CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Targeting Tumor-Associated Sialic Acids Using Chimeric Switch Receptors Based on Siglec-9 Enhances the Antitumor Efficacy of Engineered T Cells.
Targeting Tumor-Associated Sialic Acids Using Chimeric Switch Receptors Based on Siglec-9 Enhances the Antitumor Efficacy of Engineered T Cells.
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癌症利用不同机制逃逸T细胞免疫监视，包括检查点配体过表达、免疫抑制分子分泌以及异常糖基化。在此，我们报道IFNγ——一种在肿瘤微环境中分泌的强效免疫调节因子——可在来源于多种组织学类型的癌细胞系中诱导α2,6高唾液酸化。
我们聚焦于Siglec-9，一种唾液酸基团受体，并证明Siglec-9+ T细胞群体表现出效应功能降低。我们推测原代人T细胞中的Siglec-9可作为检查点分子，并证明使用成簇规律间隔短回文重复序列（CRISPR）/Cas9系统敲除Siglec-9可增强原代人T细胞的功能。
最后，我们旨在利用肿瘤高唾液酸化来增强癌症特异性T细胞活性。因此，我们设计了几种基于Siglec-9的嵌合开关受体（CSR），其包含来源于共刺激分子（CD28/41BB）的胞内部分以及不同的铰链区。在抗原特异性背景下，转导Siglec-9 CSR的T细胞表现出细胞因子分泌增加和激活标志物上调。
此外，装备特定Siglec-9 CSR的T细胞在人肿瘤异种移植模型中介导了强效抗肿瘤活性。总体而言，这项工作揭示了由唾液酸化残基介导的肿瘤逃逸机制，并例证了一种改善工程化T细胞癌症治疗的方法。参见Abken的相关Spotlight，第1310页。
Cancer exploits different mechanisms to escape T-cell immunosurveillance, including overexpression of checkpoint ligands, secretion of immunosuppressive molecules, and aberrant glycosylation.
Herein, we report that IFNγ, a potent immunomodulator secreted in the tumor microenvironment, can induce α2,6 hypersialylation in cancer cell lines derived from various histologies.
We focused on Siglec-9, a receptor for sialic acid moieties, and demonstrated that the Siglec-9+ T-cell population displayed reduced effector function.
We speculated that Siglec-9 in primary human T cells can act as a checkpoint molecule and demonstrated that knocking out Siglec-9 using a clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system enhanced the functionality of primary human T cells.
Finally, we aimed to augment cancer-specific T-cell activity by taking advantage of tumor hypersialylation.
Thus, we designed several Siglec-9-based chimeric switch receptors (CSR), which included an intracellular moiety derived from costimulatory molecules (CD28/41BB) and different hinge regions. In an antigen-specific context, T cells transduced with Siglec-9 CSRs demonstrated increased cytokine secretions and upregulation of activation markers.
Moreover, T cells equipped with specific Siglec-9 CSRs mediated robust antitumor activity in a xenograft model of human tumors.
Overall, this work sheds light on tumor evasion mechanisms mediated by sialylated residues and exemplifies an approach to improve engineered T cell-based cancer treatment. See related Spotlight by Abken, p. 1310.
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