圖1. 巨噬細胞(未標記，例如白色箭頭)的一種共同培養物，在對組合療法(EGFR抑制劑及CD47阻斷抗體)作出反應上，不斷咀嚼一群EGFR突變的肺癌細胞(綠色)。

A co-culture of macrophages (unlabeled, white arrow for example) chewing away at a population of EGFR mutant lung cancer cells (green) in response to the combination therapy (EGFR inhibitor and a CD47-blocking antibody).

Through millions of years of evolutionary refinement, the human body has developed a sophisticated surveillance mechanism — the immune system. This intricate network is constantly scanning the body for invaders like bacteria, viruses, and cancer cells. Scientists have long been captivated by its prowess, and, in recent years, they’ve turned their attention towards leveraging its capabilities to fight cancer.

經過數百萬年的演化改進，人體已經發展出一種，複雜的監視機制─免疫系統。此錯綜複雜的網絡不斷掃描身體，尋找如細菌、病毒及癌細胞等入侵物。長久以來，科學家們一直著迷於其卓越的能耐。於最近幾年，他們已經將注意力轉向，利用其諸多能耐，來對抗癌腫。

Whitehead Institute Valhalla Fellow Kipp Weiskopf’s lab investigates how a group of immune cells integral to the body’s innate defense system can slow down, stop, and kill cancer cells. Among them, macrophages — derived from the Greek words “large eaters” — possess a remarkable ability to engulf and digest cancer cells. Yet, too often, cancer cells manage to elude these vigilant patrollers of the immune system and proliferate unchecked.

美國懷特海生物醫學研究所瓦爾哈拉特別研究員，Kipp Weiskopf的實驗室調查研究了一群，人體先天防禦系統不可或缺的免疫細胞，如何能減緩、阻止及殺死癌細胞。其中，巨噬細胞(源自希臘語“大食者”)具有一種，吞噬及消化癌細胞的非凡能耐。不過，癌細胞太頻繁設法規避，這些免疫系統的警戒偵察者，而不受抑制地增殖。

Now, Weiskopf, alongside research technician Kyle Vaccaro and former lab member Juliet Allen, has developed a novel drug screen in collaboration with the Hata Lab at Massachusetts General Hospital (MGH). This screening method aims to identify existing cancer therapies capable of rendering lung cancer cells more vulnerable to attack by macrophages.

目前，Weiskopf與研究技術員Kyle Vaccaro，及前實驗室成員Juliet Allen並肩，已經與馬薩諸塞州總醫院(MGH)的Hata實驗室合作，開發了一種新型藥物篩選法。這種篩選方法旨在，確認現有的癌腫療法，能使得肺癌細胞更容易被巨噬細胞攻擊。

The researchers’ detailed findings, published in The Journal of Clinical Investigation on March 14, reveal that therapies blocking the activity of cancer-driving genes outperform hundreds of FDA-approved drugs in priming lung cancer cells for destruction by macrophages.

此些研究人員發表於(2024年)3月14日《臨床調查研究雜誌》的詳細研究結果顯示，阻斷驅動癌腫之基因活性的療法，在促使肺癌細胞遭巨噬細胞摧毀上，優於數百種美國食品藥物管理局(FDA：Food & Drug Administration)批准的藥物。

“Cancer cells have certain molecules on their surface that protect them from macrophages and targeted therapies help remove some of those barriers, making these cells more vulnerable,” Weiskopf says. “It’s almost like these drugs stress cancer cells in a way that butters them up to make them more palatable for macrophages.”

Weiskopf宣稱：「癌細胞表面有某些保護它們，免於遭受巨噬細胞侵害的分子。而標靶療法有助於移除其中一些障礙，使此些細胞更容易遭受侵害。這幾乎如同這些藥物，以一種阿諛方式，對癌細胞施加壓力，使它們更適合巨噬細胞。」

Despite being the second most common cancer in the U.S., an estimated 53% of lung cancer cases are diagnosed after they have metastasized. This means there’s often limited treatment options and clinicians end up relying on conventional routes like chemotherapy and radiation to kill off rapidly dividing cells. But some tumors respond by growing back faster and more aggressively.

儘管，在美國是第二種最常見的癌症。不過，據估53%的肺癌病例，是在轉移後才被診斷出。這意味著，往往有有限的治療可供選擇，臨床醫生們最終仰賴諸如化學療法及放射療法等，傳統途徑來殺死快速分裂的細胞。不過，有些腫瘤以更快速且更侵犯性地重新長出，作出反應。

Cancer cells often cloak themselves with a signaling protein called CD47. When macrophages encounter cells adorned with this protein, the interaction triggers a "don't eat me" signal via receptors on the macrophages' surface. Radiation and chemotherapy can influence the production and signaling of CD47, at times even enhancing cancer cells’ ability to evade immune system surveillance.

通常，癌細胞用一種被稱為CD47的發信號蛋白，掩護自己。當巨噬細胞遭遇，配載有此種蛋白質的細胞時，相互作用經由巨噬細胞表面的受體，觸發"不要吃我"信號。放射療法及化學療法會影響，CD47的產生及發信號。有時候，甚至增強癌細胞，規避免疫系統監視的能力。

To beat cancer cells at this game of hide-and-seek, scientists have made strides in the past decade in developing antibodies that bind to the CD47 protein, blocking its interaction with macrophage receptors. However, there’s a growing recognition in the field that relying solely on CD47 blockers may not be sufficient for triggering an onslaught by the immune system.

為了在這場捉迷藏遊戲中，擊敗癌細胞。於過去十年間，科學家們在開發與CD47蛋白結合、阻止其與巨噬細胞受體相互作用的抗體方面，已經獲得進展。然而，在該只仰賴CD47阻斷劑的領域中，有一種增強的認同，這可能不足以觸發免疫系統的攻擊。

While working as a Hematology and Oncology Fellow at the Dana-Farber Cancer Institute in Boston, Weiskopf examined one of his first patients — an individual who had recently received a diagnosis of lung cancer. In caring for this patient, he came to appreciate that about 50% of individuals with a new diagnosis of lung cancer have a specific genetic alteration — also called a driver mutation — that prompts cells to divide uncontrollably.

在身為波士頓達納-法伯癌症研究所，血液學及腫瘤學特別研究員，進行研究期間。Weiskopf檢查了其最早的病人之—，一名最近被診斷出患有肺癌的人。在照顧這名患者中，他開始意識到，大約50%新診斷出肺癌的個體，具有一種促使細胞不受控制地分裂之特定基因的改變(也被稱為，一種驅動物突變)。

Could pairing targeted therapies for these genetic alterations with CD47-blocking agents serve as a gateway for enhanced macrophage attack?

將有關此些基因改變的標靶療法與CD47阻斷劑組合起來，能充當增強巨噬細胞攻擊的一種途徑？

To explore this intriguing possibility, researchers in the Weiskopf lab began by investigating macrophage function in response to a common genetic alteration found in lung cancer called the EGFR (epidermal growth factor receptor) gene mutation. This type of alteration leads to the EGFR protein — which is typically involved in cell growth and division — becoming hyperactive.

為了探索此引人感興趣的可能性，Weiskopf實驗室的研究人員們藉由，調查研究巨噬細胞，在對肺癌中所發現，被稱為EGFR(表皮生長因子受體)的一種常見基因改變，作出反應的功能。這類型的改變會導致，通常涉及細胞生長及分裂的EGFR蛋白，變得過度活躍。

They cultured human macrophages alongside EGFR-mutant lung cancer cells. These cancer cells were modified to produce a green fluorescent protein, enabling the scientists to easily monitor their behavior and interaction with macrophages. Then, they introduced FDA-approved cancer drugs to the mixture in order to assess their effectiveness in eliminating cancer cells, in the presence of CD47-blocking antibodies.

他們一起培養了，人類巨噬細胞與EGFR突變的肺癌細胞。此些癌細胞經修飾來產生一種綠色螢光蛋白，使科學家們能輕易監視，它們的行為及與巨噬細胞的相互作用。然後，為了評估它們於存在CD47阻斷抗體的情況下，消除癌細胞的有效性，他們將FDA批准的抗癌藥物，引入此混合物中。

Out of the 800 drugs tested, two targeting the EGFR-mutant protein — erlotinib and gefitinib —stood out: macrophages in these mixtures were markedly better at identifying and killing cancer cells that had been exposed to these drugs.

在測試的800種藥物中，兩種鎖定EGFR突變蛋白的藥物，厄洛替尼與吉非替尼，脫穎而出：於此些混合物中的巨噬細胞，在識別及殺死已經被曝露於此些藥物的癌細胞上，明顯較佳。

“Combining targeted therapies with CD47-blocking antibodies could help activate macrophage antitumor functions even in resistant cell lines,” says Allen. “In the clinic, this would mean that patients with tumors that have become resistant to targeted therapies because of previous treatment could have hope of being treated again with new immunotherapies.”

Allen宣稱：「結合標靶治療與CD47阻斷抗體，即使在具抗藥性細胞系中，可是有助於活化巨噬細胞抗腫瘤功能。在臨床上，這將意味著，由於先前的治療已經對標靶治療具抗藥性的腫瘤患者，可能有希望再次被使用新免疫療法治療。」

To confirm if these findings would be consistent over a longer stretch of time, the Weiskopf lab developed an assay that allowed them to observe macrophage efficacy in killing the cancer cells in different drug combinations for up to two weeks.

為了確認此些研究發現，在較長的一段時間是否會是一致，Weiskopf實驗室開發了一種，使他們得以觀察，於不同藥物組合中，巨噬細胞在殺死癌細胞上，長達兩周的功效。

When the researchers used only one type of drug, the cancer cells often survived, forming small clusters. But when they paired drugs that target the EGFR-mutant protein with antibodies that block CD47 protein, the cancer cells dramatically reduced. These effects were consistent at different drug concentrations.

當此些研究人員只使用一種藥物時，癌細胞往往存活下來，形成小簇。不過，當他們將鎖定EGFR突變蛋白的藥物與阻斷CD47蛋白的抗體結合時，癌細胞急劇減少。在不同藥物濃度下，此些效應是一致的。

Researchers say these findings aren’t limited to EGFR-mutant lung cancer alone — they’ve demonstrated in the study that other types of driver mutations can benefit from the same approach. This is particularly exciting, according to Weiskopf, since pancreatic and gastrointestinal cancers often involve mutations in a gene called KRAS, which fuels the growth and spread of cancer cells.

研究人員們表示，此些研究發現不只限於EGFR突變的肺癌。在該項研究中，他們已經證實，其他類型的驅動物突變，也能從該相同的方法，獲得益處。根據Weiskopf的說法，這特別令人振奮，因為胰臟癌及胃腸道癌，往往涉及一種，刺激癌細胞生長與擴散，被稱為KRAS基因的突變。

The Weiskopf lab is currently investigating whether combining therapies that target the KRAS-mutant protein with CD47 blockers might be effective for combating these aggressive forms of cancer. They’re also working with clinicians at MGH and Dana-Farber to design clinical trials that will take the lab’s research on lung cancer from the bench to patients.

目前，Weiskopf實驗室正在調查研究，結合鎖定KRAS突變蛋白與CD47阻斷劑的療法，供對抗這些具侵犯性癌腫，是否會是有效。

“This collaboration between our group and the Hata lab has been exceptional,” Weiskopf says. “We’ve benefitted tremendously from their clinical expertise and foundational knowledge of targeted therapies for lung cancer, and we’re thrilled to continue building on this synergy to help patients.”

Weiskopf宣稱：「我們團隊與Hata實驗室之間的該項合作，一直非常出色。從他們的臨床專業及肺癌標靶治療的基礎知識，我們已經獲益匪淺。因此我們很高興，持續以此協同作用來協助患者。」

網址：https://wi.mit.edu/news/targeted-therapies-outperform-hundreds-other-drugs-priming-lung-cancer-cells-destruction

翻譯：許東榮