Linkage of CD8+ T cell exhaustion with high-fat diet-induced tumourigenesis
Linkage of CD8+ T cell exhaustion with high-fat diet-induced tumourigenesis
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DOI：
10.1038/s41598-019-48678-0
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发表时间：
2019-08-22
影响因子：
4.6
通讯作者：
Tobe, Kazuyuki
中科院分区：
文献类型：
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作者：
Kado, Tomonobu;Nawaz, Allah;Tobe, Kazuyuki
肥胖会增加患癌症的风险。已知肥胖受试者体内激素（如雌激素、胰岛素、胰岛素样生长因子和瘦素）水平升高、游离脂肪酸诱导的活性氧产生、肠道微生物群改变和慢性炎症与癌症风险增加有关。然而，肥胖和癌症发展之间联系的潜在机制仍然难以捉摸。本研究表明，在小鼠乳腺癌模型中，高脂肪饮食（HFD）促进肿瘤的发生/进展，并诱导PD-1(-) CD8（+）非耗竭T细胞向PD-1(+) CD8（+）耗竭T细胞的表型转换。PD-1(-) CD8（+）非耗竭T细胞在正常饮食（ND）喂养小鼠的乳腺中占主导地位，而PD-1(+) CD8（+）耗竭T细胞在hfd喂养小鼠的肿瘤中积累。基因表达谱表明，与PD-1(-) CD8(+) T细胞相比，PD-1(+) CD8(+) T细胞表达更高水平的肿瘤营养基因Opn和更低水平的细胞毒性基因Ifng和Gzmb。我们的研究提供了肥胖和癌症之间可能的机制联系。
Obesity increases the risk of cancer. Increased levels of hormones (such as oestrogen, insulin, insulin-like growth factor, and leptin), free fatty acid-induced production of reactive oxygen species, an altered intestinal microbiome and chronic inflammation are known to be associated with an increased cancer risk in obese subjects. However, the mechanism underlying the connection between obesity and cancer development remains elusive. Here, we show that a high-fat diet (HFD) promotes tumour initiation/progression and induces a phenotypic switch from PD-1(-) CD8(+) non-exhausted T cells to PD-1(+) CD8(+) exhausted T cells in a murine breast cancer model. While PD-1(-) CD8(+) non-exhausted T cells predominated in the mammary glands of normal diet (ND)-fed mice, PD-1(+) CD8(+) exhausted T cells accumulated in the developing tumours of HFD-fed mice. Gene expression profiles indicated that PD-1(+) CD8(+) T cells expressed higher levels of the tumour-trophic gene Opn and lower levels of the cytotoxic genes Ifng and Gzmb than did PD-1(-) CD8(+) T cells. Our study provides a possible mechanistic linkage between obesity and cancer.