A new study finds an unexpected role for hepatocytes in anticancer immunity.

一項新研究發現，肝臟細胞在抗癌免疫方面，一種意想不到的角色。

When harnessing immune cells to fight cancer, researchers traditionally focused on T cells or natural killer cells circulating through the blood. However, the critical cell types coordinating this immune response may be hidden in unexpected organs. For the past five years, Gregory Beatty, an oncologist at the University of Pennsylvania, has suspected one organ in particular: the liver.

當利用免疫細胞來對抗癌腫時，傳統上研究人員們著重於，透過血液循環的T細胞或天然的殺手細胞。然而，協調此免疫反應的關鍵性細胞類型，或許隱藏於意想不到的器官中。過去五年來，美國賓州大學腫瘤學家，Gregory Beatty一直懷疑，一種器官：肝臟。

Hepatocytes, the workhorses of the liver, are known for filtering blood toxins and metabolizing nutrients, but they also release proteins that can signal to far-off immune cells.

肝細胞是肝臟的主運作物，以過濾血液毒素及代謝營養素聞名。不過，它們也釋出能向遠處免疫細胞，發出信號的蛋白質。

Some of these proteins make up a phenomenon known as the acute phase reaction: a tsunami of inflammatory molecules that course through the bloodstream in the hours after an infection to spur an immune response. Despite this core function of hepatocytes, “most immunologists do not think of the liver,” said Cliona O’Farrelly, a researcher at Trinity College Dublin who has separately studied the role of the liver in immunity.

其中一些蛋白質構成一種，被通稱為急性期反應的可觀察事象：在感染後數小時，大量透過血流流動，來刺激免疫反應的發炎分子。儘管肝細胞的此核心功能，不過英國都柏林三一學院，一直獨立研究肝臟，在免疫方面之角色的研究員，Cliona O’Farrelly宣稱：「大多數免疫學家，並未考慮到肝臟。」

Evidence suggests that the liver is a potent player in cancer immunology, as liver metastases and high levels of certain liver-related immune proteins reduce patients’ responses to immunotherapy.

證據表明，在癌腫免疫學方面，肝臟是一個強有力的好手。因為，肝轉移(從身體某部位開始擴散到肝臟的癌腫)及高水平之某些肝臟相關的免疫蛋白，降低了病患對免疫療法的反應。

 In a new study published in Nature Immunology, Beatty and his team further underscored the importance of the liver in anticancer immunity by showing that activation of a specific signaling pathway in hepatocytes reduced T cell infiltration into tumors outside the liver.

在發表於《自然•免疫學》期刊的一項新研究中，Beatty及其團隊藉由證實，於肝細胞中，一種特定發信號途徑的活化，減少了T細胞滲透到肝臟外部腫瘤中。這進一步強調了，肝臟在抗癌免疫方面的重要性。

This, in turn, led to worse cancer outcomes. These findings highlight the potential of using the liver to control the immune system’s effective attack on a tumor.

“The liver is a new immune checkpoint for us to think about,” Beatty said. “Finding ways to target that therapeutically holds a lot of promise.”

依序，這導致了更糟糕的癌腫結果。這些研究發現強調了，利用肝臟來控制免疫系統，對腫瘤之有效攻擊的潛力。Beatty宣稱：「肝臟是適合我們思考的新免疫檢查點。找尋治療上鎖定的方法，擁有很大的指望。」

Beatty’s team previously investigated patterns of immune molecule levels in hepatocytes during cancer, but they still wondered how these liver changes might parallel changes in the tumor itself that have consequences for long-term outcomes. For example, tumors with many T cells typically have better outcomes after treatment.

先前，Beatty的團隊調查研究了，在癌腫期間之肝細胞中，免疫分子水平的模式。不過，他們仍感疑惑，此些肝臟諸變化，如何能與腫瘤本身中，對長期結果有諸多影響的變化，平行發生。例如，具有許多T細胞的腫瘤，在治療後，通常具有較佳的結果。

In the new study, the researchers compared mice with varying numbers of T cells in their pancreatic tumors. They found that the livers of animals with high T cell infiltration in the tumors had lower levels of the immune transcription factor signal transducer and activator of transcription (STAT3).

在該項新研究中，此些研究人員比較了，於胰臟腫瘤中，具有不同T細胞數的小鼠。他們發現，在腫瘤中，具有高T細胞滲入的動物肝臟中，有較低的免疫轉錄因子訊號轉導物及轉錄激活物(STAT3)水平。

Moreover, when they measured the acute phase protein serum amyloid A (SAA) that is typically produced in the liver, its levels were lower in mice with high T cell infiltration. In a previous study, the researchers showed that these molecules promote liver metastases.

此外，當他們測量，通常於肝臟中，產生之急性期血清澱粉樣蛋白A(SAA) 時，其水平在具有高T細胞滲入的小鼠中較低。在一項先前的研究中，此些研究人員證實，這些分子促進了肝轉移。

To further elucidate the liver’s role in this immune pathway, the team genetically reduced the production of these molecules specifically in hepatocytes. “Suddenly there were all these T cells in the tumors,” Beatty said. “It was remarkable.” With additional genetic experiments, the team determined that SAA signaled to the toll-like receptor 2 protein on another immune cell type that directs T cells to penetrate the tumors.

為了進一步闡明，肝臟在此免疫途徑中的角色。該團隊遺傳上具體減少了此些分子，於肝細胞中產生。Beatty宣稱：「突然間，腫瘤中有了所有此些T細胞，這是值得注意的。」隨著額外的遺傳實驗，該研究團隊確定了，SAA向在另一型，引導T細胞穿透腫瘤之免疫細胞上的toll樣受體2蛋白，發信號。

Motivated by these findings, Beatty wanted to know whether reduced levels of SAA could drive anticancer responses and survival. He partnered with Vinod Balachandran, an oncologist at Memorial Sloan Kettering Cancer Center, to genetically reduce SAA in mice with pancreatic tumors with few T cells.

受此些研究發現的激發，Beatty想知曉，降低的SAA水平，是否能驅使抗癌反應及持續生存。他與斯隆凱特琳紀念癌症中心的腫瘤學家， Vinod Balachandran合作，以進行遺傳上減少，於罹患胰腺腫瘤、具有很少T細胞之小鼠中的SAA。

Compared to mice with normal SAA, the genetically modified animals had more T cells in their tumors and longer survival after surgery to remove the tumors. When the team looked at data from 25 people with pancreatic cancer, they found a similar pattern; those who survived longer after surgery had lower SAA levels than those who survived short-term.

與具有正常SAA的小鼠進行了相比，此些遺傳上經改造的動物，於其腫瘤中，有較多的T細胞。且在手術切除腫瘤後，持續存活的時間較長。當該團隊檢視25名胰腺癌病患的數據時，他們發現了類似的模式；手術後存活時間較長病患的SAA水平，低於那些短期存活病患。

“Even though there's huge amounts written about SAA, we really don't actually know what its primary role is,” said O’Farrelly, who was not involved in the study. “For this paper to give a whole other different role to SAA is utterly fascinating.”

未參與該項研究的O’Farrelly宣稱：「即使有大量攸關SAA的記述。不過，實際上我們並不知曉，什麼是其主要角色。就此論文而言，賦予SAA一個完全不同的角色，是十足吸引人的。」

Although Beatty focused on pancreatic cancer and melanoma for this work, previous research from his group showed the importance of SAA in lung and colorectal cancers, suggesting that this protein could play a role in many types of cancer.

有關該項研究，雖然Beatt著重於胰腺癌及黑色素瘤。來自其團隊先前的研究證實了，SAA在肺癌及結腸直腸癌中的重要性。表明此蛋白質，在諸多類型的癌腫中，可能扮演一種角色。

Andreas Bergthaler, an immunologist at the Center for Molecular Medicine in Vienna who was not involved in the research, believes that the study adds an important piece to the puzzle of the liver’s immune capabilities. “It's a great example of delineating organ crosstalk,” he said.

奧地利維也納分子醫學中心，未涉及該項研究的免疫學家，Andreas Bergthaler認為，該項研究為肝臟免疫能力之謎，增添了一項重要片段。他宣稱：「這是描述，器官串擾的一個極佳例子。」

However, Bergthaler knows from his own experience linking liver-produced proteins to antiviral T cell responses that it can be hard to nail down the operative proteins among the dozens involved in a given pathway.  He hopes that future studies will show that interfering with the SAA protein or other elements of the STAT3 pathway slows cancer progression.

不過，來自其自身將肝臟產生的蛋白質與抗病毒之T細胞反應聯繫起來的經驗，Bergthaler知道，會是難以確定，在數十個涉及特定途徑中，起作用的蛋白質。

Finding these targets is Beatty’s priority. Moreover, he recognizes that other conditions, such as cardiovascular disease and diabetes, can cause liver inflammation, so he hopes to study how those conditions may influence anticancer immunity.

找尋此些目標是Beatty的重點。此外，他自認為，諸如心血管疾病及糖尿病等，其他疾病也會導致肝臟炎症。因此，他希望研究那些疾病，如何能影響抗癌免疫力。

“If we could come up with strategies that intervene in liver inflammation, we could change [the] outcomes for patients that are undergoing surgery,” he said. “That could be a game changer for many patients.”

他宣稱：「倘若我們能想出，干預肝臟發炎的策略。我們可能改變，正在接受外科手術病患的結果。」

網址：https://www.the-scientist.com/liver-proteins-keep-t-cells-out-of-tumors-71952

翻譯：許東榮