Amping up T cells to target cancer

增强 T 细胞以靶向癌症

Vaccines that turn the body’s immune system against tumors have shown promise in clinical trials, and a handful have been FDA approved for certain cancers. In many patients, however, these vaccines don’t stimulate enough of a response, and the approach some researchers have taken to strengthening it—delivering the vaccine along with immune-stimulating molecules called cytokines—can cause severe side effects. 旨在调动人体免疫系统对抗肿瘤的疫苗在临床试验中已展现出前景，其中少数已获得美国食品药品监督管理局（FDA）批准用于治疗特定癌症。然而，在许多患者身上，这些疫苗无法激发足够的免疫反应；而一些研究人员为增强效果所采取的方法——即在接种疫苗的同时递送被称为“细胞因子”的免疫刺激分子——往往会引发严重的副作用。

Now MIT chemical engineer Daniel Anderson and colleagues at MIT, Harvard, and the University of Houston have reported promising results with a different way of attacking the problem: amplifying the T-cell response to mRNA vaccines. The advance could lead to much more powerful cancer vaccines as well as stronger protection against infectious diseases. 近日，麻省理工学院（MIT）化学工程师丹尼尔·安德森（Daniel Anderson）及其在麻省理工学院、哈佛大学和休斯顿大学的同事报告了一种解决该问题的新方法，并取得了令人鼓舞的成果：通过放大 mRNA 疫苗的 T 细胞反应来增强疗效。这一进展有望带来效力更强的癌症疫苗，并为预防传染病提供更坚实的保护。

Most vaccines generate not only antibodies but also T cells that can activate antigen-presenting cells, which help tell the immune system what to attack. In their study, the researchers boosted that response with a new type of vaccine adjuvant (a material that can help stimulate the immune system). It consists of mRNA molecules encoding two genes that can switch immune cells into a more active state by turning on certain signaling pathways. 大多数疫苗不仅能产生抗体，还能产生能够激活抗原呈递细胞的 T 细胞，从而帮助引导免疫系统识别攻击目标。在研究中，研究人员利用一种新型疫苗佐剂（一种有助于刺激免疫系统的物质）增强了这种反应。该佐剂由编码两个基因的 mRNA 分子组成，这些基因可以通过开启特定的信号通路，将免疫细胞切换到更活跃的状态。

In studies of mice modeling bladder cancer, colon carcinoma, melanoma, metastatic lung cancer, and more, injections of lipid nanoparticles containing the mRNA-encoded adjuvant enabled the immune system to slow growth of some tumors and eradicate many others. This happened even when the mice were not given a vaccine against a specific cancer antigen, but when they were, the response was stronger still. 在针对膀胱癌、结肠癌、黑色素瘤、转移性肺癌等多种小鼠癌症模型的研究中，注射含有这种 mRNA 编码佐剂的脂质纳米颗粒，使免疫系统能够减缓某些肿瘤的生长并根除许多其他肿瘤。即使在未接种针对特定癌症抗原疫苗的情况下，这种效果依然存在；而当配合疫苗使用时，免疫反应则更为强烈。

“When these adjuvant mRNAs are included in the vaccines, the number of antigen-targeted T cells is substantially increased. These T cells play an important role in the immune response,” Anderson says. “当这些佐剂 mRNA 被包含在疫苗中时，靶向抗原的 T 细胞数量会显著增加。这些 T 细胞在免疫反应中发挥着重要作用，”安德森说道。

The mRNA adjuvant also enhanced the immune response to immunotherapy drugs called checkpoint blockade inhibitors, which work by lifting a brake that tumor cells put on T cells and are FDA approved to treat several kinds of cancer. 这种 mRNA 佐剂还增强了对“检查点阻断抑制剂”类免疫治疗药物的免疫反应。这类药物通过解除肿瘤细胞对 T 细胞的抑制作用来发挥疗效，目前已被 FDA 批准用于治疗多种癌症。

“The microenvironment of solid tumors is often hostile to T cells and represents a major barrier to effective immunotherapy. We find that immune remodeling with these adjuvants creates a T-cell-permissive environment and promotes tumor rejection,” says Christopher Garris, an assistant professor at Harvard Medical School and one of the paper’s senior authors. “实体瘤的微环境通常对 T 细胞具有敌意，这是有效免疫治疗的主要障碍。我们发现，利用这些佐剂进行免疫重塑，可以创造一个允许 T 细胞生存的环境，并促进肿瘤排斥，”哈佛医学院助理教授、该论文的资深作者之一克里斯托弗·加里斯（Christopher Garris）表示。

The researchers also explored whether their adjuvant could boost the immune response to vaccination against viral infection. When they delivered the mRNA particles to mice along with covid or flu vaccines, they found that the vaccine generated a T-cell response 10 to 15 times stronger than usual. The researchers now plan to test this approach in additional animal models, in hopes of developing it for use in both cancer and infectious diseases. 研究人员还探讨了该佐剂是否能增强针对病毒感染的疫苗接种免疫反应。当他们将这些 mRNA 颗粒与新冠或流感疫苗一同递送给小鼠时，发现疫苗产生的 T 细胞反应比通常水平强 10 到 15 倍。研究人员目前计划在更多动物模型中测试这一方法，希望能将其开发用于癌症和传染病治疗。

Meanwhile, they are not the only MIT scientists making exciting advances with adjuvants. A group led by Ana Jaklenec, a principal investigator at the Koch Institute for Integrative Cancer Research, has used one to help the injectable form of the polio vaccine induce a strong mucosal immune response in the GI tract. That could help reduce viral shedding and transmission, a key objective of polio eradication efforts. But to date this immunity has been produced mainly by the oral form of the vaccine, and many countries have stopped using it because it carries rare risks that the injectable version does not. 与此同时，他们并非唯一在佐剂领域取得令人兴奋进展的麻省理工学院科学家。科赫综合癌症研究所（Koch Institute for Integrative Cancer Research）首席研究员安娜·雅克莱内克（Ana Jaklenec）领导的团队利用一种佐剂，帮助注射型脊髓灰质炎疫苗在胃肠道诱导产生强烈的黏膜免疫反应。这有助于减少病毒的脱落和传播，而这正是根除脊髓灰质炎工作的关键目标。然而，迄今为止，这种免疫力主要由口服疫苗产生，但许多国家已停止使用口服疫苗，因为它存在注射型疫苗所没有的罕见风险。