IFN-β激活IDO1-Kyn-AhR信号通路调节肿瘤再生细胞休眠

How immunological cues induce stem-like cancer cells to enter dormancy remains an enigma. Previously, we developed 3D fibrin gel culture system to select and amplify tumor-repopulating cells (TRC). Adapting this method, we found that IFN-β induced TRCs into dormancy with an increased IDO1 expression. IDO1 is an enzyme that metabolizes tryptophan to kynurenine (Kyn), an endogenous ligand of AhR. Intriguingly, we found that Kyn treatment also induced TRCs into dormancy, while IDO1/AhR inhibitor resulted in apoptosis of IFN-β-induced dormant TRCs. Based on these results, we hypothesize that IFN-β induces TRCs into dormancy by regulating IDO1-Kyn-AhR pathway and blocking this pathway leads to the death of dormant TRCs. In this study, we will elucidate that different types of TRCs can be induced into dormancy by IFN-β through the IDO1-Kyn-AhR pathway both in vitro and in vivo. Meanwhile, we will identify the AhR-targeted genes involved in IFN-β induced TRC dormancy and investigate the novel tumor immunotherapy to kill dormant TRCs. This study will provide insights into how innate immunological cues induce TRCs into dormancy and provide potent strategies for effective tumor immunotherapy against tumor recurrence and resistance.

先天免疫信号诱导干性的肿瘤细胞进入休眠机理尚不清。课题组前期建立了一种纤维蛋白三维软胶技术，体外扩增干性的肿瘤再生细胞（TRC）。利用该方法，申请人发现IFN-β促进TRC上调表达吲哚胺2,3-双加氧酶（IDO1），其催化的中间代谢产物犬尿氨酸（Kyn）作为内源性配体，结合芳香烃族受体（AhR），从而诱导TRC休眠，而针对IDO1或AhR的抑制剂则导致休眠的TRC凋亡。基于此，本课题提出科学假设：IFN-β通过IDO1-Kyn-AhR通路诱导TRC进入休眠，而阻断此信号通路则引起休眠的TRC凋亡。为此，本项目拟体内外证实：IFN-β诱导不同肿瘤类型的TRC进入休眠；IDO1-Kyn-AhR介导休眠机理以及相关靶基因鉴定；最后探究以休眠TRC为靶点的新型免疫疗法。本项目探究先天免疫信号诱导干性肿瘤细胞休眠这一肿瘤免疫全新领域，具有创新性，为以肿瘤复发与耐药为靶标的免疫疗法提供新思路。

免疫系统与肿瘤的互作可以调控肿瘤细胞进入休眠。然而，免疫信号如何触发肿瘤细胞进入休眠，至今不清。在此，我们发现IFN-β治疗通过激活吲哚胺2,3-双加氧酶/犬尿氨酸/芳基烃受体/p27（IDO/Kyn/AhR/p27）信号通路诱导肿瘤再生细胞（TRC）进入休眠状态。在小鼠和人黑色素瘤模型中，阻断这种代谢回路的策略并不能解除休眠，但会导致休眠的TRC凋亡。具体而言，阻断AhR可通过酪氨酸和丝氨酸位点将IFN-β信号重新定向到STAT3磷酸化，从而促进STAT3核易位，并随后与细胞核中的p53启动子结合。p53的上调反过来破坏磷酸戊糖途径，导致ROS过度产生和休眠TRC死亡。此外，在黑色素瘤患者中，IFN-β的高表达与肿瘤细胞休眠相关。IFN-β控制TRC休眠机制的探索为癌症-免疫相互作用和潜在的新型癌症免疫治疗模式提供了更深入的见解。