STAT3 Activation-Induced Fatty Acid Oxidation in CD8+ T Effector Cells Is Critical for Obesity-Promoted Breast Tumor Growth
STAT3 Activation-Induced Fatty Acid Oxidation in CD8+ T Effector Cells Is Critical for Obesity-Promoted Breast Tumor Growth
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DOI：
10.1016/j.cmet.2019.10.013
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发表时间：
2020-01-07
期刊：
影响因子：
29
通讯作者：
Yu, Hua
中科院分区：
文献类型：
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作者：
Zhang, Chunyan;Yue, Chanyu;Yu, Hua
虽然肥胖对癌症的发展至关重要，但肥胖如何对抗肿瘤免疫反应产生负面影响在很大程度上仍不清楚。在这里，我们表明，在CD8(+)T效应细胞中，由激活的STAT3驱动的脂肪酸氧化(FAO)增加是肥胖相关乳腺肿瘤进展的关键。切除T细胞STAT3或用FAO抑制剂治疗自发发展为乳腺癌的肥胖小鼠可降低FAO，增加糖酵解和CD8(+)T效应细胞功能，从而抑制乳腺肿瘤的发展。此外，CDS T细胞中的PD-1连接激活STAT3增加FAO，抑制CD8(+)T效应细胞的糖酵解和功能。最后，乳房脂肪细胞和脂肪组织中丰富的瘦素通过激活STAT3-FAO和抑制糖酵解而下调CD8(+)T细胞效应器功能。我们发现由瘦素和PD-1通过STAT3驱动的脂肪酸氧化增加在抑制CD8(+)T效应细胞糖酵解和促进肥胖相关的乳腺肿瘤发生方面发挥了关键作用。
Although obesity is known to be critical for cancer development, how obesity negatively impacts antitumor immune responses remains largely unknown. Here, we show that increased fatty acid oxidation (FAO) driven by activated STAT3 in CD8(+) T effector cells is critical for obesity-associated breast tumor progression. Ablating T cell Stat3 or treatment with an FAO inhibitor in obese mice spontaneously developing breast tumor reduces FAO, increases glycolysis and CD8(+) T effector cell functions, leading to inhibition of breast tumor development. Moreover, PD-1 ligation in CDS' T cells activates STAT3 to increase FAO, inhibiting CD8(+) T effector cell glycolysis and functions. Finally, leptin enriched in mammary adipocytes and fat tissues downregulates CD8(+) T cell effector functions through activating STAT3-FAO and inhibiting glycolysis. We identify a critical role of increased oxidation of fatty acids driven by leptin and PD-1 through STAT3 in inhibiting CD8(+) T effector cell glycolysis and in promoting obesity-associated breast tumorigenesis.