期刊
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
卷 14, 期 4, 页码 769-788出版社
ELSEVIER INC
DOI: 10.1016/j.jcmgh.2022.07.005
关键词
CD73 Ecto-enzyme; Colorectal Cancer; Extracellular Adenosine; Programmed Death-Ligand 1
资金
- National research foundation of Korea (NRF) of the the Korean government [2021R1C1C1011899]
- Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry (IPET) through the Animal Disease Management Technology Development Program of the Ministry of Agriculture, Food, and Rural Affairs (MAFRA) of the Korean government [318070-3]
- KIT [2021R1C1C1011899]
- KRICT from the Korean government [2021R1C1C1011899]
- [1711159828]
- [SI2231-10]
- National Research Foundation of Korea [2021R1C1C1011899] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
In this study, a novel combination therapy of AB680 and palbociclib was demonstrated to be advantageous for the treatment of CRC.
BACKGROUND & AIMS: Although cancer immunotherapies are effective for advanced-stage cancers, there are no clinically approved immunotherapies for colon cancers (CRCs). Therefore, there is a high demand for the development of novel therapies. Extracellular adenosine-mediated signaling is considered a promising target for advanced-stage cancers that are nonresponsive to programmed death 1 (PD-1)-/programmed death-ligand 1 (PD-L1)-targeted immunotherapies. In this study, we aimed to elucidate novel tumorigenic mechanisms of extracellular adenosine. METHODS: To investigate the effects of extracellular adenosine on tumor-associated macrophages, peripheral blood-derived human macrophages were treated with adenosine and analyzed using flow cytometry and Western blot. Changes in adenosine-treated macrophages were further assessed using multi-omits analysis, including total RNA sequencing and proteomics. Colon cancer mouse models were used to measure the therapeutic efficacy of AB680 and palbociclib. We also used tissue microarrays of patients with CRC, to evaluate their clinical relevance. RESULTS: Extracellular adenosine-mediated reduction of cyclin D1 (CCND1) was found to be critical for the regulation of immune checkpoint molecules and PD-L1 levels in human macrophages, indicating that post-translational modification of PDL1 is affected by adenosine. A potent CD73 selective inhibitor, AB680, reversed the effects of adenosine on CCND1 and PD-L1. This result strongly suggests that AB680 is a combinatory therapeutic option to overcome the undesired side effects of the cyclin-dependent kinase 4/6 inhibitor, palbociclib, which increases PD-L1 expression in tumors. Because palbociclib is undergoing clinical trials for metastatic CRC in combination with cetuximab (clinical trial number: NCT03446157), we validated that the combination of AB680 and palbociclib significantly improved anti-tumor efficacy in CRC animal models, thereby highlighting it as a novel immunotherapeutic strategy. We further assessed whether the level of CCND1 in tumor-associated macrophages was indeed reduced in tumor sections obtained from patients with CRC, for evaluating the clinical relevance of this strategy. CONCLUSIONS: In this study, we demonstrated that a novel combination therapy of AB680 and palbociclib may be advantageous for the treatment of CRC.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据