Targeting Tumor-Associated Sialic Acids Using Chimeric Switch Receptors Based on Siglec-9 Enhances the Antitumor Efficacy of Engineered T Cells.

IF 8.1 1区 医学 Q1 IMMUNOLOGY
Vasyl Eisenberg, Shiran Hoogi, Erel Katzman, Nimrod Ben Haim, Raphaelle Zur-Toledano, Maria Radman, Yishai Reboh, Oranit Zadok, Iris Kamer, Jair Bar, Irit Sagi, Ayal Hendel, Cyrille J Cohen
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Abstract

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.

利用基于 Siglec-9 的嵌合开关受体靶向肿瘤相关的 Sialic 酸可增强工程 T 细胞的抗肿瘤功效
癌症利用不同的机制逃避 T 细胞的免疫监视,包括检查点配体的过度表达、免疫抑制分子的分泌和异常糖基化。在本文中,我们报告了在肿瘤微环境中分泌的强效免疫调节剂 IFNγ 可诱导不同组织结构的癌细胞株中α2,6 过度糖基化。我们随后重点研究了Siglec-9--一种针对sialic acid分子的受体,结果表明Siglec-9+ T细胞群的效应功能降低了。我们推测原代人类 T 细胞中的 Siglec-9 可充当检查点分子,并证明使用 CRISPR/Cas9 系统敲除 Siglec-9 可增强原代人类 T 细胞的功能。最后,我们的目标是利用肿瘤的高ialylation 增强癌症特异性 T 细胞的活性。因此,我们设计了几种基于 Siglec-9 的嵌合开关受体 (CSR),其中包括源自成本刺激分子(CD28/41BB)的细胞内分子和不同的铰链区。在抗原特异性的情况下,用 Siglec-9 CSRs 转导的 T 细胞表现出细胞因子分泌增加和活化标志物上调。此外,在人类肿瘤的异种移植模型中,装有特异性 Siglec-9 CSRs 的 T 细胞具有很强的抗肿瘤活性。总之,这项工作揭示了由硅戊基化残基介导的肿瘤逃避机制,并为改进基于工程 T 细胞的癌症治疗提供了一种方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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