Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Gut. 2024 Feb 23;73(3):509-520. doi: 10.1136/gutjnl-2023-330024.
Liver metastases are often resistant to immune checkpoint inhibitor therapy (ICI) and portend a worse prognosis compared with metastases to other locations. Regulatory T cells (Tregs) are one of several immunosuppressive cells implicated in ICI resistance of liver tumours, but the role played by Tregs residing within the liver surrounding a tumour is unknown.
Flow cytometry and single-cell RNA sequencing were used to characterise hepatic Tregs before and after ICI therapy.
We found that the murine liver houses a Treg population that, unlike those found in other organs, is both highly proliferative and apoptotic at baseline. On administration of αPD-1, αPD-L1 or αCTLA4, the liver Treg population doubled regardless of the presence of an intrahepatic tumour. Remarkably, this change was not due to the preferential expansion of the subpopulation of Tregs that express PD-1. Instead, a subpopulation of CD29 (, integrin β1) Tregs, that were highly proliferative at baseline, doubled its size in response to αPD-1. Partial and full depletion of Tregs identified CD29 Tregs as the prominent niche-filling subpopulation in the liver, and CD29 Tregs demonstrated enhanced suppression when derived from the liver but not the spleen. We identified IL2 as a critical modulator of both CD29 and CD29 hepatic Tregs, but expansion of the liver Treg population with αPD-1 driven by CD29 Tregs was in part IL2-independent.
We propose that CD29 Tregs constitute a unique subpopulation of hepatic Tregs that are primed to respond to ICI agents and mediate resistance.
与转移至其他部位相比，肝转移通常对免疫检查点抑制剂治疗（ICI）有抗性，并预示着更差的预后。调节性 T 细胞（Tregs）是几种被认为与肝肿瘤 ICI 耐药有关的免疫抑制细胞之一，但肿瘤周围肝内 Tregs 所起的作用尚不清楚。
使用流式细胞术和单细胞 RNA 测序来描述 ICI 治疗前后肝 Tregs 的特征。
我们发现，与其他器官中的 Tregs 不同，鼠类肝脏中存在一种 Treg 群体，在基线时就具有高度增殖性和凋亡性。在用 αPD-1、αPD-L1 或 αCTLA4 给药后，无论是否存在肝内肿瘤，肝 Treg 群体都会增加一倍。值得注意的是，这种变化不是由于表达 PD-1 的 Treg 亚群的优先扩增所致。相反，在基线时具有高度增殖性的 CD29（整联蛋白β1）Treg 的一个亚群，在响应 αPD-1 时其数量增加了一倍。Treg 的部分和完全耗竭鉴定出 CD29 Treg 是肝内的主要填充龛亚群，并且 CD29 Treg 从肝脏而不是脾脏衍生时表现出增强的抑制作用。我们确定了 IL2 是 CD29 和 CD29 肝 Treg 的关键调节剂，但由 CD29 Treg 驱动的 αPD-1 扩增肝 Treg 群体在一定程度上是 IL2 非依赖性的。
我们提出 CD29 Treg 构成了肝 Treg 的一个独特亚群，它们已准备好对 ICI 药物做出反应并介导耐药性。
