Dabrafenib Alters MDSC Differentiation and Function by Activation of GCN2.
Dabrafenib Alters MDSC Differentiation and Function by Activation of GCN2.
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Dabrafenib 通过激活 GCN2 改变 MDSC 分化和功能。
DOI：
10.1158/2767-9764.crc-23-0376
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
McGaha,TracyL
中科院分区：
文献类型：
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作者：
Ciudad,MTeresa;Quevedo,Rene;Lamorte,Sara;Jin,Robbie;Nzirorera,Nadine;Koritzinsky,Marianne;McGaha,TracyL
靶向治疗对抗癌免疫反应的影响还知之甚少。据报道，BRAF抑制剂达普拉非尼可以激活整合应激反应(ISR)激酶GCN2，其治疗作用部分归因于GCN2的激活。由于ISR信号是髓系来源的抑制细胞(MDSC)发育和功能的关键组成部分，我们检测了达普拉非尼对MDSC分化和抑制活性的影响。我们的数据显示，达普拉非尼减弱了MDSC抑制T细胞活性的能力，这与GCN2依赖阻止单核祖细胞向多形核(PMN)-MDSC的转变和导致PMN-MDSC的增殖停止有关。转录图谱显示，达普拉非尼驱动的GCN2激活改变了MDSCs的代谢特征，增强了氧化呼吸，并减弱了PMN发育所需的转录程序。此外，我们观察到与PMN发育途径相关的转录网络的广泛下调，以及由Atf5、Mafg和Zbtb7a驱动的转录调控蛋白活性的增加。这种转录程序的改变是PMN-MDSC发育停滞的基础，使未成熟的MDSC发育向单核细胞系细胞倾斜。在体内，我们观察到达普拉非尼治疗的荷瘤小鼠的PMN-MDSC显著减少，这表明达普拉非尼在肿瘤免疫渗透中对MDSC群体产生了系统和局部的影响。因此，我们的数据揭示了管理MDSC发育计划的转录网络，以及GCN2应激信号对肿瘤固有免疫格局的影响，为达普拉非尼的潜在有益非靶点效应提供了新的见解。意义癌症靶向治疗的一个重要但鲜为人知的方面是对抗肿瘤免疫反应的影响。本文表明，达普拉非尼激活GCN2激酶的非靶点效应在体内外影响MDSC的发育和降低PMN-MDSC的功能。这对于我们理解这种BRAF抑制剂如何影响肿瘤生长并提供新的治疗靶点和组合可能性具有重要意义。
The effect of targeted therapeutics on anticancer immune responses is poorly understood. The BRAF inhibitor dabrafenib has been reported to activate the integrated stress response (ISR) kinase GCN2, and the therapeutic effect has been partially attributed to GCN2 activation. Because ISR signaling is a key component of myeloid-derived suppressor cell (MDSC) development and function, we measured the effect of dabrafenib on MDSC differentiation and suppressive activity. Our data showed that dabrafenib attenuated MDSC ability to suppress T-cell activity, which was associated with a GCN2-dependent block of the transition from monocytic progenitor to polymorphonuclear (PMN)-MDSCs and proliferative arrest resulting in PMN-MDSC loss. Transcriptional profiling revealed that dabrafenib-driven GCN2 activation altered metabolic features in MDSCs enhancing oxidative respiration, and attenuated transcriptional programs required for PMN development. Moreover, we observed a broad downregulation of transcriptional networks associated with PMN developmental pathways, and increased activity of transcriptional regulons driven byAtf5,Mafg, andZbtb7a. This transcriptional program alteration underlies the basis for PMN-MDSC developmental arrest, skewing immature MDSC development toward monocytic lineage cells.In vivo, we observed a pronounced reduction in PMN-MDSCs in dabrafenib-treated tumor-bearing mice suggesting that dabrafenib impacts MDSC populations systemically and locally, in the tumor immune infiltrate. Thus, our data reveal transcriptional networks that govern MDSC developmental programs, and the impact of GCN2 stress signaling on the innate immune landscape in tumors, providing novel insight into potentially beneficial off-target effects of dabrafenib.SignificanceAn important, but poorly understood, aspect of targeted therapeutics for cancer is the effect on antitumor immune responses. This article shows that off-target effects of dabrafenib activating the kinase GCN2 impact MDSC development and function reducing PMN-MDSCsin vitroandin vivo. This has important implications for our understanding of how this BRAF inhibitor impacts tumor growth and provides novel therapeutic target and combination possibilities.