Metabolic Programs of T Cell Tissue Residency Empower Tumor Immunity [Human scRNA-seq]. Metabolic Programs of T Cell Tissue Residency Empower Tumor Immunity [Human scRNA-seq]

Tissue-resident memory CD8 T cells (TRM) offer fast, robust, and long-term protection at sites of re-infection1. Tumor-infiltrating lymphocytes (TIL) with characteristics of TRM maintain enhanced effector functions, predict responses to immunotherapy, and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency could inform new approaches to empower T cell responses in tissues and solid tumors. To systematically define the basis for the metabolic reprogramming supporting TRM differentiation, survival, and function, we leveraged in vivo functional genomics, untargeted metabolomics, and transcriptomics of virus-specific memory CD8 T cell populations. We found that memory CD8 T cells deployed a range of adaptations to tissue residency, including a marked reliance on non-steroidal products of the mevalonate/cholesterol pathway, such as Coenzyme Q (CoQ), driven by increased activity of the transcription factor Srebp2. This metabolic adaptation was most pronounced in the small intestine (SI), where TRM interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional TIL in diverse tumor types in mice and humans. Enforcing CoQ synthesis through Fdft1 deletion or Pdss2 overexpression promoted mitochondrial respiration, memory formation upon viral infection, and enhanced antitumor immunity. In sum, through a systematic exploration of TRM metabolism, we reveal how these programs can be leveraged to empower CD8 T cell memory formation in the context of acute infections and enhance antitumor immunity. Overall design: Single-cell RNA-seq of immune cell from 5 human donors, profiled in the same human study contained in GSE125527.

组织驻留记忆CD8 T细胞（Tissue-resident memory CD8 T cells, TRM）可在再次感染部位提供快速、强效且长期的保护¹。具备TRM特征的肿瘤浸润淋巴细胞（Tumor-infiltrating lymphocytes, TIL）能够维持增强的效应功能，可预测免疫治疗应答，并与更佳的临床预后相关²,³。因此，深入解析赋予细胞驻留能力的代谢策略，可为增强组织及实体瘤内T细胞应答的全新方法提供理论支撑。为系统明确支持TRM分化、存活与功能的代谢重编程基础，我们采用了病毒特异性记忆CD8 T细胞群体的体内功能基因组学、非靶向代谢组学及转录组学分析手段。研究发现，记忆CD8 T细胞针对组织驻留采取了多种适应性机制，其中显著依赖甲羟戊酸/胆固醇通路的非甾体类产物，例如辅酶Q（Coenzyme Q, CoQ），该过程由转录因子Srebp2的活性上调所驱动。这一代谢适应性在小肠（Small intestine, SI）中表现最为显著——此处TRM可与膳食胆固醇接触并维持高度活化状态⁴，同时该适应性也存在于小鼠与人类多种肿瘤类型中的功能性TIL之中。通过Fdft1基因敲除或Pdss2基因过表达强化辅酶Q合成，可促进线粒体呼吸、病毒感染后的记忆细胞形成，并增强抗肿瘤免疫。综上，通过对TRM代谢的系统性探索，我们揭示了此类代谢程序可被用于强化急性感染情境下的CD8 T细胞记忆形成，并增强抗肿瘤免疫。整体实验设计：本研究对5名人类供者的免疫细胞进行单细胞RNA测序，测序数据源自GSE125527中包含的同一人类研究队列。