Abstract
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 in vivo. 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 in vitro and in vivo 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.
Highlights
MATERIALS AND METHODSGastric cancer (GC) is a malignancy characterized by the growth of neoplastic tumor cells in the stomach As at 2015, gastric cancer (GC) was ranked as the second most commonly diagnosed cancer as well as the second leading cause of cancer related death in China (Chen et al, 2016)
Enrichment of M1 Macrophages Was Associated With GC Progression
The results demonstrated that the expression of these factors was elevated after the mice treated with M1 macrophage-secreted exosomes, revealing that M1 macrophage-secreted exosomes could enhance the immune response of T cells
Summary
MATERIALS AND METHODSGastric cancer (GC) is a malignancy characterized by the growth of neoplastic tumor cells in the stomach As at 2015, GC was ranked as the second most commonly diagnosed cancer as well as the second leading cause of cancer related death in China (Chen et al, 2016). Tumor resection at the early stage of GC is often accompanied with high rates of survival while poor patient outcomes and survival are often the result of advanced stage GC, often due to metastatic GC cell migration to distant tissues and lymph nodes (Thrumurthy et al, 2015). There are various standard treatments approaches including surgery, endoscopic mucosal resection and chemoradiation, all of which are widely applied, the emergence of novel therapies such as targeted therapy and immunotherapy have been highlighted in literature (Digklia and Wagner, 2016). Immunotherapy approaches targeting PD1, PDL1, and CTLA4 have all been successfully applied in GC, with largely promising outcomes (Bonotto et al, 2017)
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