Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, BC, Canada.
Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, BC, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada.
Cell Rep. 2019 Apr 9;27(2):502-513.e5. doi: 10.1016/j.celrep.2019.03.037.
Autophagy is a cell survival process essential for the regulation of immune responses to infections. However, the role of T cell autophagy in anti-tumor immunity is less clear. Here, we demonstrate a cell-autonomous role for autophagy in the regulation of CD8 T-cell-mediated control of tumors. Mice deficient for the essential autophagy genes Atg5, Atg14, or Atg16L1 display a dramatic impairment in the growth of syngeneic tumors. Moreover, T cells lacking Atg5 have a profound shift to an effector memory phenotype and produce greater amounts of interferon-γ (IFN-γ) and tumor necrosis factor α (TNF-α). Mechanistically, Atg5 CD8 T cells exhibit enhanced glucose metabolism that results in alterations in histone methylation, increases in H3K4me3 density, and transcriptional upregulation of both metabolic and effector target genes. Nonetheless, glucose restriction is sufficient to suppress Atg5-dependent increases in effector function. Thus, autophagy-dependent changes in CD8 T cell metabolism directly regulate anti-tumor immunity.
自噬是一种对于调控免疫细胞对于感染的反应至关重要的细胞存活过程。然而，T 细胞自噬在抗肿瘤免疫中的作用尚不清楚。在这里，我们证明了自噬在调控 CD8 T 细胞介导的肿瘤控制中具有细胞自主性作用。缺乏必需自噬基因 Atg5、Atg14 或 Atg16L1 的小鼠在同种异体肿瘤的生长中表现出明显的缺陷。此外，缺乏 Atg5 的 T 细胞向效应记忆表型发生深刻转变，并产生更多的干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）。从机制上讲，Atg5 CD8 T 细胞表现出增强的葡萄糖代谢，导致组蛋白甲基化的改变、H3K4me3 密度增加，以及代谢和效应靶基因的转录上调。然而，葡萄糖限制足以抑制 Atg5 依赖性效应功能的增加。因此，CD8 T 细胞代谢中依赖自噬的变化直接调节抗肿瘤免疫。
