Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
Mol Cell. 2021 Apr 1;81(7):1469-1483.e8. doi: 10.1016/j.molcel.2021.01.038. Epub 2021 Feb 19.
We demonstrate that DNA hypomethylating agent (HMA) treatment can directly modulate the anti-tumor response and effector function of CD8 T cells. In vivo HMA treatment promotes CD8 T cell tumor infiltration and suppresses tumor growth via CD8 T cell-dependent activity. Ex vivo, HMAs enhance primary human CD8 T cell activation markers, effector cytokine production, and anti-tumor cytolytic activity. Epigenomic and transcriptomic profiling shows that HMAs vastly regulate T cell activation-related transcriptional networks, culminating with over-activation of NFATc1 short isoforms. Mechanistically, demethylation of an intragenic CpG island immediately downstream to the 3' UTR of the short isoform was associated with antisense transcription and alternative polyadenylation of NFATc1 short isoforms. High-dimensional single-cell mass cytometry analyses reveal a selective effect of HMAs on a subset of human CD8 T cell subpopulations, increasing both the number and abundance of a granzyme B, perforin effector subpopulation. Overall, our findings support the use of HMAs as a therapeutic strategy to boost anti-tumor immune response.
我们证明，DNA 低甲基化剂（HMA）治疗可以直接调节 CD8 T 细胞的抗肿瘤反应和效应功能。体内 HMA 治疗通过 CD8 T 细胞依赖性活性促进 CD8 T 细胞肿瘤浸润并抑制肿瘤生长。体外，HMAs 增强了原发性人 CD8 T 细胞激活标志物、效应细胞因子产生和抗肿瘤细胞毒性活性。表观基因组和转录组谱分析表明，HMAs 极大地调节 T 细胞激活相关转录网络，最终导致 NFATc1 短亚型的过度激活。从机制上讲，短亚型 3'UTR 下游内含子 CpG 岛的去甲基化与 NFATc1 短亚型的反义转录和可变多聚腺苷酸化有关。高维单细胞质量细胞术分析显示，HMAs 对人类 CD8 T 细胞亚群中的一部分具有选择性作用，增加了 granzyme B、穿孔素效应亚群的数量和丰度。总的来说，我们的研究结果支持将 HMAs 作为一种治疗策略，以增强抗肿瘤免疫反应。
