肿瘤微环境
免疫疗法
癌症研究
癌症免疫疗法
CD8型
免疫系统
肝细胞癌
肿瘤相关巨噬细胞
癌症
PD-L1
肝癌
单克隆抗体
T细胞
巨噬细胞
医学
免疫学
抗体
生物
体外
内科学
生物化学
作者
Limin Ding,Junjie Qian,Xiao Yu,Qinchuan Wu,Jing Mao,Lifeng Xi,Yübo Wang,Danjing Guo,Rong Su,Haiyang Xie,Shengyong Yin,Lin Zhou,Shusen Zheng
标识
DOI:10.1016/j.canlet.2023.216568
摘要
The PD-L1/PD-1 axis is a classic immunotherapy target. However, anti-PD-L1/PD-1 therapy alone can not achieve satisfactory results in solid tumors, especially liver cancer. Among the several factors involved in tumor anti-PD-L1/PD-1 treatment resistance, tumor-associated macrophages (TAMs) have attracted attention because of their immunosuppressive ability. TAMs with a macrophage receptor with a collagenous structure (MARCO) are a macrophage subset group with strong immunosuppressive abilities. Clinical specimens and animal experiments revealed a negative correlation between MARCO + TAMs and patient prognosis with liver cancer. Transcriptional data and in vitro and in vivo experiments revealed that MARCO + TAM immunosuppressive ability was related to secretion. MARCO suppressed IFN-β secretion from TAMs, reducing antigen presentation molecule expression, infiltration, and CD8+T cell dysfunction, thus producing an immunosuppressive microenvironment in liver cancer. MARCO can promote dying tumor cell clearance by macrophages, reducing tumor-derived cGAMP and ATP accumulation in the tumor microenvironment and inhibiting sting–IFN–β pathway activation mediated by P2X7R in MARCO+TAMs. Animal experiments revealed that the MARCO and PD-L1 monoclonal antibody combination could significantly inhibit liver cancer growth. Conclusively, targeting MARCO+TAMs can significantly improve anti-PD-L1 resistance in liver cancer, making it a potential novel immune target for liver cancer therapy.
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