LW106, a novel indoleamine 2,3-dioxygenase 1 inhibitor, suppresses tumour progression by limiting stroma-immune crosstalk and cancer stem cell enrichment in tumour micro-environment
LW106, a novel indoleamine 2,3-dioxygenase 1 inhibitor, suppresses tumour progression by limiting stroma-immune crosstalk and cancer stem cell enrichment in tumour micro-environment
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LW106 是一种新型吲哚胺 2,3-双加氧酶 1 抑制剂，通过限制肿瘤微环境中的基质免疫串扰和癌症干细胞富集来抑制肿瘤进展
DOI：
10.1111/bph.14351
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发表时间：
2018-07-01
影响因子：
7.3
通讯作者：
Wu, Zhao-Qiu
中科院分区：
文献类型：
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作者：
Fu, Rong;Zhang, Yi-Wei;Wu, Zhao-Qiu
背景与目的吲哚胺2,3-双加氧酶1 （IDO1）正成为治疗以色氨酸代谢失调为特征的恶性肿瘤的重要新靶点。然而，现有的IDO1小分子抑制剂的抗肿瘤效果仍不令人满意，其潜在机制仍未明确。因此，我们发现了一种新的有效的IDO1小分子抑制剂LW106，并在两种肿瘤模型中研究了其抗肿瘤作用及其潜在机制。实验方法c57bl6小鼠、胸腺裸小鼠或Ido1（-/-）小鼠分别接种表达Ido1和不表达Ido1的肿瘤细胞，用载药、依帕加他或增加剂量的LW106处理。采集异种移植的肿瘤、血浆、脾脏和其他重要器官，进行犬尿氨酸/色氨酸测定、流式细胞术、组织学和免疫组织化学分析。slw106剂量依赖性地抑制C57BL6小鼠而非裸小鼠或Ido1（-/-）小鼠的外植肿瘤生长，显示出比现有Ido1抑制剂epacadostat更强的抗肿瘤作用。LW106显著提高肿瘤内增殖性T-eff细胞的浸润，同时减少增殖性t - regg细胞和非造血基质细胞（如内皮细胞和癌症相关成纤维细胞）的募集。LW106治疗导致异种移植肿瘤中癌症干细胞（CSCs）亚群减少，其中增殖/侵袭性肿瘤细胞减少，凋亡肿瘤细胞增多。结论和意义slw106通过限制肿瘤微环境中基质免疫串扰和CSC富集抑制肿瘤生长。LW106有潜力作为一种免疫治疗剂与免疫检查点抑制剂和（或）化疗药物联合使用，用于癌症治疗。
Background and PurposeIndoleamine 2,3-dioxygenase 1 (IDO1) is emerging as an important new therapeutic target for treatment of malignant tumours characterized by dysregulated tryptophan metabolism. However, the antitumour efficacy of existing small-molecule inhibitors of IDO1 is still unsatisfactory and the underlying mechanism remains largely undefined. Hence, we discovered a novel potent small-molecule inhibitor of IDO1, LW106, and studied its antitumour effects and the underlying mechanisms in two tumour models.Experimental ApproachC57BL6 mice, athymic nude mice or Ido1(-/-) mice were inoculated with IDO1-expressing and -nonexpressing tumour cells and treated with vehicle, epacadostat or increasing doses of LW106. Xenografted tumours, plasma, spleens and other vital organs were harvested and subjected to kynurenine/tryptophan measurement and flow cytometric, histological and immunohistochemical analyses.Key ResultsLW106 dose-dependently inhibited the outgrowth of xenografted tumours that were inoculated in C57BL6 mice but not nude mice or Ido1(-/-) mice, showing a stronger antitumour efficacy than epacadostat, an existing IDO1 inhibitor. LW106 substantially elevated intratumoural infiltration of proliferative T-eff cells, while reducing recruitment of proliferative T-reg cells and non-haematopoietic stromal cells such as endothelial cells and cancer-associated fibroblasts. LW106 treatment resulted in a reduced subpopulation of cancer stem cells (CSCs) in xenografted tumours in which fewer proliferative/invasive tumour cells and more apoptotic tumour cells were observed.Conclusions and ImplicationsLW106 inhibits tumour outgrowth by limiting stroma-immune crosstalk and CSC enrichment in the tumour micro-environment. LW106 has potential as a immunotherapeutic agent for use in combination with immune checkpoint inhibitors and (or) chemotherapeutic drugs for cancer treatment.