奥沙利铂
结直肠癌
癌症研究
医学
肿瘤微环境
免疫疗法
髓源性抑制细胞
癌症
免疫学
髓样
抑制器
内科学
作者
Zhipeng Liu,Yue Xie,Yao Xiong,Siliang Liu,Chen Qiu,Zhenhao Zhu,Hua Mao,Meng Yu,Xinying Wang
出处
期刊:Cancer Letters
[Elsevier]
日期:2019-10-17
卷期号:469: 173-185
被引量:124
标识
DOI:10.1016/j.canlet.2019.10.020
摘要
Resistance to oxaliplatin is a major obstacle hindering the clinical treatment of colorectal cancer, but the underlying immunological mechanism has not yet been well illustrated. As a pivotal immunosuppressive component in tumor microenvironment, myeloid-derived suppressor cells (MDSCs) and their differentiated tumor-associated macrophages (TAMs) have been considered to be associated with resistance to chemotherapy. The aim of current study was to investigate the role of MDSCs in oxaliplatin-resistance and antitumor activity in colorectal cancer. Here, we found that tumor-bearing mice treated with oxaliplatin performed remarkably decreasing M-MDSCs and M1-type TAMs differentiated from MDSCs in tumor site, which inspired us to combine immunotherapy that activates M1-like TAMs to conquer oxaliplatin resistance. In addition, this study further confirmed a dose-dependent improvement of M1-like macrophage supernatants on enhancing pro-apoptotic effect and inhibiting migration and invasion of cancer cells incubated with oxaliplatin. Administration of oxaliplatin combined with Toll-like receptors agonists R848 reversed the functional orientation of MDSCs towards M1-like macrophages and strengthened antitumor effect of oxaliplatin. In this study, we uncovered novel immunological mechanism of oxaliplatin-resistance and showed the great potential of TLR7/8 agonist as a new immunologic adjuvant in chemotherapy for oxaliplatin-resistant colorectal cancer.
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