当前位置: X-MOL 学术Nature › 论文详情
TIM-3 restrains anti-tumour immunity by regulating inflammasome activation
Nature ( IF 42.778 ) Pub Date : 2021-06-09 , DOI: 10.1038/s41586-021-03626-9
Karen O. Dixon, Marcin Tabaka, Markus A. Schramm, Sheng Xiao, Ruihan Tang, Danielle Dionne, Ana. C. Anderson, Orit Rozenblatt-Rosen, Aviv Regev, Vijay K. Kuchroo

T cell immunoglobulin and mucin-containing molecule 3 (TIM-3), first identified as a molecule expressed on interferon-γ producing T cells1, is emerging as an important immune-checkpoint molecule, with therapeutic blockade of TIM-3 being investigated in multiple human malignancies. Expression of TIM-3 on CD8+ T cells in the tumour microenvironment is considered a cardinal sign of T cell dysfunction; however, TIM-3 is also expressed on several other types of immune cell, confounding interpretation of results following blockade using anti-TIM-3 monoclonal antibodies. Here, using conditional knockouts of TIM-3 together with single-cell RNA sequencing, we demonstrate the singular importance of TIM-3 on dendritic cells (DCs), whereby loss of TIM-3 on DCs—but not on CD4+ or CD8+ T cells—promotes strong anti-tumour immunity. Loss of TIM-3 prevented DCs from expressing a regulatory program and facilitated the maintenance of CD8+ effector and stem-like T cells. Conditional deletion of TIM-3 in DCs led to increased accumulation of reactive oxygen species resulting in NLRP3 inflammasome activation. Inhibition of inflammasome activation, or downstream effector cytokines interleukin-1β (IL-1β) and IL-18, completely abrogated the protective anti-tumour immunity observed with TIM-3 deletion in DCs. Together, our findings reveal an important role for TIM-3 in regulating DC function and underscore the potential of TIM-3 blockade in promoting anti-tumour immunity by regulating inflammasome activation.



中文翻译:

TIM-3通过调节炎症小体激活抑制抗肿瘤免疫

T 细胞免疫球蛋白和含粘蛋白的分子 3 (TIM-3),首先被鉴定为在产生干扰素-γ 的 T 细胞上表达的分子1,正在成为一种重要的免疫检查点分子,TIM-3 的治疗性阻断正在研究中多种人类恶性肿瘤。TIM-3 在肿瘤微环境中CD8 + T 细胞上的表达被认为是 T 细胞功能障碍的主要标志;然而,TIM-3 也在其他几种类型的免疫细胞上表达,混淆了使用抗 TIM-3 单克隆抗体阻断后结果的解释。在这里,使用 TIM-3 的条件敲除和单细胞 RNA 测序,我们证明了 TIM-3 对树突状细胞 (DC) 的奇异重要性,即 TIM-3 在 DC 上丢失,但在 CD4 +或 CD8 + T 细胞——促进强大的抗肿瘤免疫。TIM-3 的缺失阻止了 DC 表达调节程序,并促进了 CD8 +效应子和干细胞样 T 细胞的维持。DCs 中 TIM-3 的条件性缺失导致活性氧的积累增加,从而导致 NLRP3 炎症小体激活。抑制炎性体激活或下游效应细胞因子白细胞介素-1β(IL-1β)和IL-18,完全消除了在DC 中TIM-3 缺失时观察到的保护性抗肿瘤免疫。总之,我们的研究结果揭示了 TIM-3 在调节 DC 功能中的重要作用,并强调了 TIM-3 阻断通过调节炎性体激活促进抗肿瘤免疫的潜力。

更新日期:2021-06-09
全部期刊列表>>
virulence
欢迎新作者ACS
中国作者高影响力研究精选
虚拟特刊
屿渡论文,编辑服务
浙大
上海中医药大学
深圳大学
上海交通大学
南方科技大学
浙江大学
清华大学
徐晶
张大卫
彭孝军
北京大学
隐藏1h前已浏览文章
课题组网站
新版X-MOL期刊搜索和高级搜索功能介绍
ACS材料视界
华辉
天合科研
x-mol收录
试剂库存
down
wechat
bug