一項(xiàng)新的研究發(fā)現(xiàn)，一種名為反式異丙酸(TVA)的長(zhǎng)鏈脂肪酸，能夠提高CD8+ T細(xì)胞滲透腫瘤并殺死癌細(xì)胞的能力。這種脂肪酸存在于放牧牲畜(如牛和羊)的肉類和乳制品中。這項(xiàng)研究由芝加哥大學(xué)的研究人員進(jìn)行，發(fā)表在《自然》雜志上。

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.
研究顯示，血液中TVA水平較高的患者對(duì)免疫治療的反應(yīng)更好，這表明TVA可能作為一種營養(yǎng)補(bǔ)充劑，作為臨床治療癌癥的輔助方法。

"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.
“有許多研究試圖解密飲食與人類健康之間的聯(lián)系，但由于人們吃的食物種類繁多，要理解其背后的機(jī)制非常困難。但如果我們只關(guān)注食物中的營養(yǎng)物質(zhì)和代謝產(chǎn)物，我們就開始看到它們是如何影響生理和病理的”，芝加哥大學(xué)醫(yī)學(xué)院珍妮特·戴維森·羅利杰出服務(wù)教授、本研究論文的主要作者陳靖博士說。

"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."
“通過重點(diǎn)研究能激活 T 細(xì)胞反應(yīng)的營養(yǎng)素，我們發(fā)現(xiàn)了一種營養(yǎng)素，它能通過激活一條重要的免疫途徑來增強(qiáng)抗腫瘤免疫力。”

尋找激活免疫細(xì)胞的營養(yǎng)素

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.
陳靖團(tuán)隊(duì)專注于研究血液中的代謝物、營養(yǎng)素和其他分子是如何影響癌癥的發(fā)展和對(duì)癌癥治療的反應(yīng)。

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.
兩位博士后研究員范浩和夏思源都是該項(xiàng)最新研究的共同第一作者，他們從大約700種已知的食物來源的代謝物中篩選出了235種具有生物活性的分子，組成了一個(gè)“血液營養(yǎng)物質(zhì)”化合物庫。

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.
研究人員篩選了這個(gè)新化合物庫中的化合物，以了解它們通過激活CD8+ T細(xì)胞來影響抗腫瘤免疫的能力，CD8+ T細(xì)胞是對(duì)殺死癌變或病毒感染的細(xì)胞至關(guān)重要的免疫細(xì)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.
在對(duì)人類和小鼠細(xì)胞進(jìn)行了六種候選分子的評(píng)估后，科學(xué)家們發(fā)現(xiàn)TVA的表現(xiàn)最好。TVA是母乳中最豐富的反式脂肪酸，但人體無法自己合成。只有大約20%的TVA被分解成其他的副產(chǎn)品，剩下的80%在血液中循環(huán)?！斑@意味著它一定還有其他作用，所以我們開始對(duì)其進(jìn)一步研究”，陳靖說。

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.
研究人員隨后用不同腫瘤類型的細(xì)胞和小鼠模型進(jìn)行了一系列實(shí)驗(yàn)。與喂食對(duì)照飲食的小鼠相比，喂食富含TVA的飲食能顯著降低小鼠黑色素瘤和結(jié)腸癌細(xì)胞的腫瘤生長(zhǎng)潛能。TVA 飲食還能增強(qiáng) CD8+ T 細(xì)胞浸潤(rùn)腫瘤的能力。

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.
該團(tuán)隊(duì)還進(jìn)行了一系列的分子和遺傳分析，以了解TVA是如何影響T細(xì)胞的。這些分析包括一種用于監(jiān)測(cè)單鏈DNA轉(zhuǎn)錄的新技術(shù)，稱為酮戊二醛輔助單鏈DNA測(cè)序，或KAS-seq，由芝加哥大學(xué)化學(xué)系約翰·T·威爾遜杰出服務(wù)教授、本研究的另一位主要作者何川博士開發(fā)。

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.
陳靖和何川的實(shí)驗(yàn)室完成的這些實(shí)驗(yàn)顯示TVA能夠使細(xì)胞表面的一種受體失活，這種受體叫做GPR43，通常被腸道菌群產(chǎn)生的短鏈脂肪酸激活。TVA壓制了這些短鏈脂肪酸，激活了一種稱為CREB通路的細(xì)胞信號(hào)過程，CREB通路參與多種功能，包括細(xì)胞的生長(zhǎng)、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.
研究團(tuán)隊(duì)還發(fā)現(xiàn)，CD8+ T 細(xì)胞中的 GPR43 受體被完全清除的小鼠模型也無法提高抗腫瘤能力。

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，研究小組還與芝加哥大學(xué)醫(yī)學(xué)教授、醫(yī)學(xué)博士賈斯汀·克萊恩合作，對(duì)接受CAR-T細(xì)胞免疫療法治療的淋巴瘤患者的血液樣本進(jìn)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.
他們發(fā)現(xiàn)，TVA水平較高的患者往往比TVA水平較低的患者對(duì)治療的反應(yīng)更好。他們還與 醫(yī)學(xué)教授Anjuli Seth Nayak、醫(yī)學(xué)博士溫迪·施托克合作測(cè)試了白血病細(xì)胞系，發(fā)現(xiàn) TVA 增強(qiáng)了免疫療法藥物殺死白血病細(xì)胞的能力。

來源：medicalxperss
編輯：董靜