《自然》杂志：研究发现牛羊肉中营养素可提高癌症治疗效果

一项新的研究发现，一种名为反式异丙酸(TVA)的长链脂肪酸，能够提高CD8+ T细胞渗透肿瘤并杀死癌细胞的能力。这种脂肪酸存在于放牧牲畜(如牛和羊)的肉类和乳制品中。这项研究由芝加哥大学的研究人员进行，发表在《自然》杂志上。

The study shows that patients with higher levels of TVA circulating in the blood responded better to immunotherapy, suggesting that it could have potential as a nutritional supplement to complement clinical treatments for cancer.
研究显示，血液中TVA水平较高的患者对免疫治疗的反应更好，这表明TVA可能作为一种营养补充剂，作为临床治疗癌症的辅助方法。

"There are many studies trying to decipher the link between diet and human health, and it's very difficult to understand the underlying mechanisms because of the wide variety of foods people eat. But if we focus on just the nutrients and metabolites derived from food, we begin to see how they influence physiology and pathology," said Jing Chen, Ph.D., the Janet Davison Rowley Distinguished Service Professor of Medicine at UChicago and one of the senior authors of the study.
“有许多研究试图解密饮食与人类健康之间的联系，但由于人们吃的食物种类繁多，要理解其背后的机制非常困难。但如果我们只关注食物中的营养物质和代谢产物，我们就开始看到它们是如何影响生理和病理的”，芝加哥大学医学院珍妮特·戴维森·罗利杰出服务教授、本研究论文的主要作者陈靖博士说。

"By focusing on nutrients that can activate T cell responses, we found one that actually enhances anti-tumor immunity by activating an important immune pathway."
“通过重点研究能激活 T 细胞反应的营养素，我们发现了一种营养素，它能通过激活一条重要的免疫途径来增强抗肿瘤免疫力。”

Chen's lab focuses on understanding how metabolites, nutrients and other molecules circulating in the blood influence the development of cancer and response to cancer treatments.
陈靖团队专注于研究血液中的代谢物、营养素和其他分子是如何影响癌症的发展和对癌症治疗的反应。

For the new study, two postdoctoral fellows, Hao Fan, Ph.D. and Siyuan Xia, Ph.D., both co-first authors, started with a database of around 700 known metabolites that come from food and assembled a "blood nutrient" compound library consisting of 235 bioactive molecules derived from nutrients.
两位博士后研究员范浩和夏思源都是该项最新研究的共同第一作者，他们从大约700种已知的食物来源的代谢物中筛选出了235种具有生物活性的分子，组成了一个“血液营养物质”化合物库。

They screened the compounds in this new library for their ability to influence anti-tumor immunity by activating CD8+ T cells, a group of immune cells critical for killing cancerous or virally-infected cells.
研究人员筛选了这个新化合物库中的化合物，以了解它们通过激活CD8+ T细胞来影响抗肿瘤免疫的能力，CD8+ T细胞是对杀死癌变或病毒感染的细胞至关重要的免疫细胞。

After the scientists evaluated the top six candidates in both human and mouse cells, they saw that TVA performed the best. TVA is the most abundant trans fatty acid present in human milk, but the body cannot produce it on its own. Only about 20% of TVA is broken down into other byproducts, leaving 80% circulating in the blood. "That means there must be something else it does, so we started working on it more," Chen said.
在对人类和小鼠细胞进行了六种候选分子的评估后，科学家们发现TVA的表现最好。TVA是母乳中最丰富的反式脂肪酸，但人体无法自己合成。只有大约20%的TVA被分解成其他的副产品，剩下的80%在血液中循环。“这意味着它一定还有其他作用，所以我们开始对其进一步研究”，陈靖说。

The researchers then conducted a series of experiments with cells and mouse models of diverse tumor types. Feeding mice a diet enriched with TVA significantly reduced the tumor growth potential of melanoma and colon cancer cells compared to mice fed a control diet. The TVA diet also enhanced the ability of CD8+ T cells to infiltrate tumors.
研究人员随后用不同肿瘤类型的细胞和小鼠模型进行了一系列实验。与喂食对照饮食的小鼠相比，喂食富含TVA的饮食能显著降低小鼠黑色素瘤和结肠癌细胞的肿瘤生长潜能。TVA 饮食还能增强 CD8+ T 细胞浸润肿瘤的能力。

The team also performed a series of molecular and genetic analyses to understand how TVA was affecting the T cells. These included a new technique for monitoring transcription of single-stranded DNA called kethoxal-assisted single-stranded DNA sequencing, or KAS-seq, developed by Chuan He, Ph.D., the John T. Wilson Distinguished Service Professor of Chemistry at UChicago and another senior author of the study.
该团队还进行了一系列的分子和遗传分析，以了解TVA是如何影响T细胞的。这些分析包括一种用于监测单链DNA转录的新技术，称为酮戊二醛辅助单链DNA测序，或KAS-seq，由芝加哥大学化学系约翰·T·威尔逊杰出服务教授、本研究的另一位主要作者何川博士开发。

These additional assays, done by both the Chen and He labs, showed that TVA inactivates a receptor on the cell surface called GPR43 which is usually activated by short-chain fatty acids often produced by gut microbiota. TVA overpowers these short-chain fatty acids and activates a cellular signaling process known as the CREB pathway, which is involved in a variety of functions including cellular growth, survival, and differentiation.
陈靖和何川的实验室完成的这些实验显示TVA能够使细胞表面的一种受体失活，这种受体叫做GPR43，通常被肠道菌群产生的短链脂肪酸激活。TVA压制了这些短链脂肪酸，激活了一种称为CREB通路的细胞信号过程，CREB通路参与多种功能，包括细胞的生长、存活和分化。

The team also showed that mouse models where the GPR43 receptor was exclusively removed from CD8+ T cells also lacked their improved tumor fighting ability.
研究团队还发现，CD8+ T 细胞中的 GPR43 受体被完全清除的小鼠模型也无法提高抗肿瘤能力。

Finally, the team also worked with Justin Kline, MD, Professor of Medicine at UChicago, to analyze blood samples taken from patients undergoing CAR-T cell immunotherapy treatment for lymphoma.
最后，研究小组还与芝加哥大学医学教授、医学博士贾斯汀·克莱恩合作，对接受CAR-T细胞免疫疗法治疗的淋巴瘤患者的血液样本进行了分析。

They saw that patients with higher levels of TVA tended to respond to treatment better than those with lower levels. They also tested cell lines from leukemia by working with Wendy Stock, MD, the Anjuli Seth Nayak Professor of Medicine, and saw that TVA enhanced the ability of an immunotherapy drug to kill leukemia cells.
他们发现，TVA水平较高的患者往往比TVA水平较低的患者对治疗的反应更好。他们还与 医学教授Anjuli Seth Nayak、医学博士温迪·施托克合作测试了白血病细胞系，发现 TVA 增强了免疫疗法药物杀死白血病细胞的能力。