Gong Pei, Zhao Lijiao, Ma Yunlong, Shu Qiuting, Sun Hui, Lu Jing, Meng Fanhua, Wan Fang
Tumor Molecular Pharmacology Laboratory, College of Life Sciences, Inner Mongolia Agricultural University, Hohhot 010011, China.
Pharmaceuticals (Basel). 2025 Mar 27;18(4):471. doi: 10.3390/ph18040471.
Glioblastoma is "cold". Consequently, immune checkpoint blockade therapy has failed to improve patients' survival, which is negatively correlated with patients' peripheral MDSC counts. AHR is known to mediate immune-suppressive functions of certain tryptophan metabolites such as kynurenine; yet, there lack of reports on how AHR agonists affect glioma immunity. : We hypothesized that ITE could synergize with PD1 antibody as AHR is one major node of immune-suppressive pathways, and tested it using an immune-competent mouse glioma model. : The combination of ITE+PD1 antibody glioma MDSC was significantly reduced, along with increased infiltration of the CD4-CD8+ and CD4+CD8+ T cells, leading to extended mouse survival. ITE treatment alone significantly reduces the infiltration of CD11b+Ly6G+Ly6Clo cells, namely PMN-MDSCs, and neutrophils, while the combination with PD1 antibody significantly reduces all MDSCs plus neutrophils. The presence of ITE inhibits the expression of IL11 and the in vitro induction of MDSCs from mouse PBMCs by IL11. The identification of the ITE-AHR-IL11-MDSC pathway provides more mechanistic insights into AHR's effects. The fact that ITE, which is otherwise immune-suppressive, can activate immunity in glioma indicates that searching for drugs targeting AHR should go beyond antagonists.
胶质母细胞瘤是“冷”肿瘤。因此，免疫检查点阻断疗法未能提高患者的生存率，这与患者外周髓源性抑制细胞（MDSC）计数呈负相关。已知芳烃受体（AHR）介导某些色氨酸代谢产物如犬尿氨酸的免疫抑制功能；然而，关于AHR激动剂如何影响胶质瘤免疫的报道却很少。我们假设，由于AHR是免疫抑制途径的一个主要节点，ITE可以与PD1抗体协同作用，并使用具有免疫活性的小鼠胶质瘤模型进行了测试。ITE + PD1抗体联合使用可显著减少胶质瘤MDSC，同时增加CD4 - CD8 +和CD4 + CD8 + T细胞的浸润，从而延长小鼠生存期。单独使用ITE治疗可显著减少CD11b + Ly6G + Ly6Clo细胞（即多形核MDSC，PMN - MDSC）和中性粒细胞的浸润，而与PD1抗体联合使用则可显著减少所有MDSC以及中性粒细胞。ITE的存在可抑制IL11的表达以及IL11对小鼠外周血单个核细胞（PBMC）体外诱导MDSC的作用。ITE - AHR - IL11 - MDSC途径的确定为AHR的作用提供了更多的机制性见解。原本具有免疫抑制作用的ITE能够激活胶质瘤中的免疫反应，这一事实表明，寻找靶向AHR的药物不应局限于拮抗剂。
