Pharmacological Targeting of ALDH1a2 in Dendritic Cells Enhances Antigen Presentation, T Cell Activation and Anti-tumor immunity

Dendritic cell (DC) vaccines have been proposed as cancer immunotherapies due to their role as crucial antigen-presenting cells that regulate T cell functions. Despite considerable efforts to optimize ex vivo priming of DCs, DC vaccines have rarely been successful, suggesting the presence of unknown inhibitory factors. Here, we examined DC differentiation dynamics and discovered that ALDH1a2-produced retinoic acid (RA) acts as a bottleneck factor, initiating negative feedback to inhibit DC maturation. Removing this inhibition through either genetic knockout or pharmacological blockade using KyA33, an ALDH1a2 inhibitor we developed, significantly enhances DC maturation, phagocytosis, antigen presentation, and T cell activation, in part by downregulating glucose metabolism. KyA33 demonstrates favorable drug-like properties, including low toxicity, high membrane permeability, and low cell efflux rate. Its non-covalent binding to ALDH1A2 was also validated through X-ray crystallography. Importantly, application of KyA33 generates more robust DCs vaccines, promoting anti-tumor immunity through enhancing antigen-specific T cell responses. Our investigation highlights the intricate interplay between retinoid signaling, dendritic cell maturation, and immune metabolism, offering promising avenues for enhancing cancer immunotherapies.

树突状细胞（dendritic cell, DC）疫苗因其作为调控T细胞功能的关键抗原呈递细胞的作用，被提出作为癌症免疫疗法候选方案。尽管在优化DC体外预激活方面已付出大量努力，但DC疫苗鲜有获得成功的案例，这提示存在尚未被阐明的抑制性因素。本研究对DC分化动态进行了系统考察，发现ALDH1a2生成的视黄酸（retinoic acid, RA）作为瓶颈因子，启动负反馈通路以抑制DC成熟。通过基因敲除或使用我们自主开发的ALDH1a2抑制剂KyA33进行药物阻断来解除该抑制作用，可显著增强DC成熟、吞噬作用、抗原呈递及T细胞活化能力，其部分机制为下调葡萄糖代谢通路。KyA33展现出优良的类药性质，包括低毒性、高膜通透性及低细胞外排速率。通过X射线晶体学实验，我们验证了其与ALDH1A2的非共价结合特性。值得注意的是，使用KyA33可制备出活性更强的DC疫苗，通过增强抗原特异性T细胞应答来促进抗肿瘤免疫。本研究揭示了类视黄醇信号通路、DC成熟与免疫代谢之间的复杂相互作用，为优化癌症免疫疗法提供了极具潜力的研究方向。