髓源性抑制细胞（MDSCs）是一类具有免疫抑制功能的细胞，在肿瘤发生发展中起重要作用，且与肿瘤耐受抗PD-L1抗体治疗密切相关, 已成为肿瘤治疗重要靶标, 但目前抑制MDSC的治疗缺乏特异性。我们先前研究显示,MDSCs聚集与IL-1beta诱发胃癌的发生密切相关；抑制MDSCs激活，预防了胃癌发生和发展。研究发现, MDSCs特异性高表达肿瘤坏死因子相关凋亡诱导配体受体2 (TRAIL-2, DR5）；应用抗DR5抗体（MD5-1）能够特异性清除荷瘤小鼠体内的MDSCs, 而对其它免疫细胞没有影响，显示靶向DR5特异性抑制MDSCs治疗胃癌的潜力。在上述研究基础上，我们拟进一步研究MD5-1靶向抑制MDSCs对IL-1beta转基因小鼠原发性胃癌和同源性小鼠胃癌移植瘤的治疗作用及机制；研究MD5-1联合抗PD-L1抗体治疗胃癌的作用、机制和安全性，为胃癌免疫治疗提供一个新方法和策略。

Myeloid-derived suppressor cells (MDSCs) are widely considered as an important immunosuppressant cells and play important roles in the development and progression of cancers. MDSC accumulation has been reported to be associated with tumor resistance of anti-PD-L1 antibody treatment. Therefore, MDSCs have been considered as a target for cancer therapy. However, so far, no specific target for MDSC inhibition has been developed. Our previous studies have shown that MDSCs accumulation was associated with gastric cancer development in IL-1beta transgenic mice and allograft gastric cancer mice models. Inhibition of MDSCs mobilization increased the number of CD8+T cells and prevented the development of gastric cancer in IL-1beta mice. Furthermore, we found that tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptor 2 (TRAIL-R2, DR5) was highly expressed in MDSCs and target inhibition of DR5 using anti-DR5 agonist antibody (MD5-1) could deplete specifically MDSCs in tumor-bearing mice and did not affect other normal the function immune cells. This data suggest that DR5 may be a specific target for MDSC inhibition. In this study, we will further: (1) investigate the effects of MD5-1 treatment on gastric cancer growth in IL-1beta mice and gastric cancer allograft mice models and determine the mechanisms by which MD5-1 treatment depletes MDSCs and inhibits gastric cancer growth; (3) explore the effects of combination treatment with inhibition of MDSCs (using anti-DR5 antibody MD5-1) and anti-PD-L1 antibody (10F.9G2) on gastric cancer growth; (4) evaluate the safety of combination therapy of anti-DR5 antibody and anti-PD-L1 antibody in mice. The results from the study will provide a new strategy for specific targeting inhibition of MDSCs for cancer therapy and provide a new method for immunotherapy of gastric cancer by using the combination of anti-DR5 antibody and anti-PD-L1 antibody.