PTPRT缺失可通过调节STING通路增强非小细胞肺癌抗PD-1疗法的疗效。

IF 15.8 1区 医学 Q1 CELL BIOLOGY Science Translational Medicine Pub Date : 2024-09-04 DOI:10.1126/scitranslmed.adl3598
Zhuo Chen, Wenxiang Ji, Wenxin Feng, Jingchuan Cui, Yuchen Wang, Fan Li, Jiachen Chen, Ziheng Guo, Liliang Xia, Xiaokuan Zhu, Xiaomin Niu, Yanshuang Zhang, Ziming Li, Alice S. T. Wong, Shun Lu, Weiliang Xia
{"title":"PTPRT缺失可通过调节STING通路增强非小细胞肺癌抗PD-1疗法的疗效。","authors":"Zhuo Chen,&nbsp;Wenxiang Ji,&nbsp;Wenxin Feng,&nbsp;Jingchuan Cui,&nbsp;Yuchen Wang,&nbsp;Fan Li,&nbsp;Jiachen Chen,&nbsp;Ziheng Guo,&nbsp;Liliang Xia,&nbsp;Xiaokuan Zhu,&nbsp;Xiaomin Niu,&nbsp;Yanshuang Zhang,&nbsp;Ziming Li,&nbsp;Alice S. T. Wong,&nbsp;Shun Lu,&nbsp;Weiliang Xia","doi":"10.1126/scitranslmed.adl3598","DOIUrl":null,"url":null,"abstract":"<div >With the revolutionary progress of immune checkpoint inhibitors (ICIs) in non–small cell lung cancer, identifying patients with cancer who would benefit from ICIs has become critical and urgent. Here, we report protein tyrosine phosphatase receptor type T (PTPRT) loss as a precise and convenient predictive marker independent of PD-L1 expression for anti–PD-1/PD-L1 axis therapy. Anti–PD-1/PD-L1 axis treatment markedly increased progression-free survival in patients with PTPRT-deficient tumors. PTPRT-deficient tumors displayed cumulative DNA damage, increased cytosolic DNA release, and higher tumor mutation burden. Moreover, the tyrosine residue 240 of STING was identified as a direct substrate of PTPRT. PTPRT loss elevated phosphorylation of STING at Y240 and thus inhibited its proteasome-mediated degradation. PTPRT-deficient tumors released more IFN-β, CCL5, and CXCL10 by activation of STING pathway and increased immune cell infiltration, especially of CD8 T cells and natural killer cells, ultimately enhancing the efficacy of anti–PD-1 therapy in multiple subcutaneous and orthotopic tumor mouse models. The response of PTPRT-deficient tumors to anti–PD-1 therapy depends on the tumor-intrinsic STING pathway. In summary, our findings reveal the mechanism of how PTPRT-deficient tumors become sensitive to anti–PD-1 therapy and highlight the biological function of PTPRT in innate immunity. Considering the prevalence of PTPRT mutations and negative expression, this study has great value for patient stratification and clinical decision-making.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8000,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adl3598","citationCount":"0","resultStr":"{\"title\":\"PTPRT loss enhances anti–PD-1 therapy efficacy by regulation of STING pathway in non–small cell lung cancer\",\"authors\":\"Zhuo Chen,&nbsp;Wenxiang Ji,&nbsp;Wenxin Feng,&nbsp;Jingchuan Cui,&nbsp;Yuchen Wang,&nbsp;Fan Li,&nbsp;Jiachen Chen,&nbsp;Ziheng Guo,&nbsp;Liliang Xia,&nbsp;Xiaokuan Zhu,&nbsp;Xiaomin Niu,&nbsp;Yanshuang Zhang,&nbsp;Ziming Li,&nbsp;Alice S. T. Wong,&nbsp;Shun Lu,&nbsp;Weiliang Xia\",\"doi\":\"10.1126/scitranslmed.adl3598\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >With the revolutionary progress of immune checkpoint inhibitors (ICIs) in non–small cell lung cancer, identifying patients with cancer who would benefit from ICIs has become critical and urgent. Here, we report protein tyrosine phosphatase receptor type T (PTPRT) loss as a precise and convenient predictive marker independent of PD-L1 expression for anti–PD-1/PD-L1 axis therapy. Anti–PD-1/PD-L1 axis treatment markedly increased progression-free survival in patients with PTPRT-deficient tumors. PTPRT-deficient tumors displayed cumulative DNA damage, increased cytosolic DNA release, and higher tumor mutation burden. Moreover, the tyrosine residue 240 of STING was identified as a direct substrate of PTPRT. PTPRT loss elevated phosphorylation of STING at Y240 and thus inhibited its proteasome-mediated degradation. PTPRT-deficient tumors released more IFN-β, CCL5, and CXCL10 by activation of STING pathway and increased immune cell infiltration, especially of CD8 T cells and natural killer cells, ultimately enhancing the efficacy of anti–PD-1 therapy in multiple subcutaneous and orthotopic tumor mouse models. The response of PTPRT-deficient tumors to anti–PD-1 therapy depends on the tumor-intrinsic STING pathway. In summary, our findings reveal the mechanism of how PTPRT-deficient tumors become sensitive to anti–PD-1 therapy and highlight the biological function of PTPRT in innate immunity. Considering the prevalence of PTPRT mutations and negative expression, this study has great value for patient stratification and clinical decision-making.</div>\",\"PeriodicalId\":21580,\"journal\":{\"name\":\"Science Translational Medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":15.8000,\"publicationDate\":\"2024-09-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.science.org/doi/reader/10.1126/scitranslmed.adl3598\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Translational Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/scitranslmed.adl3598\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/scitranslmed.adl3598","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

随着免疫检查点抑制剂(ICIs)在非小细胞肺癌领域取得革命性进展,确定哪些癌症患者可从 ICIs 中获益已变得至关重要且刻不容缓。在此,我们报告了蛋白酪氨酸磷酸酶受体T型(PTPRT)缺失作为一种独立于PD-L1表达的精确、便捷的预测指标,可用于抗PD-1/PD-L1轴治疗。抗PD-1/PD-L1轴治疗显著提高了PTPRT缺失肿瘤患者的无进展生存期。PTPRT缺陷型肿瘤显示出累积性DNA损伤、细胞膜DNA释放增加以及更高的肿瘤突变负荷。此外,STING 的酪氨酸残基 240 被确定为 PTPRT 的直接底物。PTPRT的缺失会增加STING在Y240处的磷酸化,从而抑制蛋白酶体介导的降解。PTPRT 缺失的肿瘤通过激活 STING 通路释放出更多的 IFN-β、CCL5 和 CXCL10,并增加了免疫细胞的浸润,尤其是 CD8 T 细胞和自然杀伤细胞,最终提高了抗 PD-1 治疗在多种皮下和正位肿瘤小鼠模型中的疗效。PTPRT缺陷肿瘤对抗PD-1疗法的反应取决于肿瘤内在STING通路。总之,我们的研究结果揭示了PTPRT缺陷肿瘤如何对抗PD-1治疗变得敏感的机制,并强调了PTPRT在先天免疫中的生物学功能。考虑到PTPRT突变和阴性表达的普遍性,本研究对患者分层和临床决策具有重要价值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

摘要图片

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
PTPRT loss enhances anti–PD-1 therapy efficacy by regulation of STING pathway in non–small cell lung cancer
With the revolutionary progress of immune checkpoint inhibitors (ICIs) in non–small cell lung cancer, identifying patients with cancer who would benefit from ICIs has become critical and urgent. Here, we report protein tyrosine phosphatase receptor type T (PTPRT) loss as a precise and convenient predictive marker independent of PD-L1 expression for anti–PD-1/PD-L1 axis therapy. Anti–PD-1/PD-L1 axis treatment markedly increased progression-free survival in patients with PTPRT-deficient tumors. PTPRT-deficient tumors displayed cumulative DNA damage, increased cytosolic DNA release, and higher tumor mutation burden. Moreover, the tyrosine residue 240 of STING was identified as a direct substrate of PTPRT. PTPRT loss elevated phosphorylation of STING at Y240 and thus inhibited its proteasome-mediated degradation. PTPRT-deficient tumors released more IFN-β, CCL5, and CXCL10 by activation of STING pathway and increased immune cell infiltration, especially of CD8 T cells and natural killer cells, ultimately enhancing the efficacy of anti–PD-1 therapy in multiple subcutaneous and orthotopic tumor mouse models. The response of PTPRT-deficient tumors to anti–PD-1 therapy depends on the tumor-intrinsic STING pathway. In summary, our findings reveal the mechanism of how PTPRT-deficient tumors become sensitive to anti–PD-1 therapy and highlight the biological function of PTPRT in innate immunity. Considering the prevalence of PTPRT mutations and negative expression, this study has great value for patient stratification and clinical decision-making.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
期刊最新文献
Transient anti-interferon autoantibodies in the airways are associated with recovery from COVID-19 Nociceptor-to-macrophage communication through CGRP/RAMP1 signaling drives endometriosis-associated pain and lesion growth in mice Dysregulation of zebrin-II cell subtypes in the cerebellum is a shared feature across polyglutamine ataxia mouse models and patients The R1441C-Lrrk2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner in mice Monoclonal antibodies against the spike protein alter the endogenous humoral response to SARS-CoV-2 vaccination and infection
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1