余建华博士Cell最新发文：一种可以直接击杀癌细胞的免疫细胞

LOS ANGELES -- According to preclinical research published online on Jan. 10 in Cell, one of the world’s premier scientific journals, researchers with City of Hope, one of the largest cancer treatment and research organizations in the United States, have discovered that a type of immune cell in the human body known to be important for allergy and other immune responses can also attack cancer.Furthermore, these cells, called human type 2 innate lymphoid cells (ILC2s), can be expanded outside of the body and applied in larger numbers to overpower a tumor’s defenses and eliminate malignant cells in mouse models with cancer.“The City of Hope team has identified human ILC2 cells as a new member of the cell family capable of directly killing all types of cancers, including blood cancers and solid tumors,” said Jianhua Yu, Ph.D., a professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope and the study’s senior author. “In the future, these cells could be manufactured, preserved by freezing, and then administered to patients. Unlike T cell-based therapies, such as CAR T cells, which necessitate using the patient’s own cells due to their specific characteristics, ILC2s might be sourced from healthy donors, presenting a distinct potential therapeutic approach as an allogeneic and ‘off-the-shelf’ product.”In previous research focused on mouse cells, ILC2s had not consistently shown promise when tested for their cancer-killing abilities.However in the highly translational labs at City of Hope, researchers prioritized the examination of human cells and found that human ILC2s do not work the same as mouse ILC2s.“Typically, mice are reliable models for predicting human immunity, so it was a real surprise in the field to find that human ILC2s function as direct cancer killers while their mouse counterparts do not,” said Michael Caligiuri, M.D., who is a co-senior author of the study and also a City of Hope professor in the Department of Hematology & Hematopoietic Cell Transplantation. “It is remarkable that something has evolved so distinctly in going from mouse to human.”Finding a New FunctionTo test human ILC2s, Yu and the team first isolated the cells from a blood sample. Then, they developed a novel platform, which in four weeks can expand ILC2s 2000-fold from those harvested in the body. They next injected these ex-vivo expanded ILC2s into mice engrafted with human acute myeloid leukemia (AML) or solid tumors, including pancreatic cancer, lung cancer, and glioblastoma. The results showed that this ILC2 population could kill these tumors via a previously unknown cancer-killing mechanism.“One convincing and direct piece of evidence appeared when we placed one ILC2 and one tumor cell directly together and found that the tumor cell died, but the ILC2 cell survived,” explained Yu. “This proves that the ILC2s directly killed the cancer cell in that absence of any other cell.”Yu noted that the ILC2s do not need to come from the cancer patient’s own cells, meaning that there may be the possibility of harvesting and freezing ILC2s from healthy donors for ILC2 treatment options in the future.Investigating Killer CellsYu and Caligiuri have been investigating a different type of cancer killer called natural killer cells, or NK cells, for decades. In fact, Yu is founding director of the Natural Killer Cell Biology Research Program at City of Hope, a national leader in the field.Yu and Caligiuri said ILC2s now represent a new member of the cytotoxic immune effector cell family, alongside NK cells and CD8+ T cells, which help the body fight against cancer. They are excited to see how researchers might be able to harness the collective power of these different killer cells to better fight other diseases as well.Next StepsYu and Caligiuri caution that because they are still in the early days of understanding ILC2s’ cancer-killing functions, many questions remain. However, they plan to continue to work with their collaborators to understand and learn more about human ILC2s now that they know the cells are killers.“We aim to really expand the applications of these findings, potentially beyond cancer treatments,” Yu said, noting that ILC2s may even work against viruses, such as COVID-19. “Additionally, we are working towards translating our discovery into tangible clinical benefits.”The team has already jumped at least one hurdle in getting ILC2s to clinical trials, which is having enough of the product to test. ILC2s are rare in the body, Caligiuri said. The team has a platform to grow them quickly.“You have to be able to expand these cells for human clinical trials and one of the exciting things is that we are on the right track,” Caligiuri said. “At City of Hope, we have the advantage of access to our good manufacturing practices-compliant facilities that can manufacture cells for us and speed discoveries into clinical trials.”The study team also included lead authors Zhenlong Li, Rui Ma, and Hejun Tang from the Yu and Caligiuri labs, as well as David Artis, Ph.D., the Michael Kors Professor of Immunology and director of the Jill Roberts Institute for Inflammatory Bowel Disease Research at Weill Cornell Medicine. The work was supported by grants from the National Institutes of Health and The Leukemia & Lymphoma Society.About City of HopeCity of Hope’s mission is to deliver the cures of tomorrow to the people who need them today. Founded in 1913, City of Hope has grown into one of the largest cancer research and treatment organizations in the U.S. and one of the leading research centers for diabetes and other life-threatening illnesses. City of Hope research has been the basis for numerous breakthrough cancer medicines, as well as human synthetic insulin and monoclonal antibodies. With an independent, National Cancer Institute-designated comprehensive cancer center at its core, City of Hope brings a uniquely integrated model to patients spanning cancer care, research and development, academics and training, and innovation initiatives. City of Hope’s growing national system includes its Los Angeles campus, a network of clinical care locations across Southern California, a new cancer center in Orange County, California, and treatment facilities in Atlanta, Chicago and Phoenix. City of Hope’s affiliated group of organizations includes Translational Genomics Research Institute and AccessHope?. For more information about City of Hope, follow us on Facebook, Twitter, YouTube, Instagram and LinkedIn.

　　

1月10日发表在科学期刊《细胞》(Cell)网站上的一项临床前研究中，“希望之城”(City of Hope)的研究人员发现，人体中一种已知对过敏和其他免疫反应很重要的免疫细胞也可以攻击癌症。

此外，这些被称为人类2型先天淋巴样细胞(ILC2s)的细胞可以在体外扩增，并在患有癌症的小鼠模型中大量应用，战胜肿瘤的防御并消除恶性细胞。

这些研究由希望之城血液学和造血细胞移植系教授余建华博士领导完成。

这一团队已经确定人类ILC2细胞是直接击杀癌细胞家族的新成员，这一家族成员能够直接杀死所有类型的癌症，包括血癌和实体瘤。

该研究的资深作者余建华博士说。“在未来，这些细胞可以被制造出来，通过冷冻保存，然后给病人使用。与基于T细胞的疗法不同，如CAR - T细胞，由于其特定的特性，必须使用患者自己的细胞，ILC2s可能来自健康的供体，作为一种异体和现成的产品，作为一种独特的潜在治疗方法。”

在之前针对小鼠细胞的研究中，ILC2s在测试其癌症杀伤能力时并没有始终显示出希望。然而，在高度转化实验室中，研究人员优先考虑了对人类细胞的检查，结果发现人类ILC2s与小鼠ILC2s的工作方式不同。

“通常情况下，小鼠是预测人类免疫的可靠模型，因此在该领域发现人类ILC2s作为直接癌症杀手的功能是一个真正的惊喜，而它们的小鼠对应物却没有，从小鼠到人类的进化如此明显，这是非常了不起的。”Michael Caligiuri医学博士说。

为了测试人类ILC2s，研究团队首先从血液样本中分离出这些细胞。然后，他们开发了一种新的平台，在四周内可以将体内收获的ILC2s扩增2000倍。接下来，他们将这些体外扩增的ILC2s注射到移植了人类急性髓性白血病(AML)或实体瘤(包括胰腺癌、肺癌和胶质母细胞瘤)的小鼠体内。结果表明，这种ILC2群体可以通过一种以前未知的癌症杀伤机制杀死这些肿瘤。

“当我们将一个ILC2和一个肿瘤细胞直接放在一起，发现肿瘤细胞死亡，但ILC2细胞存活时，一个令人信服的直接证据出现了。这证明了在没有其他细胞的情况下，ILC2s直接杀死了癌细胞。”余教授指出，ILC2s不需要来自癌症患者自己的细胞，这意味着将来有可能从健康供体中收集和冷冻ILC2s，用于ILC2的治疗选择。

几十年来，余教授和Caligiuri一直在研究一种叫做自然杀伤细胞(NK细胞)的不同类型的癌症杀手。事实上，前者是希望之城自然杀伤细胞生物学研究项目的创始主任，该项目在该领域处于全国领先地位。余教授指出，ILC2s现在代表了细胞毒性免疫效应细胞家族的新成员，与NK细胞和CD8+ T细胞一起，帮助身体对抗癌症。他们很高兴地看到研究人员如何能够利用这些不同杀伤细胞的集体力量来更好地对抗其他疾病。

同时研究人员也提醒说，由于他们仍处于了解ILC2s的抗癌功能的早期阶段，因此仍存在许多问题。不过他们计划继续与其它合作者合作，了解更多关于人类ILC2s的信息，现在他们知道这些细胞是杀手。

余教授说:“我们的目标是真正扩大这些发现的应用范围，可能超出癌症治疗范围。”他指出，ILC2s甚至可以对抗病毒，比如COVID-19。“此外，我们正在努力将我们的发现转化为切实的临床效益。”在将ILC2s推向临床试验的过程中，该团队至少已经跨越了一个障碍，那就是有足够的产品可供测试。

ILC2s在体内很少见。团队有一个平台可以让他们快速成长。Caligiuri说:“你必须能够扩大这些细胞用于人体临床试验，令人兴奋的是，我们走在正确的道路上。”“现在，我们的优势是可以使用符合良好生产规范的设备，为我们制造细胞，并将发现加速进入临床试验。”

该研究小组还包括Zhenlong Li, Rui Ma和Hejun Tang等人。