EOMES 开关重新编程癌细胞和振兴耗尽的 T 细胞

  • 影响因子:4.7160
  • DOI:10.3389/fimmu.2020.01228
  • 作者列表:"Wen Juan Tu","Wen Juan Tu","Robert D. McCuaig","Robert D. McCuaig","Abel H. Y. Tan","Kristine Hardy","Nabila Seddiki","Nabila Seddiki","Nabila Seddiki","Sayed Ali","Jane E. Dahlstrom","Jane E. Dahlstrom","Jane E. Dahlstrom","Elaine G. Bean","Jenny Dunn","Jade Forwood","Sofia Tsimbalyuk","Kate Smith","Kate Smith","Desmond Yip","Desmond Yip","Laeeq Malik","Laeeq Malik","Thiru Prasanna","Thiru Prasanna","Peter Milburn","Sudha Rao","Sudha Rao
  • 发表时间:2020-06-16
Abstract

Lysine specific demethylase 1 (LSD1) is a key epigenetic eraser enzyme implicated in cancer metastases and recurrence. Nuclear LSD1 phosphorylated at serine 111 (nLSD1p) has been shown to be critical for the development of breast cancer stem cells. Here we show that circulating tumor cells isolated from immunotherapy-resistant metastatic melanoma patients express higher levels of nLSD1p compared to responders, which is associated with co-expression of stem-like, mesenchymal genes. Targeting nLSD1p with selective nLSD1 inhibitors better inhibits the stem-like mesenchymal signature than traditional FAD-specific LSD1 catalytic inhibitors such as GSK2879552. We also demonstrate that nLSD1p is enriched in PD-1+CD8+ T cells from resistant melanoma patients and 4T1 immunotherapy-resistant mice. Targeting the LSD1p nuclear axis induces IFN-γ/TNF-α-expressing CD8+ T cell infiltration into the tumors of 4T1 immunotherapy-resistant mice, which is further augmented by combined immunotherapy. Underpinning these observations, nLSD1p is regulated by the key T cell exhaustion transcription factor EOMES in dysfunctional CD8+ T cells. EOMES co-exists with nLSD1p in PD-1+CD8+ T cells in resistant patients, and nLSD1p regulates EOMES nuclear dynamics via demethylation/acetylation switching of critical EOMES residues. Using novel antibodies to target these post-translational modifications, we show that EOMES demethylation/acetylation is reciprocally expressed in resistant and responder patients. Overall, we show for the first time that dual inhibition of metastatic cancer cells and re-invigoration of the immune system requires LSD1 inhibitors that target the nLSD1p axis.

摘要

赖氨酸特异性去甲基化酶 1 (LSD1) 是一种与癌症转移和复发有关的关键表观遗传橡皮擦酶。核 LSD1 在丝氨酸 111 (nLSD1p) 磷酸化已被证明对乳腺癌干细胞的发展至关重要。在这里,我们发现与应答者相比,从免疫治疗耐药的转移性黑色素瘤患者中分离的循环肿瘤细胞表达更高水平的 nLSD1p,这与干细胞样、间充质基因的共表达相关。与传统的 FAD 特异性 LSD1 催化抑制剂如 gsk2879552 相比,选择性 nLSD1 抑制剂靶向 nLSD1p 更好地抑制茎样间充质信号。我们还证明 nLSD1p 富集在来自耐药黑色素瘤患者和 4T1 免疫治疗耐药小鼠的 PD-1 + CD8 + T 细胞中。靶向 LSD1p 核轴诱导表达 IFN-γ/TNF-α 的 CD8 + T 细胞浸润到 4T1 免疫治疗耐药小鼠的肿瘤中,联合免疫治疗进一步增强。支撑这些观察结果,nLSD1p 在功能失调的 CD8 + T 细胞中受关键的 T 细胞耗竭转录因子 EOMES 调控。EOMES 在耐药患者的 PD-1 + CD8 + T 细胞中与 nLSD1p 共同存在,nLSD1p 通过关键 EOMES 残基的去甲基化/乙酰化转换调节 EOMES 核动力学。使用新型抗体靶向这些翻译后修饰,我们发现 EOMES 去甲基化/乙酰化在耐药和应答患者中相互表达。总体而言,我们首次发现,转移性癌细胞的双重抑制和免疫系统的再激活需要靶向 nLSD1p 轴的 LSD1 抑制剂。

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