FGFR3 Destabilizes PD-L1 via NEDD4 to Control T-cell–Mediated Bladder Cancer Immune Surveillance

泛素连接酶 癌症研究 内德4 膀胱癌 泛素 免疫系统 癌症 免疫疗法 肿瘤微环境 癌症免疫疗法 成纤维细胞生长因子受体3
作者
Weiqiang Jing,Ganyu Wang,Zhiwei Cui,Gaozhong Xiong,Xin Jiang,Yue Li,Wushan Li,Bo Han,Shouzhen Chen,Benkang Shi
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:82 (1): 114-129 被引量:5
标识
DOI:10.1158/0008-5472.can-21-2362
摘要

Abstract Fibroblast growth factor receptor 3 (FGFR3) is frequently activated by mutation or overexpression, and it is a validated therapeutic target in urothelial carcinoma (UC) of the bladder. However, the role and detailed molecular mechanism of FGFR3 in the immune microenvironment of bladder cancer remain largely unknown. Here, we demonstrate that inhibition of FGFR3 in FGFR3-activated bladder cancer elevates PD-L1 protein levels by affecting its ubiquitination, thereby inhibiting the antitumor activity of CD8+ T cells. Tissue microarray analysis in human UC showed an inverse correlation between FGFR3 and PD-L1. Furthermore, NEDD4, an E3 ubiquitin ligase of the NEDD4 family of proteins, was phosphorylated by FGFR3 activation and served as a regulator of PD-L1 ubiquitination. Mechanistically, NEDD4 interacted with PD-L1 and catalyzed Lys48 (K48)-linked polyubiquitination of PD-L1. In mice bearing NEDD4 knockout bladder cancer, CD8+ T-cell infiltration and antitumor activity were significantly inhibited due to PD-L1 upregulation in bladder cancer cells. Furthermore, multiple FGFR3-activated tumor-bearing mouse models suggested that attenuated CD8+ T-cell–mediated antitumor efficacy following FGFR3-targeted therapy could be rescued by a combination with anti-PD-1 immunotherapy, which leads to effective tumor suppression. This study establishes a key molecular link between targeted therapy and immune surveillance and identifies NEDD4 as a crucial E3 ubiquitin ligase that targets PD-L1 for degradation in FGFR3-activated bladder cancer. These findings may potentially be exploited for combination therapies in UC of the bladder and possibly other malignancies with activated FGFR3. Significance: NEDD4 links two important molecules associated with targeted therapy and immune surveillance, providing mechanistic rationale and preclinical support for immuno-targeted combination therapy for FGFR3-activated bladder cancer.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
kerio发布了新的文献求助10
刚刚
1秒前
2秒前
乐乐应助过分动真采纳,获得10
2秒前
stefdee发布了新的文献求助10
4秒前
5秒前
设计师做做人完成签到,获得积分10
6秒前
cctoday发布了新的文献求助10
8秒前
10秒前
12秒前
13秒前
大模型应助柿子采纳,获得10
13秒前
13秒前
rance完成签到,获得积分20
14秒前
甜蜜的代容完成签到,获得积分20
15秒前
甘总完成签到,获得积分10
15秒前
Baozi发布了新的文献求助10
16秒前
发型犀利啊应助蕉太狼采纳,获得10
16秒前
Owen应助l2023采纳,获得10
16秒前
17秒前
17秒前
杨家欢发布了新的文献求助10
18秒前
18秒前
诚心忆秋发布了新的文献求助10
18秒前
xiaoz完成签到,获得积分10
19秒前
19秒前
21秒前
小猪完成签到 ,获得积分10
21秒前
23秒前
23秒前
情怀应助soar采纳,获得30
24秒前
甜田完成签到,获得积分10
24秒前
24秒前
25秒前
垃圾桶发布了新的文献求助10
25秒前
努力生活的小柴完成签到,获得积分10
25秒前
迷宫废墟完成签到,获得积分10
25秒前
殷勤的阑悦完成签到 ,获得积分10
26秒前
朱少龙发布了新的文献求助10
27秒前
小二郎应助双眸若星辰采纳,获得10
27秒前
高分求助中
Sustainability in Tides Chemistry 2800
The Young builders of New china : the visit of the delegation of the WFDY to the Chinese People's Republic 1000
юрские динозавры восточного забайкалья 800
English Wealden Fossils 700
Foreign Policy of the French Second Empire: A Bibliography 500
Chen Hansheng: China’s Last Romantic Revolutionary 500
XAFS for Everyone 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3145276
求助须知:如何正确求助?哪些是违规求助? 2796719
关于积分的说明 7820904
捐赠科研通 2452997
什么是DOI,文献DOI怎么找? 1305336
科研通“疑难数据库(出版商)”最低求助积分说明 627483
版权声明 601464