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. (3rd June 2018)

• Record Type: Journal Article
• Authors: Fu, Rong; Zhang, Yi‐Wei; Li, Hong‐Mei; Lv, Wen‐Cong; Zhao, Li; Guo, Qing‐Long; Lu, Tao; Weiss, Stephen J; Li, Zhi‐Yu; Wu, Zhao‐Qiu
• Is Part Of: British journal of pharmacology. Volume 175:Number 14(2018)
• Page Start: 3034
• Page End: 3049
• Publication Date: 2018-06-03
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.14351
• Languages: English
• ISSNs: 0007-1188

Abstract

Abstract : Background and Purpose: Indoleamine 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 Approach: C57BL6 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 Results: LW106 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 Teff cells, while reducing recruitment of proliferative Treg 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 Implications: LW106 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.