PO.CL05.04 · 临床研究
靶向ITGB3逆转终末期T细胞耗竭以增强食管鳞状细胞癌的治疗疗效
Targeting ITGB3 reverses terminal T cell exhaustion to enhance therapeutic efficacy in esophageal squamous cell carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
终末期T细胞耗竭是限制免疫检查点阻断疗法在实体瘤中疗效的关键障碍，但其潜在机制仍有待充分阐明。基于我们前期工作建立的食管鳞状细胞癌（ESCC）小鼠细胞系mEC25，我们成功构建了能够有效反映ESCC免疫动态的免疫健全型ESCC小鼠CDX（细胞来源异种移植）模型。对这一动态皮下ESCC模型进行的单细胞测序分析勾勒出17个T细胞亚群，揭示了T细胞从激活和效应状态向耗竭及终末期耗竭的转变过程。在这些亚群中，ITGB3+ T细胞表现出中等的细胞毒性和中等的耗竭水平。拟时序分析证实，ITGB3+ T细胞位于T细胞向终末期耗竭转变的关键节点，可能通过整合素信号调控在效应状态与耗竭状态之间架起桥梁。为此，我们使用了ITGB3中和抗体。体外肿瘤-T细胞共培养实验显示，采用这些抗体处理可恢复T细胞增殖、上调IFN-gamma和颗粒酶A的分泌，并增强肿瘤杀伤能力。体内研究表明，在肿瘤早期形成阶段给予ITGB3中和处理，可有效减少ESCC肿瘤生长、促进T细胞浸润至肿瘤微环境，并减少耗竭T细胞库。此外，与PD-1抑制剂的联合治疗进一步放大了这些效应：体内实验显示协同性肿瘤抑制作用，治疗小鼠的T细胞细胞毒性增强且生存期延长。在组织芯片上进一步进行的多重免疫组织化学染色证实，PD-1+ IFN-gamma+双阳性T细胞中ITGB3表达升高与ESCC患者的肿瘤进展和不良预后相关，凸显ITGB3作为T细胞功能障碍生物标志物的价值。这些发现揭示了ESCC中T细胞治疗耐药的分子基础，并为改善实体瘤免疫治疗疗效提供了一种新策略。
查看英文原文 English abstract
Terminal T cell exhaustion represents a critical barrier limiting the efficacy of immune checkpoint blockade therapies in solid tumors, yet the underlying mechanisms remain to be fully elucidated. Based on the esophageal squamous cell carcinoma (ESCC) mouse cell line mEC25 established in our previous work, we successfully constructed an immunocompetent ESCC mouse CDX (cell-derived xenograft) model that effectively reflects the immune dynamics of ESCC. Single-cell sequencing analysis of this dynamic subcutaneous ESCC model delineated 17 T cell subpopulations, revealing the transition of T cells from activated and effector states to exhaustion and terminal exhaustion. Among these subsets, ITGB3+ T cells exhibited moderate cytotoxicity and moderate exhaustion levels. Pseudotime analysis confirmed that ITGB3+ T cells reside at a critical node in the transition of T cells toward terminal exhaustion, potentially bridging effector and exhausted states through integrin signaling modulation. To address this, we utilized ITGB3-neutralizing antibodies. In vitro tumor-T cell co-culture assays showed that treatment with these antibodies restored T cell proliferation, upregulated the secretion of IFN-gamma and granzyme A, and enhanced tumor-killing capacity. In vivo studies demonstrated that neutralizing ITGB3, when administered during early tumor formation, effectively reduces ESCC tumor growth, promotes T cell infiltration into the tumor microenvironment, and diminishes the exhausted T cell pool. Additionally, combination therapy with PD-1 inhibitors further amplified these effects: in vivo experiments showed synergistic tumor suppression, with enhanced T cell cytotoxicity and prolonged survival in treated mice. Further multiplex immunohistochemistry staining on tissue microarrays confirmed that elevated ITGB3 expression in PD-1+ IFN-gamma+ double-positive T cells correlates with tumor progression and poor patient prognosis in ESCC, highlighting ITGB3 as a biomarker of T cell dysfunction. These findings uncover a molecular basis for T cell therapy resistance in ESCC and provide a novel strategy to improve the efficacy of immunotherapy for solid tumors.
利益披露 Disclosure
B. Yao, None..
S. Zhang, None.