Dietary restriction rejuvenates NK cell antitumor immunity through Eomesdermin

Natural killer (NK) cells primarily govern tumor surveillance and their activation strictly relies on optimal metabolic signals. How NK cell anti-tumor responses adapt to nutritional stress is poorly understood. Here, we show that in mice, dietary restriction (DR) inhibits tumor growth by optimizing NK cell metabolism, which enriched the rejuvenated subset of CD27+CD11b+ NK cells, and improved NK cell activation. These beneficial effects were mainly coordinated by the transcription factor Eomesodermin (Eomes) that was upregulated during DR treatment. Eomes might reverse the differentiation of the rejuvenated NK cells to senescent NK cells by antagonizing T-bet-Zeb2 axis, while it enhanced NK cell function by promoting their chemotaxis and adhesion. In addition, DR also increased Eomes chromatin accessibility to the genes that regulate NK cell chemotaxis and adhesion. In conclusion, Eomes-regulated NK cell anti-tumor immunity is required for tumor control under nutrition restriction.

自然杀伤（NK）细胞主要负责肿瘤监视，其活化严格依赖于最佳代谢信号。目前对于NK细胞抗肿瘤应答如何适应营养应激的机制仍知之甚少。本研究发现，在小鼠模型中，饮食限制（DR）可通过优化NK细胞代谢抑制肿瘤生长：该过程富集了CD27+CD11b+ NK细胞的年轻化亚群，并改善了NK细胞的活化水平。上述有益效应主要由饮食限制处理期间上调的转录因子Eomesodermin（Eomes）协同调控。Eomes可通过拮抗T-bet-Zeb2信号轴，逆转年轻化NK细胞向衰老NK细胞的分化；同时还可通过促进NK细胞的趋化与黏附能力，增强其功能。此外，饮食限制还可提高Eomes在调控NK细胞趋化与黏附的基因位点的染色质可及性。综上，在营养限制条件下，Eomes调控的NK细胞抗肿瘤免疫是肿瘤控制所必需的。