The success of cancer vaccines relies on the ability of dendritic cells (DCs) to efficiently prime cytotoxic CD8 T cell responses against tumors. However, in solid tumors this process is often undermined by tumor-driven immunosuppression and intrinsic defects in DC activation. Among the signaling pathways implicated in DC dysfunction, β-catenin signaling has emerged as a key regulator of immune tolerance in DCs. In parallel, inhibitory receptors such as PD-L1 and TIM-3 on DCs have been recognized as critical DC-intrinsic brakes on CD8 T cell priming and on responses to immune checkpoint blockade (ICB). Recent work has identified a DC-intrinsic immunoregulatory circuit in which β-catenin activation in DCs—particularly in cross-presenting cDC1s—induces expression of TIM-3, thereby suppressing CD8 T cell cross-priming and limiting anti-tumor CD8 T cell immunity. This β-catenin–TIM-3 axis represents a previously underappreciated layer of negative regulation that may help explain, at least in part, the limited efficacy of many current DC-based cancer vaccines. In this review, we examine how β-catenin activation in DCs, particularly in cDC1s, induces TIM-3 and related inhibitory programs that suppress cross-priming of tumor antigen-specific CD8 T cells and constrain the efficacy of DC-based vaccines. We further discuss how selectively targeting this β-catenin–TIM-3 checkpoint axis—alone or together with PD-L1 and other β-catenin–linked receptors—could restore DC function and inform rational combinations of DC-based vaccination with ICB and other T cell-based immunotherapies.
癌症疫苗的成功依赖于树突状细胞有效启动针对肿瘤的细胞毒性CD8 T细胞反应的能力。然而，在实体瘤中，这一过程常因肿瘤驱动的免疫抑制及树突状细胞活化的内在缺陷而受到削弱。在导致树突状细胞功能异常的信号通路中，β-连环蛋白信号已成为调控树突状细胞免疫耐受的关键因子。同时，树突状细胞表面的PD-L1、TIM-3等抑制性受体也被确认为抑制CD8 T细胞启动及免疫检查点阻断疗效的重要内在制动机制。近期研究揭示了一种树突状细胞内在的免疫调节回路：树突状细胞（尤其是交叉呈递型cDC1）中β-连环蛋白的活化会诱导TIM-3表达，从而抑制CD8 T细胞的交叉启动并限制抗肿瘤CD8 T细胞免疫。这种β-连环蛋白–TIM-3轴代表了一种先前未被充分认识的负向调控机制，可能部分解释了当前多数基于树突状细胞的癌症疫苗疗效有限的原因。本文综述了树突状细胞（特别是cDC1）中β-连环蛋白活化如何诱导TIM-3及相关抑制程序，从而抑制肿瘤抗原特异性CD8 T细胞的交叉启动并限制树突状细胞疫苗的疗效。我们进一步探讨了选择性靶向β-连环蛋白–TIM-3检查点轴（单独或联合PD-L1等其他β-连环蛋白相关受体）如何恢复树突状细胞功能，并为基于树突状细胞的疫苗与免疫检查点阻断及其他T细胞免疫疗法的理性联合策略提供依据。
Rewiring Dendritic Cell Immunity: The β-Catenin–TIM-3 Axis as a Target to Improve DC Cancer Vaccines
肿瘤(癌症)患者之家