特异性靶向抑制髓源性抑制细胞（MDSCs）免疫治疗胃癌的研究

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.

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。

研究背景. 髓源性抑制细胞（MDSCs）是一类具有强烈免疫抑制功能的细胞，是导致免疫检查点阻断剂PD-1/PD-L1抗体治疗耐药的机制之一，已成为抗肿瘤免疫治疗新靶标。研究显示荷瘤小鼠中MDSCs表面死亡受体5(DR5)显著上调，抗DR5抗体MD5-1能够特异性清除荷瘤小鼠中的MDSCs，抑制肿瘤生长。本项目研究MD5-1清除MDSCs联合抗PD-L1治疗小鼠胃癌的疗效、机制及其安全性，为胃癌免疫治疗提供一个新方法。.研究内容.建立615小鼠移植瘤模型，应用流式细胞仪检测治疗后肿瘤组织、外周血和脾脏组织中MDSC和T细胞的变化；研究MD5-1抗体单独应用对负瘤小鼠中MDSC的清除作用及对移植瘤生长的抑制作用；研究MD5-1 抗PD-L1抗体单独或联合治疗荷瘤615小鼠的疗效、机制及其安全性。 .研究结果. 与无瘤对照615小鼠相比，荷瘤615小鼠脾脏及肿瘤组中的MDSCs显著增多，其表面DR5和PD-L1表达上调；MD5-1体外能够诱导MDSCs凋亡，体内能够清除荷瘤小鼠MDSCs，对巨噬细胞及树突细胞没有明显影响。MD5-1对615小鼠移植瘤的抑瘤作用（TGI）显著高于在T细胞缺陷裸鼠中的作用； MD5-1治疗显著减少MDSCs浸润，增加了肿瘤组织中CD8+T细胞浸润和功能，提高CD8/Treg比值。MD5-1联合抗PD-L1治疗小鼠胃癌疗效优于任一单药，能够使部分肿瘤消退且显著延长小鼠生存期；联合治疗的肿瘤组织坏死和凋亡细胞增多；对小鼠体重及重要器官无明显影响。.研究结论和意义. 本项目研究结果证明了MD5-1抗体能够特异性清除MDSC，显著提高PD-L1治疗小鼠胃癌的疗效，显著延长小鼠生存期。本项目的研究结果将为临床应用MD5-1联合抗PD-L1免疫治疗胃癌提供实验依据，有重要的临床转化应用价值。