亲爱的研友该休息了!由于当前在线用户较少,发布求助请尽量完整地填写文献信息,科研通机器人24小时在线,伴您度过漫漫科研夜!身体可是革命的本钱,早点休息,好梦!

HDACi-dependent Microenvironmental Normalization Overcomes Tumor Burden–induced T-cell Exhaustion

癌症研究 生物 重编程 肿瘤微环境 免疫疗法 CD8型 细胞毒性T细胞 T细胞 转录组 细胞 免疫学 免疫系统 生物化学 基因表达 基因 体外 遗传学
作者
Andrew Nguyen,Dominique Brown,Ramya Krishnan,Donald Bastin,Li Deng,Lan Chen,Omar Salem,Scott Walsh,Jonathan L. Bramson,Yonghong Wan
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
卷期号:29 (20): 4289-4305
标识
DOI:10.1158/1078-0432.ccr-22-2181
摘要

Abstract Purpose: T-cell exhaustion limits immunotherapy for the treatment of solid tumors. Although immune checkpoint blockade and adoptive T-cell therapy (ACT) can mediate tumor regression, their potency is often determined by tumor burden. Here, we identified tumor burden–related pathway changes that are conducive to T-cell exhaustion. We then determined whether microenvironmental reprogramming via epigenetic modulation could reverse T-cell exhaustion and improve immunotherapeutic responsiveness. Experimental Design: We developed a murine syngeneic tumor model wherein an increased burden ablated therapeutic responsiveness to ACT, which corresponded with systemic induction of T-cell exhaustion. Transcriptome analysis of these large tumors allowed us to characterize changes to immunosuppressive pathway expression during class I histone deacetylase inhibitor MS-275 treatment. We then measured the therapeutic impact of MS-275 during ACT and assessed T-cell exhaustion by transcriptome/phenotypic analysis. Results: ACT durably regressed small tumors but failed to control large tumors, which were associated with systemic T-cell exhaustion and ablation of T-cell responses. Large tumors were defined by an immunosuppressive pathway signature. MS-275 reversed this pathway signature and promoted durable regression of large tumors during ACT. Prototypical exhaustion marker Tim-3 was selectively upregulated in transferred T cells despite displaying a reduced exhaustion signature. Instead, we observed enhanced activation-dependent signaling correlating with enrichment of the IL2–STAT5 signaling axis. Activated CD8+ T-cell responses were predominantly skewed toward terminal effector cell–like CD44+ Tim-3hi TCF1− CD127− KLRG1+ differentiation. Conclusions: Tumor burden–induced pathway changes can be reversed through epigenetic reprogramming, enabling the conversion from T-cell exhaustion to effector lineage differentiation.
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
PDF的下载单位、IP信息已删除 (2025-6-4)

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
小泉完成签到 ,获得积分10
2秒前
星辰大海应助高兴的忆曼采纳,获得10
48秒前
英姑应助核桃采纳,获得10
1分钟前
科研通AI5应助核桃采纳,获得10
1分钟前
科研通AI5应助核桃采纳,获得10
1分钟前
可爱的函函应助核桃采纳,获得10
1分钟前
Liufgui应助核桃采纳,获得10
1分钟前
在水一方应助核桃采纳,获得10
1分钟前
隐形曼青应助科研通管家采纳,获得10
1分钟前
丘比特应助科研通管家采纳,获得10
1分钟前
爆米花应助科研通管家采纳,获得10
1分钟前
LONG完成签到 ,获得积分10
1分钟前
秋风今是完成签到 ,获得积分10
1分钟前
2分钟前
核桃发布了新的文献求助10
2分钟前
biubiubiu驳回了852应助
2分钟前
AUGKING27完成签到 ,获得积分10
2分钟前
2分钟前
2分钟前
2分钟前
无语的诗柳完成签到 ,获得积分10
3分钟前
nina完成签到 ,获得积分10
3分钟前
远山淡影_cy完成签到,获得积分20
3分钟前
康谨完成签到 ,获得积分10
3分钟前
blenx完成签到,获得积分10
3分钟前
3分钟前
小叶子完成签到 ,获得积分10
3分钟前
Liufgui应助徐悦月采纳,获得10
3分钟前
3分钟前
Dave完成签到,获得积分10
3分钟前
FashionBoy应助Dave采纳,获得10
4分钟前
4分钟前
4分钟前
4分钟前
顾矜应助Emon采纳,获得10
4分钟前
4分钟前
4分钟前
芝麻完成签到,获得积分10
5分钟前
5分钟前
Dave发布了新的文献求助10
5分钟前
高分求助中
The Mother of All Tableaux: Order, Equivalence, and Geometry in the Large-scale Structure of Optimality Theory 3000
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 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 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3990045
求助须知:如何正确求助?哪些是违规求助? 3532108
关于积分的说明 11256334
捐赠科研通 3270943
什么是DOI,文献DOI怎么找? 1805146
邀请新用户注册赠送积分活动 882270
科研通“疑难数据库(出版商)”最低求助积分说明 809228