Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 175, Issue 14, Pages 3034-3049Publisher
WILEY
DOI: 10.1111/bph.14351
Keywords
-
Categories
Funding
- National Natural Science Foundation of China [81572745, 91539115, 81603134]
- Jiangsu Provincial Natural Science Fund for Distinguished Young Scholar [BK20170029]
- Jiangsu Provincial Natural Science Fund for Young Scholar [BK20160758]
- Jiangsu Provincial Innovative Research Program
- State Key Laboratory of Natural Medicines of China Pharmaceutical University [SKLNMZZJQ201604]
- Collaborative Innovation Center for Gannan Oil-Tea Camellia Industrial Development [YP201608]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available