PO.IM01.08 · 免疫学
T细胞耗竭的表观遗传重编程
Epigenetic reprogramming of T cell exhaustion
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
在肿瘤进展过程中，T细胞被招募到肿瘤微环境(TME)中，在那里T细胞经历缺氧、营养剥夺、免疫抑制性细胞因子以及肿瘤抗原的持续刺激。这些恶劣条件驱动T细胞的全局表观遗传重塑，并促进其转变为T细胞耗竭状态，其特征是增殖能力受损、促炎细胞因子产生减少以及自我更新能力减弱。免疫检查点阻断(ICB)治疗彻底改变了癌症治疗；然而，它未能重编程与耗竭相关的表观遗传格局，因此仅部分恢复T细胞功能。在此，我们旨在通过异位表达表观遗传重编程因子(ERF)靶向该表观遗传格局，从而预防T细胞耗竭。为此，我们首先构建了一个可诱导ERF表达的小鼠模型，分离CD8+ T细胞，并在缺氧条件下对其进行持续刺激培养，以模拟TME。在这些条件下，ERF因子的异位表达显著下调了耗竭标志物如Tim3的表达。我们接下来评估了ERF介导的重编程是否能恢复T细胞功能。在体外，与未重编程的对照T细胞相比，ERF重编程的T细胞在应对耗竭信号时表现出更强的持久性。在体内，将ERF重编程的T细胞转移到荷瘤小鼠中时，与转移非ERF表达的对照T细胞相比，显著延迟了肿瘤生长。转录组学分析进一步揭示，ERF重编程上调了参与T细胞激活、增殖和表观遗传重塑的基因。总之，这些数据支持ERF介导的T细胞重编程作为一种有前景的策略，重塑根深蒂固的耗竭相关表观遗传格局并恢复T细胞功能，具有改善基于过继细胞转移(ACT)的疗法如肿瘤浸润淋巴细胞(TIL)和嵌合抗原受体(CAR)T疗法的潜力。
查看英文原文 English abstract
During tumor progression, T cells are recruited to the tumor microenvironment (TME), where T cells experience hypoxia, nutrient deprivation, immunosuppressive cytokines, and continuous stimulation by tumor antigens. These harsh conditions drive global epigenetic remodeling of T cells and promote their transition into a state of T cell exhaustion, characterized by impaired capacity in proliferation, reduced production of proinflammatory cytokines, and diminished self-renewal. Immune checkpoint blockade (ICB) treatment has revolutionized cancer therapy; however, it fails to reprogram the exhaustion-associated epigenetic landscape and therefore only partially restores T cell functions. Here, we aim to prevent T cell exhaustion by targeting this epigenetic landscape through ectopic expression of epigenetic reprogramming factors (ERFs). To this end, we first generated a mouse model with inducible ERF expression, isolated CD8+ T cells, and cultured them under hypoxic conditions with continuous stimulation, to mimic the TME. Under these conditions, ectopic expression of ERF factors significantly downregulates expression of exhaustion markers such as Tim3. We next assessed whether ERF-mediated reprogramming can restore the T cell function. In vitro, ERF-reprogrammed T cells exhibit increased durability compared to non-reprogrammed control T cells in response to exhaustion signals. In vivo, ERF-reprogrammed T cells, when transferred into tumor-bearing mice, significantly delays the tumor growth compared with transfer of non-ERF-expressing control T cells. Transcriptomics profiling further reveals that ERF reprogramming upregulates the genes involved in T cell activation, proliferation, and epigenetic remodeling. Collectively, these data support ERF-mediated reprogramming of T cells as a promising strategy to reshape the entrenched exhaustion-associated epigenetic landscape and restore T cell functions, with the potential to improve adoptive cell transfer (ACT)-based therapy such as Tumor-Infiltrating Lymphocytes (TIL) and Chimeric Antigen Receptor (CAR) T therapy.
利益披露 Disclosure
T. Hsieh, None..
R. Xin, None..
E. Zhao, None..
X. Tian, None.