靶向降解sICOSL可逆转细胞毒性T细胞功能障碍。

IF 13.5 1区 医学 Q1 HEMATOLOGY
Zhenghao Wu, Peng Zheng, Ruobing Qi, Yunxiao Xiao, Zihan Xi, Lei Dai, Tao Chen, Qianheng Wang, Furong Zhang, Rong Wang, Zimei Tang, Xiangwang Zhao, Jie Tan, Jie Ming, Ping Lei, Chunping Liu, Tao Huang
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引用次数: 0

摘要

细胞毒性T细胞(CTL)功能障碍仍然是肿瘤免疫逃避的主要原因,并与癌症生存率低相关。在这里,我们发现ICOSL可溶性形式(sICOSL)的增加诱导CTL功能障碍,并与乳腺癌患者的生存期缩短相关。通过直接触发ICOS内化和随后的降解,sICOSL成为CTL的强大对手,这是对CTL激活所必需的共刺激机制的关键打击。我们的研究表明二肽基肽酶-4 (DPP4)主要分解sICOSL。值得注意的是,某些化疗药物可以激活zeste同源物2的组蛋白甲基转移酶增强子(EZH2),从而抑制DPP4的表达。为了解决这个问题,我们开发了纳米体- dpp4融合蛋白,可以特异性地降解sICOSL,实现底物选择性和肿瘤靶向。总之,这项工作揭示了sICOSL协调CTL功能障碍,并建立了sICOSL的靶向降解作为免疫治疗的新策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeted degradation of sICOSL reverses cytotoxic T cells dysfunction.

Dysfunction of cytotoxic T cells (CTL) remains a major cause of tumor immune evasion and is correlated with poor cancer survival. Here, we found that increased soluble form of ICOSL (sICOSL) induced CTL dysfunction and was associated with shorter survival of patients with breast cancer. sICOSL emerged as a formidable adversary to CTLs, by directly triggering ICOS internalization and subsequent degradation-a critical blow to the co-stimulatory machinery essential for CTL activation. Our research shows that dipeptidyl peptidase-4 (DPP4) mainly breaks down sICOSL. Notably, certain chemotherapeutic drugs activate the histone methyltransferase Enhancer of zeste homolog 2 (EZH2), which in turn suppresses DPP4 expression. To address this issue, we have developed nanobody-DPP4 fusion proteins that can specifically degrade sICOSL, achieving substrate selectivity and tumor targeting. Overall, This work unveils that sICOSL orchestrates CTL dysfunction, and establishs targeted degradation of sICOSL as a new strategy for immunotherapy.

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来源期刊
CiteScore
12.60
自引率
7.30%
发文量
97
审稿时长
6 weeks
期刊介绍: Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings. Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.
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