Li Zhengtian, Suo Bing, Long Gang, Gao Yue, Song Jia, Zhang Mengzhe, Feng Baiyu, Shang Ce, Wang Dawei
Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
General Hospital of Heilongjiang Province Land Reclamation Bureau, Harbin, China.
Front Cell Dev Biol. 2020 Nov 30;8:572689. doi: 10.3389/fcell.2020.572689. eCollection 2020.
Macrophages have an affinity to developing tumors and have been shown to play a role in tumor combat and immune surveillance. However, the exact mechanism by which macrophages participate in the anti-tumor immune response remains unclear. Hence, the current study aimed to identify the effect of macrophages on gastric cancer (GC) cells via exosomes. Paired cancerous, tumor-adjacent, and non-cancerous stomach tissues were initially from 68 GC patients. T cells were isolated from peripheral blood mononuclear cells (PBMCs) obtained from both the GC patients as well as the healthy donors. Next, the exosomes were isolated from LPS and IFN-γ-induced PBMCs (M1 macrophages) and co-cultured with human GC cells. Another co-culture system comprised of CD3 T cells and exosomes-treated GC cells was then performed. BALB/c mice and NOD/SCID nude mice were prepared for effects of exosomal miR-16-5p on tumor growth and anti-tumor immune response in GC . A relationship between M1 macrophages and the poor survival of GC patients was identified, while they secreted exosomes to inhibit GC development and activate a T cell-dependent immune response. Our results revealed that miR-16-5p was transferred intercellularly from M1 macrophages to GC cells via exosomes and targeted PD-L1. M1 macrophage-derived exosomes containing miR-16-5p were found to trigger a T cell immune response which inhibited tumor formation both and by decreasing the expression of PD-L1. Taken together, the key findings of the current study suggest that M1 macrophage-derived exosomes carrying miR-16-5p exert an inhibitory effect on GC progression through activation of T cell immune response via PD-L1. Our study highlights the promise of M1 macrophages as a potential cell-based therapy for GC treatment by increasing miR-16-5p in exosomes.
巨噬细胞对正在发展的肿瘤具有亲和力，并且已被证明在肿瘤对抗和免疫监视中发挥作用。然而，巨噬细胞参与抗肿瘤免疫反应的确切机制仍不清楚。因此，本研究旨在通过外泌体确定巨噬细胞对胃癌（GC）细胞的影响。配对的癌组织、肿瘤旁组织和非癌胃组织最初来自68例GC患者。从GC患者和健康供体获得的外周血单核细胞（PBMC）中分离出T细胞。接下来，从脂多糖（LPS）和干扰素-γ（IFN-γ）诱导的PBMC（M1巨噬细胞）中分离出外泌体，并与人GC细胞共培养。然后进行另一个由CD3 T细胞和经外泌体处理的GC细胞组成的共培养系统。制备BALB/c小鼠和NOD/SCID裸鼠，以研究外泌体miR-16-5p对GC肿瘤生长和抗肿瘤免疫反应的影响。研究发现M1巨噬细胞与GC患者的不良生存之间存在关联，同时它们分泌外泌体以抑制GC发展并激活T细胞依赖性免疫反应。我们的结果显示，miR-16-5p通过外泌体在细胞间从M1巨噬细胞转移至GC细胞，并靶向程序性死亡配体1（PD-L1）。发现含有miR-16-5p的M1巨噬细胞来源的外泌体可触发T细胞免疫反应，通过降低PD-L1的表达在体内和体外抑制肿瘤形成。综上所述，本研究的关键发现表明，携带miR-16-5p的M1巨噬细胞来源的外泌体通过经由PD-L1激活T细胞免疫反应，对GC进展发挥抑制作用。我们的研究突出了M1巨噬细胞作为通过增加外泌体中miR-16-5p进行GC治疗的潜在细胞疗法的前景。
