期刊
BIOCHEMICAL PHARMACOLOGY
卷 145, 期 -, 页码 132-146出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2017.08.019
关键词
Tumor associated macrophages; Regulatory T cells; Jak2-STAT3 pathway; Tumor immunotherapy
资金
- National Basic Research Program of China [2012CB517603]
- National High Technology Research and Development Program of China [2014AA020707]
- National Natural Science Foundation of China [31271013, 31170751, 31200695, 31400671, 51173076, 51503232, 91129712, 81102489]
- Program for New Century Excellent Talents in University [NCET-13-0272]
- Nanjing University State Key Laboratory of Pharmaceutical Biotechnology Open Grant [02ZZYJ-201307]
- University of Macau [MYRG2015-00160-ICMS-QRCM]
- opening fund of the State Key Laboratory of Quality Research in Chinese Medicine, University of Macau [005]
Small molecule therapeutics can be potent tools for cancer immunotherapy. They may be devised to target the tumor associated macrophages (TAMs) and regulatory T cells (Treg), which are major immunosuppressive cells in the tumor microenvironment. The infiltration and functionalization of these cells, which essentially promote tumor development, are mediated by the hyper-activation of the Jak-STAT3 signaling pathway. Here, we demonstrated that compound 9#, a novel inhibitor of Jak2, could suppress Jak2-STAT3 signaling in macrophages (peritoneal macrophages and THP-1 cells) and direct the macrophages toward the pro-inflammatory (M1-like) phenotype. When tested in ex vivo TAM culture and in vivo tumor models, compound 9# could reverse the phenotype of TAM from M2- to M1-type by promoting IL-12 expression. Further study suggested that compound 9# also inhibited the induction of Treg both in vitro and in vivo via blockage of Jak2 signaling. Finally, compound 9# potently increased the frequency and anti-tumor activity of CD4(+) and CD/8(+) T lymphocytes, leading to effective suppression of tumor growth. Taken together, our findings indicated that compound 9# could be a potential candidate of small molecule therapeutics for cancer immunotherapy. (C) 2017 Elsevier Inc. All rights reserved.
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