美国圣裘德儿童研究医院Hongbo Chi研究组发现，cDC1中的SLC38A2和谷氨酰胺信号决定抗肿瘤的免疫力。相关论文于2023年7月5日在线发表在《自然》杂志上。

研究人员将谷氨酰胺确定为细胞间的代谢检查点，它决定了肿瘤与1型常规树突状细胞（cDC1）之间的交流，并在激活细胞毒性T细胞中许可DC1功能。瘤内谷氨酰胺补充通过增强cDC1介导的CD8⁺T细胞免疫来抑制肿瘤生长，并克服对检查点阻断和T细胞介导的免疫疗法的治疗阻力。从机制上讲，肿瘤细胞和cDC1通过转运体SLC38A2竞争谷氨酰胺的摄取，以调控抗肿瘤免疫力。营养物质筛选和综合分析表明，谷氨酰胺是促进CDC1功能的主导氨基酸。此外，通过FLCN的谷氨酰胺信号影响了TFEB的功能。DC中FLCN的缺失以TFEB依赖的方式选择性地损害了cDC1的功能，并通过消除谷氨酰胺补充的抗肿瘤治疗效果来表征SLC38A2的缺失。

这些研究结果确立了肿瘤细胞和cDC1之间谷氨酰胺介导的细胞间代谢交流，支撑了肿瘤免疫规避，并揭示了cDC1中谷氨酰胺的获取和信号传递是DC激活的限制性事件和癌症治疗的潜在靶点。

据介绍，癌细胞通过肿瘤-免疫相互作用逃避T细胞介导的杀伤，其机制尚不十分清楚。DC（特别是cDC1）介导了T细胞的启动和对肿瘤的疗效。DC的功能是由模式识别受体协调的，尽管涉及的其他信号仍未完全确定。营养物质是适应性免疫的新兴媒介，但营养物质是否影响DC的功能或先天性和适应性免疫细胞之间的沟通在很大程度上还没有解决。

附：英文原文

Title: SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity

Author: Guo, Chuansheng, You, Zhiyuan, Shi, Hao, Sun, Yu, Du, Xingrong, Palacios, Gustavo, Guy, Cliff, Yuan, Sujing, Chapman, Nicole M., Lim, Seon Ah, Sun, Xiang, Saravia, Jordy, Rankin, Sherri, Dhungana, Yogesh, Chi, Hongbo

Issue&Volume: 2023-07-05

Abstract: Cancer cells evade T cell-mediated killing through tumour–immune interactions whose mechanisms are not well understood1,2. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1s), mediate T cell priming and therapeutic efficacy against tumours3. DC functions are orchestrated by pattern recognition receptors3,4,5, although other signals involved remain incompletely defined. Nutrients are emerging mediators of adaptive immunity6,7,8, but whether nutrients affect DC function or communication between innate and adaptive immune cells is largely unresolved. Here we establish glutamine as an intercellular metabolic checkpoint that dictates tumour–cDC1 crosstalk and licenses cDC1 function in activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8+ T cell immunity, and overcomes therapeutic resistance to checkpoint blockade and T cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1s compete for glutamine uptake via the transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid in promoting cDC1 function. Further, glutamine signalling via FLCN impinges on TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner and phenocopies SLC38A2 deficiency by eliminating the anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1s that underpins tumour immune evasion, and reveal glutamine acquisition and signalling in cDC1s as limiting events for DC activation and putative targets for cancer treatment.

DOI: 10.1038/s41586-023-06299-8

Source: https://www.nature.com/articles/s41586-023-06299-8