Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism
本次带来的是“MCT11 介导的乳酸代谢加强了耗竭 T 细胞的功能障碍”~
Abstarct
CD8+ T cells are critical mediators of antitumor immunity but differentiate into a dysfunctional state, known as T cell exhaustion, after persistent T cell receptor stimulation in the tumor microenvironment (TME). Exhausted T (Tex) cells are characterized by upregulation of coinhibitory molecules and reduced polyfunctionality. T cells in the TME experience an immunosuppressive metabolic environment via reduced levels of nutrients and oxygen and a buildup of lactic acid. Here we show that terminally Tex cells uniquely upregulate Slc16a11, which encodes monocarboxylate transporter 11 (MCT11). Conditional deletion of MCT11 in T cells reduced lactic acid uptake by Tex cells and improved their effector function. Targeting MCT11 with an antibody reduced lactate uptake specifically in Tex cells, which, when used therapeutically in tumor-bearing mice, resulted in reduced tumor growth. These data support a model in which Tex cells upregulate MCT11, rendering them sensitive to lactic acid present at high levels in the TME.
论文导览
Main
在肿瘤微环境(TME)中，\(\rm{CD8^+\ T}\)往往长期且大量地被暴露在\(\rm{TCR}\)被持续刺激的条件下，诱导其耗竭，这是传统上被共同认可的观点。但文章指出，在TME严苛的代谢环境中，肿瘤细胞所释放出的大量代谢末端产物（特别是乳酸）造成的T细胞代谢应激，也会导致Tc的耗竭状态。
Note
溶质载体（SLC）超家族的成员在将大量不同代谢物转运到细胞器或细胞或从细胞中转运出方面起着关键作用。在TME中SLC被肿瘤细胞大量用于分泌代谢产物来抑制免疫细胞。
文章证明，表明肿瘤浸润性\(\rm{T_{ex}}\)细胞高度上调\(\rm{Slc16}\)单羧酸盐转运蛋白（MCT）\(Slc16a11\)（MCT11），从而在肿瘤浸润时增加单羧酸盐（如乳酸）的摄取。缺氧和慢性TCR刺激都可以使其上调。而将其敲掉可以显著改善耗竭Tc的功能。研究者指出，可以通过抗体阻断的方式，帮助TME中耗竭的\(\rm{CD8^+\ Tc}\)恢复其功能。
Tex cells express MCT11, promoting lactic acid metabolism
MCT11 expression is driven by chronic TCR stimulus
MCT11 enforces dysfunction in Tex cells
MCT11 antibody blockade reduces tumor burden in mice
MCT11 blockade promotes CD8+ T cell antitumor immunity
值得学的新东西
这篇文章有许多槽点，首先是没有详细探究乳酸是如何影响Tc的基因表达，促使其耗竭的，文中仅提到采用一个Maker来标定缺氧下的Tc。
第二个是文章最后没有提到这个研究可以开发出一种新药，似乎是因为其发现抗体对MCT11的封闭对耗竭Tc有一定改善作用，但是却不明显？