Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Pfizer Oncology Research & Development, La Jolla, California, USA.
JCI Insight. 2017 Dec 7;2(23):95692. doi: 10.1172/jci.insight.95692.
The ability of Tregs to control the development of immune responses is essential for maintaining immune system homeostasis. However, Tregs also inhibit the development of efficient antitumor responses. Here, we explored the characteristics and mechanistic basis of the Treg-intrinsic CTLA4/PKCη signaling pathway that we recently found to be required for contact-dependent Treg-mediated suppression. We show that PKCη is required for the Treg-mediated suppression of tumor immunity in vivo. The presence of PKCη-deficient (Prkch-/-) Tregs in the tumor microenvironment was associated with a significantly increased expression of the costimulatory molecule CD86 on intratumoral CD103+ DCs, enhanced priming of antigen-specific CD8+ T cells, and greater levels of effector cytokines produced by these cells. Similar to mouse Tregs, the GIT/PAK/PIX complex also operated downstream of CTLA4 and PKCη in human Tregs, and GIT2 knockdown in Tregs promoted antitumor immunity. Collectively, our data suggest that targeting the CTLA4/PKCη/GIT/PAK/PIX signaling pathway in Tregs could represent a novel immunotherapeutic strategy to alleviate the negative impact of Tregs on antitumor immune responses.
T 调节细胞（Tregs）控制免疫反应的能力对于维持免疫系统的稳态至关重要。然而，Tregs 也抑制了有效抗肿瘤反应的发展。在这里，我们探索了最近发现的 Treg 内在 CTLA4/PKCη 信号通路的特征和机制基础，该通路对于接触依赖性 Treg 介导的抑制是必需的。我们表明，PKCη 对于体内 Treg 介导的肿瘤免疫抑制是必需的。肿瘤微环境中缺乏 PKCη（Prkch-/-）的 Tregs 与肿瘤内 CD103+DC 上共刺激分子 CD86 的表达显著增加、抗原特异性 CD8+T 细胞的初始激活增强以及这些细胞产生的效应细胞因子水平增加有关。与小鼠 Tregs 相似，GIT/PAK/PIX 复合物也在人 Tregs 中 CTLA4 和 PKCη 的下游起作用，Tregs 中的 GIT2 敲低促进了抗肿瘤免疫。总之，我们的数据表明，针对 Tregs 中的 CTLA4/PKCη/GIT/PAK/PIX 信号通路可能代表一种新的免疫治疗策略，以减轻 Tregs 对抗肿瘤免疫反应的负面影响。
