Taş İsa, Varlı Mücahit, Pulat Sultan, Sim Hyun Bo, Kim Jong-Jin, Kim Hangun
College of Pharmacy, Sunchon National University, Sunchon, 57922, Jeonnam, Republic of Korea.
Department of Biomedical Science, Sunchon National University, Sunchon, 57922, Jeonnam, Republic of Korea.
Cancer Metab. 2024 Nov 26;12(1):36. doi: 10.1186/s40170-024-00365-z.
Benzo[a]pyrene (BaP) is a toxic polycyclic aromatic hydrocarbon known as an exogenous AhR ligand. This study investigates the role of BaP in inducing immune checkpoint expression in lung adenocarcinoma (LUAD) and the underlying mechanisms involving the aryl hydrocarbon receptor (AhR) and tryptophan (Trp) metabolism.
We assessed the expression of immune checkpoint molecules, including PD-L1 and ICOSL, in lung epithelial cell lines (BEAS-2B and H1975) exposed to BaP. The involvement of AhR in BaP-induced immune checkpoint expression was examined using AhR silencing (siAhR). Additionally, the role of Trp metabolism in BaP-mediated immune evasion was explored through culturing in Trp (-/+) condition media, treatments with the inhibitors of rate-limiting enzymes in Trp metabolism (TDO2 and IDO1) and analyses of Trp-catabolizing enzymes. The therapeutic potential of targeting Trp metabolism, specifically TDO2, was evaluated in vivo using C57BL/6 mice orthotopically inoculated with LUAD cells.
BaP exposure significantly upregulated the mRNA and surface expression of PD-L1 and ICOSL, with AhR playing a crucial role in this induction. Trp metabolism was found to enhance BaP-mediated immune evasion, as indicated by stronger induction of immune checkpoints in Trp (+) media and the upregulation of Trp-catabolizing enzymes. TDO2 inhibition markedly suppressed the surface expression of PD-L1 and ICOSL, demonstrating the importance of Trp metabolism in BaP-induced immune evasion. Further analysis confirmed the high TDO2 expression in lung adenocarcinoma and its association with poor patient survival. Using an orthotopic implantation mouse model, we demonstrated the inhibitory effect of two different TDO2 inhibitors on tumorigenesis, immune checkpoints, and tryptophan metabolism.
This study highlights the key mechanisms behind BaP-induced immune evasion in LUAD, particularly through the TDO2/AhR axis. It reveals how TDO2 inhibitors can counteract immune checkpoint activation and boost anti-tumor immunity, suggesting new paths for targeted lung cancer immunotherapy. The findings significantly improve our understanding of immune evasion in LUAD and underscore the therapeutic promise of TDO2 inhibition.
苯并[a]芘（BaP）是一种有毒的多环芳烃，是一种外源性芳烃受体（AhR）配体。本研究调查了BaP在诱导肺腺癌（LUAD）中免疫检查点表达中的作用以及涉及芳烃受体（AhR）和色氨酸（Trp）代谢的潜在机制。
我们评估了暴露于BaP的肺上皮细胞系（BEAS-2B和H1975）中免疫检查点分子的表达，包括程序性死亡配体1（PD-L1）和可诱导共刺激分子配体（ICOSL）。使用AhR沉默（siAhR）研究AhR在BaP诱导的免疫检查点表达中的作用。此外，通过在色氨酸（Trp）（-/+）条件培养基中培养、用色氨酸代谢限速酶抑制剂（色氨酸2,3-双加氧酶（TDO2）和吲哚胺2,3-双加氧酶1（IDO1））处理以及分析色氨酸分解代谢酶，探讨色氨酸代谢在BaP介导的免疫逃逸中的作用。使用原位接种LUAD细胞的C57BL/6小鼠在体内评估靶向色氨酸代谢（特别是TDO2）的治疗潜力。
暴露于BaP显著上调了PD-L1和ICOSL的mRNA和表面表达，AhR在这种诱导中起关键作用。发现色氨酸代谢增强了BaP介导的免疫逃逸，如在色氨酸（+）培养基中免疫检查点的更强诱导和色氨酸分解代谢酶的上调所示。TDO2抑制显著抑制了PD-L1和ICOSL的表面表达，证明了色氨酸代谢在BaP诱导的免疫逃逸中的重要性。进一步分析证实了TDO2在肺腺癌中的高表达及其与患者不良生存的关联。使用原位植入小鼠模型，我们证明了两种不同的TDO2抑制剂对肿瘤发生、免疫检查点和色氨酸代谢的抑制作用。
本研究强调了LUAD中BaP诱导免疫逃逸背后的关键机制，特别是通过TDO2/AhR轴。它揭示了TDO2抑制剂如何抵消免疫检查点激活并增强抗肿瘤免疫力，为靶向肺癌免疫治疗提出了新途径。这些发现显著提高了我们对LUAD中免疫逃逸的理解，并强调了TDO2抑制的治疗前景。
