GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment
GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment
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DOI：
10.1126/sciimmunol.aax8189
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发表时间：
2019-12-01
影响因子：
24.8
通讯作者：
McGaha, Tracy L.
中科院分区：
文献类型：
--
作者：
Halaby, Marie Jo;Hezaveh, Kebria;McGaha, Tracy L.
一般控制非阻遏蛋白2（GCN 2）是一个环境传感器，控制转录和翻译，以响应营养的可用性。虽然GCN 2是免疫肿瘤学的假定治疗靶点，但其在形成对肿瘤的免疫应答中的作用知之甚少。在这里，我们使用了大量的细胞计数，转录组学和转录因子结合分析，以确定功能的影响GCN 2对骨髓表型和免疫反应的黑色素瘤。我们发现GCN 2的髓系缺失驱动肿瘤相关巨噬细胞和髓源性抑制细胞（MDSC）表型的转变，从而促进抗肿瘤免疫。飞行时间质谱仪（CyTOF）和单细胞RNA测序显示，这是由于免疫微环境的变化，巨噬细胞和MDSC的促炎活化增加以及肿瘤内CD 8（+）T细胞中干扰素-γ的表达。从机制上讲，GCN 2通过促进转录因子CREB-2/ATF 4的翻译增加来改变骨髓功能，CREB-2/ATF 4是小鼠和人类巨噬细胞和MDSC成熟和极化所必需的，而通过小干扰RNA敲低靶向Atf 4可以减少肿瘤生长。最后，对皮肤黑色素瘤患者的分析表明，GCN 2依赖性转录特征与巨噬细胞极化、T细胞浸润和总生存率相关。因此，这些数据揭示了肿瘤对骨髓GCN 2信号的先前未知的依赖性，以保护免受免疫攻击。
General control nonderepressible 2 (GCN2) is an environmental sensor controlling transcription and translation in response to nutrient availability. Although GCN2 is a putative therapeutic target for immuno-oncology, its role in shaping the immune response to tumors is poorly understood. Here, we used mass cytometry, transcriptomics, and transcription factor-binding analysis to determine the functional impact of GCN2 on the myeloid phenotype and immune responses in melanoma. We found that myeloid-lineage deletion of GCN2 drives a shift in the phenotype of tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs) that promotes antitumor immunity. Time-of-flight mass cytometry (CyTOF) and single-cell RNA sequencing showed that this was due to changes in the immune microenvironment with increased proinflammatory activation of macrophages and MDSCs and interferon-gamma expression in intratumoral CD8(+) T cells. Mechanistically, GCN2 altered myeloid function by promoting increased translation of the transcription factor CREB-2/ATF4, which was required for maturation and polarization of macrophages and MDSCs in both mice and humans, whereas targeting Atf4 by small interfering RNA knockdown reduced tumor growth. Last, analysis of patients with cutaneous melanoma showed that GCN2-dependent transcriptional signatures correlated with macrophage polarization, T cell infiltrates, and overall survival. Thus, these data reveal a previously unknown dependence of tumors on myeloid GCN2 signals for protection from immune attack.