Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK.
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
Nat Commun. 2020 Jul 17;11(1):3588. doi: 10.1038/s41467-020-17339-6.
Tumors subvert immune cell function to evade immune responses, yet the complex mechanisms driving immune evasion remain poorly understood. Here we show that tumors induce de novo steroidogenesis in T lymphocytes to evade anti-tumor immunity. Using a transgenic steroidogenesis-reporter mouse line we identify and characterize de novo steroidogenic immune cells, defining the global gene expression identity of these steroid-producing immune cells and gene regulatory networks by using single-cell transcriptomics. Genetic ablation of T cell steroidogenesis restricts primary tumor growth and metastatic dissemination in mouse models. Steroidogenic T cells dysregulate anti-tumor immunity, and inhibition of the steroidogenesis pathway is sufficient to restore anti-tumor immunity. This study demonstrates T cell de novo steroidogenesis as a mechanism of anti-tumor immunosuppression and a potential druggable target.
肿瘤颠覆免疫细胞功能以逃避免疫反应，但驱动免疫逃逸的复杂机制仍知之甚少。在这里，我们表明肿瘤诱导 T 淋巴细胞中新生的类固醇生成以逃避抗肿瘤免疫。使用转基因类固醇生成报告小鼠系，我们鉴定和表征了新生的类固醇生成免疫细胞，并通过单细胞转录组学定义了这些产生类固醇的免疫细胞的全局基因表达特征和基因调控网络。T 细胞类固醇生成的遗传消融限制了小鼠模型中的原发性肿瘤生长和转移扩散。类固醇生成 T 细胞失调抗肿瘤免疫，抑制类固醇生成途径足以恢复抗肿瘤免疫。这项研究表明 T 细胞新生的类固醇生成是抗肿瘤免疫抑制的一种机制，也是一个潜在的可药物治疗的靶点。
