Treg Cells Promote the SREBP1-Dependent Metabolic Fitness of Tumor-Promoting Macrophages via Repression of CD8+ T Cell-Derived Interferon-γ.,Immunity

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Treg Cells Promote the SREBP1-Dependent Metabolic Fitness of Tumor-Promoting Macrophages via Repression of CD8+ T Cell-Derived Interferon-γ.
Immunity ( IF 25.5 ) Pub Date : 2019-07-23 , DOI: 10.1016/j.immuni.2019.06.017
Chang Liu ₁ , Maria Chikina ₂ , Rahul Deshpande ₃ , Ashley V Menk ₄ , Ting Wang ₅ , Tracy Tabib ₆ , Erin A Brunazzi ₁ , Kate M Vignali ₁ , Ming Sun ₇ , Donna B Stolz ₇ , Robert A Lafyatis ₆ , Wei Chen ₅ , Greg M Delgoffe ₄ , Creg J Workman ₁ , Stacy G Wendell ₈ , Dario A A Vignali ₄

Affiliation

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Health Sciences Metabolomics and Lipidomics Core, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA.
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Health Sciences Metabolomics and Lipidomics Core, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmacology and Chemical Biology, Clinical Translational Science Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Regulatory T (Treg) cells are crucial for immune homeostasis, but they also contribute to tumor immune evasion by promoting a suppressive tumor microenvironment (TME). Mice with Treg cell-restricted Neuropilin-1 deficiency show tumor resistance while maintaining peripheral immune homeostasis, thereby providing a controlled system to interrogate the impact of intratumoral Treg cells on the TME. Using this and other genetic models, we showed that Treg cells shaped the transcriptional landscape across multiple tumor-infiltrating immune cell types. Treg cells suppressed CD8+ T cell secretion of interferon-γ (IFNγ), which would otherwise block the activation of sterol regulatory element-binding protein 1 (SREBP1)-mediated fatty acid synthesis in immunosuppressive (M2-like) tumor-associated macrophages (TAMs). Thus, Treg cells indirectly but selectively sustained M2-like TAM metabolic fitness, mitochondrial integrity, and survival. SREBP1 inhibition augmented the efficacy of immune checkpoint blockade, suggesting that targeting Treg cells or their modulation of lipid metabolism in M2-like TAMs could improve cancer immunotherapy.

中文翻译：

Treg细胞通过抑制CD8 + T细胞衍生的干扰素-γ来促进肿瘤促进巨噬细胞的SREBP1依赖性代谢适应性。

调节性T（Treg）细胞对于免疫稳态至关重要，但它们也可通过促进抑制性肿瘤微环境（TME）来促进肿瘤的免疫逃逸。具有Treg细胞限制型Neuropilin-1缺陷的小鼠在维持外周免疫稳态的同时显示出抗肿瘤性，从而提供了一种可控制的系统来询问肿瘤内Treg细胞对TME的影响。使用该基因模型和其他遗传模型，我们显示Treg细胞在多种肿瘤浸润免疫细胞类型中塑造了转录景观。Treg细胞抑制CD8 + T细胞分泌的干扰素-γ（IFNγ），否则将阻止免疫抑制性（M2样）肿瘤相关巨噬细胞（TAMs）中固醇调节元件结合蛋白1（SREBP1）介导的脂肪酸合成的激活。）。因此，Treg细胞间接但选择性地维持M2样TAM代谢适应性，线粒体完整性和存活率。SREBP1抑制增强了免疫检查点封锁的功效，这表明在M2样TAM中靶向Treg细胞或调节脂质代谢可以改善癌症免疫治疗。

更新日期：2019-07-23

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