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A homing system targets therapeutic T cells to brain cancer

机译：归巢系统将治疗性T细胞靶向脑癌

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Successful T cell immunotherapy for brain cancer requires that the T cells can access tumour tissues, but this has been difficult to achieve. Here we show that, in contrast to inflammatory brain diseases such as multiple sclerosis, where endothelial cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer endothelium downregulates these molecules to evade immune recognition. By contrast, we found that cancer endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM , which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted homing system (HS). We re-engineered the natural ligand of ALCAM, CD6, in a manner that triggers initial anchorage of T cells to ALCAM and conditionally mediates a secondary wave of adhesion by sensitizing T cells to low-level ICAM1 on the cancer endothelium, thereby creating the adhesion forces necessary to capture T cells from the bloodstream. Cytotoxic HS T cells robustly infiltrated brain cancers after intravenous injection and exhibited potent antitumour activity. We have therefore developed a molecule that targets the delivery of T cells to brain cancer.
机译：成功的针对脑癌的T细胞免疫疗法要求T细胞可以进入肿瘤组织，但这很难实现。在这里，我们发现，与炎症性脑疾病（如多发性硬化症）相反，内皮细胞上调ICAM1和VCAM1来引导促炎细胞的外溢，而癌症内皮下调这些分子以逃避免疫识别。相比之下，我们发现癌症内皮上调了活化的白细胞粘附分子（ALCAM），从而使我们能够通过建立ALCAM限制的归巢系统（HS）来克服这种免疫逃逸机制。我们重新设计了ALCAM，CD6的天然配体通过触发T细胞对癌细胞内皮上低水平的ICAM1敏感，从而触发T细胞对ALCAM的初始锚定并有条件地介导第二次粘附波，从而产生从血流中捕获T细胞所需的粘附力。静脉注射后，HS T细胞能强有力地浸润脑癌，并表现出强大的抗肿瘤活性，因此，我们开发了一种靶向T细胞向脑癌输送的分子。

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