最新突破！“治愈癌症”更进一步！| 双语精选

长久以来，癌症一直是许多医学人员致力攻克的难点，癌症的高死亡率也让许多人“闻癌色变”。

2022年4月22日，基因泰克公司（Genetech）的研究人员在 Science 期刊发表了一篇研究论文，发现了癌细胞抵御T细胞攻击的方式，为肿瘤免疫治疗提出了一种新的有潜力的治疗靶点。

具体是怎么一回事？我们一起看文章。

Genentech-led team uncovers how cancer cells resist T-cell attack in potential boon to immunotherapy

基因泰克带领的团队发现了癌细胞抵御T细胞攻击的方式，为免疫疗法带来新希望

Cancer cells deploy various tactics to avoid being targeted and killed by the immune system. A research team led by Roche’s Genentech has now identified one such method that cancer cells use to resist T-cell assault by repairing damage.

癌细胞善于运用多种方法，避免被免疫系统盯住并杀死。罗氏集团旗下的基因泰克公司带领的研究团队近来确定了一种癌细胞通过修复创伤抵御T细胞攻击的方法。

To destroy their targets, cancer-killing T cells known as cytotoxic T lymphocytes (CTLs) secrete the toxin perforin to form little pores in the target cells’ surface. Another type of toxin called granzymes are delivered directly into the cells through those portals to induce cell death.

为了杀死癌细胞，被称为T细胞的细胞毒性T淋巴细胞 (CTL) 会释放毒素——穿孔素，在靶细胞表面形成小孔。而另一种毒素——颗粒酶则通过这些小孔直接进入靶细胞，并诱导细胞死亡。

By using high-res imaging in live cells, the Genentech-led team found that the membrane damage caused by perforin could trigger a repair response. The tumor cells could recruit endosomal sorting complexes required for transport (ESCRT) proteins to remove the lesions, thereby preventing granzymes from entering, the team showed in a new study published in Science.

通过在活细胞中使用高分辨率成像，基因泰克带领的团队发现，穿孔素造成的膜创伤会触发修复反应。该团队在《科学》杂志上发表的一项新研究中显示，肿瘤细胞可以募集一种称为运输所需内体分选复合物（ESCRT）的蛋白来清除损伤，从而阻止颗粒酶进入。

“[The finding] really speaks to the general issue that cancer cells are likely to have multiple ways of avoiding killing, one or all of which may contribute to inherent insensitivity to therapy,” Ira Mellman, Ph.D., Genentech’s vice president of cancer immunology, said in an email to Fierce Biotech Research.

“（这一发现）确实说明了一个普遍的问题，即癌细胞可能有多种逃避被杀死的方式，而其中一种或全部方式可能正是癌症对治疗固有不敏感性的原因。”基因泰克公司癌症免疫学副总裁艾拉·梅尔曼（Ira Mellman）博士在给Fierce Biotech Research的一封电子邮件中说道。

Mellman and Genentech postdoctoral fellow Alex Ritter, Ph.D., are co-corresponding authors of the new study. Others from Howard Hughes Medical Institute and Australia’s Peter MacCallum Cancer Centre also participated.

梅尔曼博士和基因泰克公司的博士后研究员亚历克斯·里特（Alex Ritter）博士为这项新研究的共同通讯作者。该研究的参与者还包括来自霍华德·休斯医学研究所和澳大利亚彼得·麦卡勒姆癌症中心的研究人员。

ESCRT proteins are known as repairers of small wounds and pores in the membrane caused by other sources such as bacterial toxins and mechanical wounding.

有研究表明，ESCRT蛋白可以修复由细菌毒素和机械损伤等其它原因造成质膜的微小创伤和孔洞。

In live-cell imaging, the team showed that cancer cells’ recruitment of ESCRT protein matched injury by T cells in terms of both the timing and location. Upon assault by killer T cells, the ESCRT proteins accurately accumulated at cytolytic synapses, sites where T cells bind target cells and initiate the killing process.

在活细胞成像中，该团队发现，癌细胞对ESCRT蛋白的募集在时间和位置上都与T细胞造成的损伤一致。在被杀伤性T细胞攻击时，ESCRT蛋白精确地聚集在细胞溶解突触处，即T细胞与靶细胞结合并启动杀伤过程的地方。

▲ T细胞

To further validate the finding, the researchers inhibited ESCRT by using CRISPR to remove a gene coding for an ESCRT protein or dialing up the expression of a genetic piece that impairs ESCRT function. Compared with control cells, cancer cells with ESCRT inhibited were more efficiently killed off by T cells, the team reported.

为了进一步验证这一发现，研究人员通过使用CRISPR敲除ESCRT蛋白的基因编码或增强损害ESCRT功能的基因片段的表达来抑制ESCRT。研究小组报告称，与对照组细胞相比，ESCRT受到抑制的癌细胞更能被T细胞有效杀死。

The research offers new insights into how tumor cells escape being targeted by the immune system and could be helpful in improving the efficacy of cancer immunotherapies such as PD-1/L1 checkpoint inhibitors and CAR-T cell therapies, which rely on immune cells to go after cancer.

该研究对了解肿瘤细胞如何避免被免疫系统发现带来了新观点，并可能有助于提高癌症免疫疗法的疗效，如依靠免疫细胞发现癌症的PD-1/L1检查点抑制剂和CAR-T细胞疗法。

Genentech is currently exploring the combination of its anti-TIGIT antibody tiragolumab with PD-L1 inhibitor Tecentriq and has shown promising midstage clinical results in non-small cell lung cancer. TIGIT is a receptor overexpressed on some T cells that can dampen their cancer-killing activity.

基因泰克目前正在将其抗TIGIT抗体tiragolumab与PD-L1抑制剂Tecentriq相结合进行研究，并已在中期临床上针对非小细胞肺癌取得了显著效果。TIGIT是一种在一些T细胞上过表达的受体，可抑制T细胞杀伤癌细胞的活性。

On the ever-growing list of proposals to enhance immuno-oncology agents, researchers at MD Anderson Cancer Center recently showed that antihistamines, by targeting histamine receptor H1, could reverse immune suppression and buoy responses to checkpoint inhibitors. A team from the Karolinska Institute and U.S biotech Aileron Therapeutics previously found that blocking the MDM2 protein could reactivate the p53 protein, known as the “guardian of the genome,” thereby boosting various aspects of an antitumor immune response.

德州大学安德森癌症中心的研究人员最近表示，在不断增加的免疫肿瘤学药物的建议清单中，抗组胺药通过找到组胺H1受体，可以逆转免疫抑制并促进对检查点抑制剂的应答。卡罗林斯卡学院和美国生物技术公司艾勒朗制药（Aileron Therapeutics）的一支团队此前发现，阻断MDM2蛋白可以重新激活被称为“基因组卫士”的P53蛋白，从而促进抗肿瘤免疫应答。

Although ESCRT inhibition represents a promising strategy to enhance T cells’ attack on tumor cells, it isn’t immediately clear how to achieve that with a drug, Mellman noted, because ESCRT proteins are also essential for cell division.

梅尔曼博士指出，尽管抑制ESCRT为增强T细胞对肿瘤细胞的攻击带来了希望，但目前尚不清楚如何通过药物实现这一点，因为ESCRT蛋白对细胞分裂也是至关重要的。

“But I would predict that the complexity of the system, in this case, will yield a ‘way in’ to the problem,” Mellman said. He suspected that some members of the family may be needed for membrane repair but not for other functions.

“但我预测，在这种情况下，系统的复杂性将为这个问题找到解决的‘入口’”，梅尔曼博士说。他怀疑这个蛋白质家族的某些蛋白质可能只是进行膜修复所需要的，而不会对其他功能产生影响。

“Certainly, the ESCRT inhibition experiments, at least in cell culture, produce pretty dramatic increases in sensitivity to CTL attack. So, we will be evaluating this pathway further,” Mellman said.

“当然，ESCRT抑制实验，至少在细胞培养中，已大大提升了其对CTL攻击的敏感性。因此我们会进一步评估这一途径，”梅尔曼博士说。

In an accompanying commentary, University of Maryland cell biologist Norma Andrews, Ph.D., suggests that future studies also explore the roles of other cellular processes in repairing membrane wounds. “This is important because a comprehensive understanding of the plasma membrane resealing mechanism may reveal steps amenable to therapeutic intervention.”

马里兰大学细胞生物学家诺玛·安德鲁斯（Norma Andrews）博士在一篇附带的评论中建议，未来的研究还应探索其他细胞过程在修复膜损伤中的作用。“这一点很重要，因为全面了解质膜再封闭机制可能有助于发现可用于治疗干预的步骤。”

译者：Julie

英文来源：Fierce Biotech

*对应译文由译介翻译团队完成，仅供参考，不当之处欢迎大家在评论区讨论！转载请注明来源！

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