TLR 7/8 agonist reverses oxaliplatin resistance in colorectal cancer via directing the myeloid-derived suppressor cells to tumoricidal M1-macrophages

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]
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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