小柯机器人

美国哈佛大学医学院Vijay K. Kuchroo研究组发现，TIM-3通过调节炎症小体激活抑制抗肿瘤免疫。2021年6月9日，《自然》杂志在线发表了这项成果。

研究人员表示，T细胞免疫球蛋白和含粘蛋白分子3（TIM-3）是首先被确定为一种在产生干扰素-γ的T细胞上表达的分子，正在成为一种重要的免疫检查点分子，TIM-3的治疗性阻断正在多个人类恶性肿瘤研究中进行研究。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。

通过使用TIM-3的条件敲除和单细胞RNA测序，研究人员证明了TIM-3在树突状细胞（DC）上的独特重要性，由于在DC上丢失了TIM-3（但在CD4⁺或 CD8⁺T 细胞上没有），从而促进了强大的抗肿瘤免疫力。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。DC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，这些研究结果揭示了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。

附：英文原文

Title: TIM-3 restrains anti-tumour immunity by regulating inflammasome activation

Author: 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

Issue&Volume: 2021-06-09

Abstract: 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.

DOI: 10.1038/s41586-021-03626-9

Source: https://www.nature.com/articles/s41586-021-03626-9

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html