唾液酸酶靶向PD1增强T细胞功能和肿瘤控制

IF 10.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Brett M. Garabedian, Eleanor E. Bashian, Xiaoshuang Wang, Andrew J. Thompson and James C. Paulson*, 
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引用次数: 0

摘要

靶向PD1轴的免疫疗法通过增强T细胞介导的免疫反应改变了癌症治疗的结果。然而,许多肿瘤通过正交逃逸机制逃避免疫清除。含有免疫抑制性唾液酸的聚糖(唾液聚糖)的过量产生可以通过向免疫突触招募抑制性Siglecs来损害免疫监视,在免疫突触中,像PD1一样,它们充当细胞激活的检查点。唾液酸还可以通过抑制共刺激受体CD28与其配体的连接来影响T细胞的激活。这种多药理学暗示唾液聚糖是肿瘤免疫的关键,可以进一步改善PD1治疗的结果。本研究将唾液酸酶偶联到抗PD1 (αPD1-S)上,选择性地降解表达PD1的免疫细胞上的唾液酸。聚糖谱分析证实了靶向去氮化,功能分析证实了T细胞活化和细胞毒能力的增强。在黑色素瘤模型中,αPD1- s促进炎性巨噬细胞极化,减少T细胞耗竭,共同限制黑色素瘤的生长,而不仅仅是抗pd1 (αPD1)。αPD1-S通过同时阻断PD1和降解唾液聚糖,为增强T细胞介导的免疫应答和改善难治性癌症的肿瘤控制提供了一种新的策略。与抗PD1偶联的唾液酸苷酶降解来自PD1+ T细胞和肿瘤细胞的抑制性唾液聚糖,在难治性癌症中增强T细胞的激活和肿瘤控制,而不是单独阻断PD1。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting Sialidase to PD1 Enhances T cell Function and Tumor Control

Immune therapies targeting the PD1 axis have transformed outcomes in cancer treatment by enhancing T cell-mediated immune responses. However, many tumors evade immune clearance through orthogonal escape mechanisms. Excessive production of immunosuppressive sialic acid-containing glycans (sialoglycans) can impair immune surveillance by recruiting inhibitory Siglecs to the immune synapse where, like PD1, they act as checkpoints for cell activation. Sialic acids can also impact T cell activation by dampening the ligation of the costimulatory receptor CD28 with its ligands. This polypharmacology implicates sialoglycans as a linchpin of tumor immunity that can be targeted to further improve outcomes of PD1 therapies. In this work we conjugated sialidase to anti-PD1 (αPD1-S) to selectively degrade sialic acids on immune cells expressing PD1. Glycan profiling confirmed targeted desialylation, and functional assays demonstrated enhancements to T cell activation and cytotoxic capacity. In a melanoma model, αPD1-S promoted inflammatory macrophage polarization and reduced T cell exhaustion, collectively restricting melanoma growth beyond anti-PD1 (αPD1) alone. By simultaneously blocking PD1 and degrading sialoglycans, αPD1-S provides a novel strategy to enhance T cell-mediated immune responses and improve tumor control in refractory cancers.

Sialidase conjugated to anti-PD1 degrades inhibitory sialoglycans from PD1+ T cells and tumor cells, enhancing T cell activation and tumor control beyond PD1 blockade alone in refractory cancers.

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来源期刊
ACS Central Science
ACS Central Science Chemical Engineering-General Chemical Engineering
CiteScore
25.50
自引率
0.50%
发文量
194
审稿时长
10 weeks
期刊介绍: ACS Central Science publishes significant primary reports on research in chemistry and allied fields where chemical approaches are pivotal. As the first fully open-access journal by the American Chemical Society, it covers compelling and important contributions to the broad chemistry and scientific community. "Central science," a term popularized nearly 40 years ago, emphasizes chemistry's central role in connecting physical and life sciences, and fundamental sciences with applied disciplines like medicine and engineering. The journal focuses on exceptional quality articles, addressing advances in fundamental chemistry and interdisciplinary research.
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