抗癌新突破：重振衰竭的免疫细胞

编辑翻译：奇奇

译文校对：菁菁

文献在2021年1月最新的美国医学学术期刊《癌症免疫疗法杂志》（ Journal for Immuno Therapy of Cancer）首次刊发。德克萨斯大学西南医学中心的研究人员发现，衰竭的免疫细胞可以通过基因工程改造重新获得抗癌能力。

德克萨斯大学西南医学中心（UTSW）的研究人员主导的一项新研究表明，消除单个基因可以让衰竭的抗癌免疫细胞CD8+T细胞发生转变，从而能够继续与恶性肿瘤对抗。该发现于本周通过线上发表，刊登在《癌症免疫疗法杂志》(Journal for Immuno Therapy of Cancer)上，它为利用人体免疫系统对抗癌症提供了一种新方法。

2017年，美国食品药品监督管理局（FDA）批准了涉及嵌合抗原受体T（CAR-T）细胞的治疗方法，该细胞由被称为T细胞的免疫细胞组成，这些细胞被改造后可以识别癌细胞表面的特殊蛋白质。当这些细胞通过输液递送时，它们会对癌细胞产生针对性的免疫反应。

UTSW内科和免疫学副教授Venuprasad Poojary博士说，CAR-T细胞已成功用于治疗白血病和淋巴瘤等血液癌，通常效果显著。但是，这种疗法在抵抗实体瘤方面收效甚微，比如在结肠、乳腺和肺部出现的实体瘤。

Poojary解释说，当CAR-T细胞进入这些实体瘤时，它们会迅速功能异常并失去抗癌能力。这些抗癌细胞（包括PD1和Tim3）表面蛋白质增加，使得它们无法产生常规的免疫刺激分子，例如干扰素-γ和肿瘤坏死因子，这种状态称为“精疲力竭”。Poojary还补充说，找到一种防止CAR-T细胞失效的方法已成为癌症研究的重要目标。

为此，他和他的同事们搜集已发表研究，对比了生效和衰竭的T细胞中的基因活性。研究人员很快地将注意力集中到Cbl-b基因上，该基因在衰竭的细胞中更加活跃或其活性更强。

在一个结肠癌小鼠模型中，Poojary和他的同事证实了Cbl-b在进入实体瘤的T细胞中被激活。这些细胞不仅失去了对抗肿瘤的能力，而且还产生了一组特有的细胞表面蛋白，这导致其无法产生或传递衰竭的免疫分子。然而，当科学家们使用基因编辑工具CRISPR删除这些细胞中的Cbl-b时，它们恢复了抗癌能力，并且失去了其他衰竭特征。

为证明Cbl-b在T细胞衰竭中的关键作用，研究人员对限制了Cbl-b基因的小鼠进行实验。当他们将癌细胞移植到这些动物中时，这些细胞生长出的肿瘤明显小于具有活性Cbl-b基因的小鼠。

Poojary补充说，进一步的实验表明，去除Cbl-b还可以专门阻止CAR-T细胞的衰竭。他和他的团队删除了CAR-T细胞中的Cbl-b，这些细胞改造后可以识别癌胚抗原（癌胚抗原是一种在结肠癌中通常过度表达的细胞表面蛋白），这种细胞有效地抵抗了携带肿瘤的小鼠的癌症，显著延长了它们的生存时间。然而，具有Cbl-b功能的CAR-T细胞很快变得无用，在动物模型中几乎没有抗肿瘤作用。

Poojary和他的同事正在努力探索Cbl-b引起T细胞衰竭的分子机制。他指出，一旦研究人员更好地理解了这种机制，那么使用CAR-T细胞有效治疗实体瘤，就可以像本次通过基因编辑去除Cbl-b一样简单。

Poojary说：“在使用CAR-T细胞对抗实体瘤这一方向，我们的研究实现了重大的突破。这可以克服目前一些癌症免疫治疗策略的局限性。”

英文原文

Reviving Exhausted Immune Cells to Fight Cancer

Eliminating a single gene can turn exhausted cancer-fighting immune cells known as CD8+ T cells back into refreshed soldiers that can continue to battle malignant tumors, a new study led by UT Southwestern researchers suggests. The findings, published online this week in the Journal for Immuno Therapy of Cancer, could offer a new way to harness the body's immune system to attack cancers.

In 2017, the Food and Drug Administration approved treatments involving chimeric antigen receptor T (CAR-T) cells, which consist of immune cells known as T cells that have been engineered to recognize specific proteins on the surface of cancer cells. When these cells are delivered by infusion, they mount a targeted immune response against cancer cells.

CAR-T cells have been successfully used to treat blood cancers such as leukemia and lymphoma, often with dramatic results, says Venuprasad Poojary, Ph.D., associate professor of internal medicine and immunology at UTSW. However, these treatments have had little success against solid tumors, such as those that develop in the colon, breast, and lung.

When CAR-T cells enter these solid tumors, Poojary explains, they quickly become dysfunctional and lose their cancer-fighting abilities. This state, referred to as "exhaustion," is accompanied by the addition of proteins, including PD1 and Tim3 on their surfaces and an inability to produce their usual immune-inciting molecules, such as Interferon-gamma and tumor necrosis factor. Finding a way to prevent CAR-T cells from becoming exhausted has become a significant goal in cancer research, Poojary adds.

Toward this end, he and his colleagues scoured published research comparing gene activity in working and exhausted T cells. The researchers quickly zeroed in on a gene called Cbl-b, which is more active, or upregulated, in exhausted cells.

Poojary and his colleagues confirmed that Cbl-b was activated in T cells that infiltrated tumors in a mouse model of colon cancer. Not only did these cells lose their tumor-fighting abilities, but they also developed a characteristic set of cell surface proteins and inability to produce, or express, immune molecules characteristic of exhaustion. However, when the scientists used the gene editing tool CRISPR to delete Cbl-b in these cells, they regained their cancer-fighting capacity and lost other exhaustion features.

Adding evidence to Cbl-b's key role in T cell exhaustion, the researchers used genetically altered mice in which this gene was shut down. When they transplanted cancer cells into these animals, the cells grew tumors markedly smaller than in cancer cells of mice with active Cbl-b.

Further experiments showed that removing Cbl-b also prevented exhaustion specifically in CAR-T cells, Poojary adds. When he and his team deleted this gene from CAR-T cells engineered to recognize carcinoembryonic antigen, a cell surface protein commonly overexpressed in colon cancer, the cells effectively fought cancer in mice bearing these tumors—significantly extending their survival. However, CAR-T cells with functioning Cbl-b quickly became useless, providing little anti-tumor effect in animal models.

Poojary and his colleagues are working to understand the molecular mechanisms behind how Cbl-b causes T cell exhaustion. Once researchers better understand this mechanism, he notes, using CAR-T cells to effectively treat solid tumors could be as simple as genetically engineering them without Cbl-b.

"Our study is a major step forward in developing CAR-T cells to fight solid tumors," Poojary says. "This could overcome the limitations of some current immunotherapy strategies for cancer."

参考文献

Jitendra Kumar et al. Deletion of Cbl-b inhibits CD8+ T-cell exhaustion and promotes CAR T-cell function, Journal for Immuno Therapy of Cancer (2021). DOI: 10.1136/jitc-2020-001688

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