The findings could help doctors identify cancer patients who would benefit the most from drugs called checkpoint blockade inhibitors.
此些研究發現可能助於醫生們確認，哪些癌症患者最能從，被稱為檢查點阻斷抑制劑藥物獲益。
圖1. 在此種具有一種導致其高度DNA錯配修復缺陷的結腸腫瘤中，T細胞(標記為黑色、綠色及紅色)主要聚集於支持性組織(粉色區域)中，而很少有浸潤的腫瘤細胞(被支持組織包圍的孤立區域)。
In this colon tumor, which has a mutation that gives it a high degree of DNA mismatch repair deficiency, T cells (labeled black, green, and red) have accumulated primarily in the supportive tissues (pink regions), while very few have infiltrated tumor cells (islands surrounded by the supportive tissues).
Cancer drugs known as checkpoint blockade inhibitors have proven effective for some cancer patients. These drugs work by taking the brakes off the body’s T cell response, stimulating those immune cells to destroy tumors.
被通稱為檢查點阻斷抑制劑的癌症藥物已經證實，對某些癌症患者有效。 此些藥物藉由進行，抑制人體的T細胞反應、刺激那些免疫細胞，來消滅腫瘤。
Some studies have shown that these drugs work better in patients whose tumors have a very large number of mutated proteins, which scientists believe is because those proteins offer plentiful targets for T cells to attack. However, for at least 50 percent of patients whose tumors show a high mutational burden, checkpoint blockade inhibitors don’t work at all.
有些研究已經證實，此些藥物在腫瘤具有大量突變蛋白質的患者中，較佳地起作用。科學家們認為，這是因為此些蛋白質為T細胞提供了，大量的攻擊標的。不過，對至少50%腫瘤顯示出高突變負擔的患者而言，檢查點阻斷抑制劑根本不起作用。
A new study from MIT reveals a possible explanation for why that is. In a study of mice, the researchers found that measuring the diversity of mutations within a tumor generated much more accurate predictions of whether the treatment would succeed than measuring the overall number of mutations.
來自美國麻省理工學院的一項新研究揭露了，那是為何的一種可能解釋。在一項小鼠的研究中，此些研究人員發現，是否治療能成功，測量腫瘤內突變的多樣性產生了，比測量突變總數更準確的預測。
If validated in clinical trials, this information could help doctors to better determine which patients will benefit from checkpoint blockade inhibitors.
倘若在臨床試驗中經證實有效，此信息可能有助於醫生們更適切地決定，哪些患者能從檢查點阻斷抑制劑獲益。
“While very powerful in the right settings, immune checkpoint therapies are not effective for all cancer patients. This work makes clear the role of genetic heterogeneity in cancer in determining the effectiveness of these treatments,” says Tyler Jacks, the David H. Koch Professor of Biology and a member of MIT’s Koch Institute for Cancer Research.
美國麻省理工學院科赫癌症研究所成員，兼大衛·H·科赫(David H. Koch)生物學教授，Tyler Jacks宣稱：「儘管免疫檢查點療法，在正確的環境中非常有效力，不過並非對所有癌症患者皆有效。此研究使明確了，癌腫中遺傳之異質性，在決定此些治療有效性的角色。」
Jacks; Peter Westcott, a former MIT postdoc in the Jacks lab who is now an assistant professor at Cold Spring Harbor Laboratory; and Isidro Cortes-Ciriano, a research group leader at EMBL’s European Bioinformatics Institute (EMBL-EBI), are the senior authors of the paper, which appears today in Nature Genetics.
Jacks、Peter Westcott(前麻省理工學院於Jacks實驗室的博士後研究員，目前是冷泉港實驗室助理教授)及一支歐洲分子生物學實驗室(EMBL：European Molecular Biology Laboratory)之歐洲生物信息學研究所(EMBL-EBI)研究團隊的領導人Isidro Cortes-Ciriano，是該篇論文資深撰文人。該論文今天(2023年9月14日)發表於《自然•遺傳學》雜誌。
Across all types of cancer, a small percentage of tumors have what is called a high tumor mutational burden (TMB), meaning they have a very large number of mutations in each cell. A subset of these tumors has defects related to DNA repair, most commonly in a repair system known as DNA mismatch repair.
在所有類型的癌腫中，一小部分具有，被稱為高腫瘤突變負荷(TMB)的腫瘤。這意味著，於每一細胞中，它們具有極大量的突變。這些腫瘤的一部分，具有與DNA修復相關的缺陷。在修復體系中最常見的是，被通稱為DNA錯配修復的缺陷。
Because these tumors have so many mutated proteins, they are believed to be good candidates for immunotherapy treatment, as they offer a plethora of potential targets for T cells to attack.
由於此些腫瘤具有很多突變的蛋白質，因此它們被認為是免疫療法的良好候選物。因為它們為T細胞提供了，大量的潛在攻擊標的。
Over the past few years, the FDA has approved a checkpoint blockade inhibitor called pembrolizumab, which activates T cells by blocking a protein called PD-1, to treat several types of tumors that have a high TMB.
在過去的幾年間，美國食品暨藥物管理局(FDA：Food & Drug Administration) 已經批准一種，藉由阻斷一種被稱為PD-1之蛋白質，來激活T細胞。以治療幾種具有高腫瘤突變負荷(TMB)之腫瘤，被稱為pembrolizumab的檢查點阻斷抑制劑，
However, subsequent studies of patients who received this drug found that more than half of them did not respond well or only showed short-lived responses, even though their tumors had a high mutational burden. The MIT team set out to explore why some patients respond better than others, by designing mouse models that closely mimic the progression of tumors with high TMB.
不過，隨後諸多有關接受此種藥物之患者的研究發現，即使他們的腫瘤具有高的突變負擔，其中半數以上的患者沒有適切作出反應，或僅展現出短暫的反應。該麻省理工學院團隊藉由設計，密切模擬具高TMB腫瘤進展的小鼠模型，來著手探索為何有些患者的反應，比其他患者更佳。
These mouse models carry mutations in genes that drive cancer development in the colon and lung, as well as a mutation that shuts down the DNA mismatch repair system in these tumors as they begin to develop.
此些小鼠模型，在結腸及肺中，驅動癌腫形成的基因中，具有諸多突變及一種，在當它們開始形成時的此些腫瘤中，關閉DNA錯配修復體系的突變。
This causes the tumors to generate many additional mutations. When the researchers treated these mice with checkpoint blockade inhibitors, they were surprised to find that none of them responded well to the treatment.
這導致了，腫瘤產生許多額外的突變。當此些研究人員使用檢查點阻斷抑制劑，來治療此些小鼠時，訝異地發現，無一對此治療適切作出反應。
“We verified that we were very efficiently inactivating the DNA repair pathway, resulting in lots of mutations. The tumors looked just like they look in human cancers, but they were not more infiltrated by T cells, and they were not responding to immunotherapy,” Westcott says.
Westcott宣稱：「我們證實能非常有效地鈍化DNA修復途徑，從而導致大量的突變。此些腫瘤看起來就如同，他們在人類癌腫看到的。不過，它們並沒有遭到T細胞更多的浸潤，而且不對免疫療法作出反應。」
The researchers discovered that this lack of response appears to be the result of a phenomenon known as intratumoral heterogeneity. This means that, while the tumors have many mutations, each cell in the tumor tends to have different mutations than most of the other cells.
此些研究人員發現，缺乏此反應似乎是一種，被稱為腫瘤內異質性現象的結果。這意味著，儘管此腫瘤具有許多突變，不過此腫瘤中的每一細胞，傾向比大多數其他細胞，具有不同的突變。
As a result, each individual cancer mutation is “subclonal,” meaning that it is expressed in a minority of cells. (A “clonal” mutation is one that is expressed in all of the cells.)
因此，每一個體的癌腫突變皆是“亞克隆”的。這意味著，它在少數細胞中，作出表現。(“克隆”突變(無性繁殖系的突變)是一種，在所有細胞中，作出表現的突變。)
In further experiments, the researchers explored what happened as they changed the heterogeneity of lung tumors in mice. They found that in tumors with clonal mutations, checkpoint blockade inhibitors were very effective. However, as they increased the heterogeneity by mixing tumor cells with different mutations, they found that the treatment became less effective.
在諸多進一步的實驗中，此些研究人員探索了，當他們改變於小鼠肺部腫瘤的異質性時，發生了什麼。他們發現，在具有克隆突變的腫瘤中，檢查點阻斷抑制劑，非常有效。不過，當他們藉由混合具有不同突變的腫瘤細胞，來增加異質性時。他們發現，治療變得較無效。
“That shows us that intratumoral heterogeneity is actually confounding the immune response, and you really only get the strong immune checkpoint blockade responses when you have a clonal tumor,” Westcott says.
Westcott宣稱：「那告知我們，腫瘤內異質性實際上擾亂了免疫反應。且當罹患克隆性腫瘤時，才會真正獲得強烈的免疫檢查點阻斷反應。」
It appears that this weak T cell response occurs because the T cells simply don’t see enough of any particular cancerous protein, or antigen, to become activated, the researchers say. When the researchers implanted mice with tumors that contained subclonal levels of proteins that normally induce a strong immune response, the T cells failed to become powerful enough to attack the tumor.
此些研究人員表示，出現這種微弱的T細胞反應，似乎是因為T細胞完全沒有發現，足夠之任何特定癌變的蛋白質或抗原，來發生被激活。當此些研究人員將具有，通常引起強烈免疫反應之亞克隆水平蛋白質的腫瘤植入小鼠體內時，T細胞未能變得強有力，足以攻擊此腫瘤。
“You can have these potently immunogenic tumor cells that otherwise should lead to a profound T cell response, but at this low clonal fraction, they completely go stealth, and the immune system fails to recognize them,” Westcott says. “There’s not enough of the antigen that the T cells recognize, so they’re insufficiently primed and don’t acquire the ability to kill tumor cells.”
Westcott宣稱：「人們能具有此些，在別的狀況下，會導致極度T細胞反應之強有力的免疫原性腫瘤細胞。不過，在此低的克隆比率下，它們完全隱身。因此，免疫系統無法識別它們。沒有足夠T細胞識別的抗原，因此它們不足以被啟動，而無法獲得殺死腫瘤細胞的能耐。」
To see if these findings might extend to human patients, the researchers analyzed data from two small clinical trials of people who had been treated with checkpoint blockade inhibitors for either colorectal or stomach cancer. After analyzing the sequences of the patients’ tumors, they found that patients’ whose tumors were more homogeneous responded better to the treatment.
為了瞭解，此些研究發現是否能擴及人類患者。此些研究人員分析了，來自兩項就結腸直腸癌或胃癌，已經被使用檢查點阻斷抑制劑治療之患者的小型臨床試驗數據。在分析患者腫瘤的序列後，他們發現腫瘤較均勻的患者，對治療的反應較佳。
“Our understanding of cancer is improving all the time, and this translates into better patient outcomes,” Cortes-Ciriano says. “Survival rates following a cancer diagnosis have significantly improved in the past 20 years, thanks to advanced research and clinical studies. We know that each patient’s cancer is different and will require a tailored approach. Personalized medicine must take into account new research that is helping us understand why cancer treatments work for some patients but not all.”
Cortes-Ciriano宣稱：「我們有關癌腫的了解一直改善中，因此這轉化成更佳的患者治療結果。於過去20年間，由於先進的研究及臨床研究，在癌症診斷之後的生存率已經顯著提高。我們知曉，每位患者的癌腫皆不同，因此將需要一種量身定制的方法。個人化的醫療必須將，有助於我們瞭解為何癌症治療對某些患者，但並非所有患者起作用的新研究，納入考量。」
The findings also suggest that treating patients with drugs that block the DNA mismatch repair pathway, in hopes of generating more mutations that T cells could target, may not help and could be harmful, the researchers say. One such drug is now in clinical trials.
此些研究人員表示，這些研究發現也暗示，用阻斷DNA錯配修復途徑的藥物治療患者。在希望產生T細胞能鎖定的更多突變上，可能無助益，且可能有害。目前，一種此類藥物正於臨床試驗中。
“If you try to mutate an existing cancer, where you already have many cancer cells at the primary site and others that may have disseminated throughout the body, you’re going to create a super heterogeneous collection of cancer genomes. And what we showed is that with this high intratumoral heterogeneity, the T cell response is confused and there is absolutely no response to immune checkpoint therapy,” Westcott says.
Westcott宣稱：「倘若試圖使現有的癌腫突變，而在原發部位及其他可能已經擴散到全身的其他部位，已經有許多癌細胞的地方，會產生一處超級異質之癌腫基因體的積聚。因此，我們所證實的是，由於腫瘤內的高度異質性、T細胞反應是混亂。因此，對免疫檢查點治療絕對沒有反應。」
The research was funded by the Koch Institute Support (core) Grant from the U.S. National Cancer Institute, the Howard Hughes Medical Institute, and a Damon Runyon Fellowship Award.
該項研究是由，來自美國國家癌症研究所科赫研究所資助(要點)獎助金、霍華德休斯醫學研究所及達蒙·魯尼恩獎學金所資助。
網址：https://news.mit.edu/2023/study-explains-checkpoint-blockade-inhibitors-0914
翻譯：許東榮
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