Exosomal circZNF451 restrains anti-PD1 treatment in lung adenocarcinoma via polarizing macrophages by complexing with TRIM56 and FXR1.
Exosomal circZNF451 restrains anti-PD1 treatment in lung adenocarcinoma via polarizing macrophages by complexing with TRIM56 and FXR1.
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外泌体circZNF 451通过与TRIM 56和FXR1复合使巨噬细胞极化来抑制肺腺癌中的抗PD 1治疗。
DOI：
10.1186/s13046-022-02505-z
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发表时间：
2022-10-08
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尽管对少数晚期肺腺癌（LUAD）患者的治疗取得了成功，但在大多数LUAD患者中发现了抗程序性死亡1（PD 1）耐药性。在此，我们旨在揭示外泌体环状RNA（circRNA）在PD 1阻断难治性LUAD中的潜在作用。进行circRNA测序和qRT-PCR以确定随后用抗PD 1治疗的LUAD患者中的外泌体circRNA水平。然后，利用RNA pulldown、RNA免疫沉淀、质谱、染色质免疫沉淀、荧光素酶报告基因分析、流式细胞术、RNA测序以及体内外模型，揭示circZNF 451在LUAD抗PD 1治疗抵抗中的生物学功能和潜在机制。circRNA测序和qRT-PCR鉴定了与PD 1阻断治疗后部分缓解（PR）的患者相比，患有进展性疾病（PD）的LUAD患者的外泌体circZNF 451的上调。此外，circZNF 451升高与LUAD患者预后不良相关。此外，外泌体circZNF 451被证明诱导巨噬细胞中的抗炎表型和细胞毒性CD 8 + T细胞的耗竭，并增强TRIM 56介导的FXR 1降解以激活巨噬细胞中的ELF 4-IRF 4途径。通过转基因小鼠，发现敲除巨噬细胞中的ELF 4可以挽救具有高水平外泌体circZNF 451的肿瘤中的免疫治疗功效。外泌体circZNF 451通过经由FXR 1-ELF 4-IRF 4轴诱导巨噬细胞极化来重塑肿瘤免疫微环境，并且是用于预测LUAD中PD 1阻断敏感性的新型生物标志物。在线版本包含补充材料，可通过10.1186/s13046-022-02505-z获得。
Although success was achieved in the therapy for a minority of advanced lung adenocarcinoma (LUAD) patients, anti-programmed death 1 (PD1) resistance was found in most LUAD patients. Here, we aimed to uncover a potential role of exosomal circular RNAs (circRNAs) in LUAD refractory to PD1 blockade. circRNA sequencing and qRT-PCR were performed to determine the level of exosomal circRNAs in LUAD patients subsequently treated with anti-PD1. Then, the RNA pulldown, RNA immunoprecipitation, mass spectrometry, chromatin immunoprecipitation, luciferase reporter assays, flow cytometry, RNA sequencing, and in vitro and in vivo models were used to uncover the biological functions and underlying mechanism of circZNF451 in LUAD anti-PD1 treatment resistance. circRNA sequencing and qRT-PCR identified the up-regulation of exosomal circZNF451 from LUAD patients with progressive disease (PD) compared to those with partial remission (PR) after PD1 blockade therapy. Furthermore, elevated circZNF451 was revealed to be associated with poor prognosis of LUAD patients. Additionally, exosomal circZNF451 was demonstrated to induce an anti-inflammatory phenotype in macrophages and exhaustion of cytotoxic CD8+ T cells, and enhanced TRIM56-mediated degradation of FXR1 to activate the ELF4–IRF4 pathway in macrophages. By transgenic mice, knockout of ELF4 in macrophages was found to rescue immunotherapy efficacy in tumors with high level of exosomal circZNF451. Exosomal circZNF451 reshapes the tumor immune microenvironment by inducing macrophages polarization via the FXR1- ELF4–IRF4 axis and is a novel biomarker for predicting the sensitivity of PD1 blockade in LUAD. The online version contains supplementary material available at 10.1186/s13046-022-02505-z.
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影响因子：
10.1
作者：
Gabrilovich DI
通讯作者：
Gabrilovich DI
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
DOI：
10.1038/s41577-019-0218-4
发表时间：
2020-01
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Kalbasi A;Ribas A
通讯作者：
Ribas A
影响因子：
30.5
作者：
Satoh, Takashi;Takeuchi, Osamu;Akira, Shizuo
通讯作者：
Akira, Shizuo
影响因子：
16
作者：
Rybak-Wolf, Agnieszka;Stottmeister, Christin;Rajewsky, Nikolaus
通讯作者：
Rajewsky, Nikolaus