The impact of non-small cell lung cancer (NSCLC) metabolism on the immune microenvironment is not well understood within platinum resistance. We have identified crucial metabolic differences between cisplatin-resistant (CR) and cisplatin-sensitive (CS) NSCLC cells with elevated indoleamine 2,3-dioxygenase-1 (IDO1) activity in CR, recognized by increased kynurenine (KYN) production. Co-culture, syngeneic, and humanize mice models were utilized. C57BL/6 mice were inoculated with either Lewis lung carcinoma mouse cells (LLC) or their platinum-resistant counterpart (LLC-CR) cells. Humanized mice were inoculated with either A (human CS cells) or ALC (human CR cells). Mice were treated with either IDO1 inhibitor or TDO2 (tryptophan 2,3-dioxygenase-2) inhibitor at 200 mg/kg P.O. once a day for 15 days; or with a new-in-class, IDO1/TDO2 dual inhibitor AT-0174 at 170 mg/kg P.O. once a day for 15 days with and without anti-PD1 antibody (10 mg/kg, every 3 days). Immune profiles and KYN and tryptophan (TRP) production were evaluated. CR tumors exhibited a more highly immunosuppressive environment that debilitated robust anti-tumor immune responses. IDO1-mediated KYN production from CR cells suppressed NKG2D on immune effector natural killer (NK) and CD8+ T cells and enhanced immunosuppressive populations of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Importantly, while selective IDO1 inhibition attenuated CR tumor growth, it concomitantly upregulated the TDO2 enzyme. To overcome the compensatory induction of TDO2 activity, we employed the IDO1/TDO2 dual inhibitor, AT-0174. Dual inhibition of IDO1/TDO2 in CR mice suppressed tumor growth to a greater degree than IDO1 inhibition alone. Significant enhancement in NKG2D frequency on NK and CD8+ T cells and a reduction in Tregs and MDSCs were observed following AT-1074 treatment. PD-L1 (programmed death-ligand-1) expression was increased in CR cells; therefore, we assessed dual inhibition + PD1 (programmed cell death protein-1) blocking and report profound anti-tumor growth and improved immunity in CR tumors which in turn extended overall survival in mice. Our study reports the presence of platinum-resistant lung tumors that utilize both IDO1/TDO2 enzymes for survival, and to escape immune surveillance as a consequence of KYN metabolites. We also report early in vivo data in support of the potential therapeutic efficacy of the dual IDO1/TDO2 inhibitor AT-0174 as a part of immuno-therapeutic treatment that disrupts tumor metabolism and enhances anti-tumor immunity.

中文翻译：

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IDO1/TDO2 双重抑制增强铂耐药非小细胞肺癌的抗肿瘤免疫力

非小细胞肺癌 (NSCLC) 代谢对免疫微环境的影响在铂类耐药性方面尚不清楚。我们已经确定了顺铂耐药 (CR) 和顺铂敏感 (CS) NSCLC 细胞之间的关键代谢差异，CR 中吲哚胺 2,3-双加氧酶-1 (IDO1) 活性升高，犬尿氨酸 (KYN) 产量增加。使用了共培养、同基因和人源化小鼠模型。C57BL/6 小鼠接种 Lewis 肺癌小鼠细胞 (LLC) 或其铂抗性对应物 (LLC-CR) 细胞。用 A（人 CS 细胞）或 ALC（人 CR 细胞）接种人源化小鼠。用 IDO1 抑制剂或 TDO2（色氨酸 2,3-双加氧酶-2）抑制剂以 200 mg/kg PO 每天一次治疗小鼠，持续 15 天；或与班级新人一起，IDO1/TDO2 双抑制剂 AT-0174，170 mg/kg PO，每天一次，持续 15 天，使用和不使用抗 PD1 抗体（10 mg/kg，每 3 天一次）。评估了免疫概况以及 KYN 和色氨酸 (TRP) 的产生。CR 肿瘤表现出更高的免疫抑制环境，削弱了强大的抗肿瘤免疫反应。IDO1 介导的 CR 细胞 KYN 产生抑制了免疫效应自然杀伤细胞 (NK) 和 CD8+ T 细胞上的 NKG2D，并增强了调节性 T 细胞 (Treg) 和髓源性抑制细胞 (MDSC) 的免疫抑制群体。重要的是，虽然选择性 IDO1 抑制减弱了 CR 肿瘤的生长，但它同时上调了 TDO2 酶。为了克服 TDO2 活性的补偿性诱导，我们采用了 IDO1/TDO2 双重抑制剂 AT-0174。与单独抑制 IDO1 相比，CR 小鼠中 IDO1/TDO2 的双重抑制在更大程度上抑制了肿瘤生长。在 AT-1074 处理后观察到 NKG2D 频​​率在 NK 和 CD8+ T 细胞上的显着增强以及 Treg 和 MDSC 的减少。PD-L1（程序性死亡配体-1）表达在 CR 细胞中增加；因此，我们评估了双重抑制 + PD1（程序性细胞死亡蛋白-1）阻断，并报告了 CR 肿瘤的显着抗肿瘤生长和提高的免疫力，从而延长了小鼠的总体存活率。我们的研究报告了铂耐药肺肿瘤的存在，这些肿瘤利用 IDO1/TDO2 酶来生存，并由于 KYN 代谢物而逃避免疫监视。