Department of Radiation Oncology, Qilu Hospital of Shandong University (Qingdao), Qingdao, China.
Department of Medical Oncology, Qilu Hospital of Shandong University (Qingdao), Qingdao, China.
Clin Exp Immunol. 2023 Oct 13;213(3):328-338. doi: 10.1093/cei/uxad069.
Tumor immunotherapy represented by programmed cell death protein 1 (PD-1) inhibitors is considered as the most promising cancer treatment method and has been widely used in the treatment of advanced gastric cancer (GC). However, the effective rate of PD-1 inhibitor monotherapy is low. In this study, we constructed a transplanted tumor model in GC mice by inoculating mouse forestomach carcinoma cell (MFC) GC cells into 615 mice. Interventions were conducted with normal saline, anti-PD-1 monoclonal antibody (mAb), bevacizumab, Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PA-MSHA), anti-PD-1 mAb combined with bevacizumab, anti-PD-1 mAb combined with PA-MSHA, bevacizumab combined with PA-MSHA, anti-PD-1 mAb combined with bevacizumab and PA-MSHA, respectively. The tumor growth curves were drawn. TUNEL assay, western blotting, and immunohistochemistry were used to detect tumor proliferation and apoptosis. Flow cytometry and ELISA were used to detect the expression of tumor infiltrating lymphocytes and cytokines. This study found that anti-PD-1 mAb alone could not significantly inhibit the growth of transplanted tumors in mice. Anti-PD-1 mAb combined with bevacizumab, anti-PD-1 mAb combined with PA-MSHA, anti-PD-1 mAb combined with bevacizumab and PA-MSHA could all significantly inhibit tumor growth in mice, and the combination of three drugs presented the highest tumor inhibition rate. Anti-PD-1 mAb combined with bevacizumab and PA-MSHA could significantly upregulate the number of Th1-type cells, CD8 + T cells, and Type I tumor-associated macrophages (TAMs), while downregulate the number of Th2-type cells, myeloid-derived suppressor cells, regulatory T cells, and Type II TAMs. Therefore, we conclude that anti-PD-1 mAb combined with bevacizumab and/or PA-MSHA has a synergistic effect. Bevacizumab and PA-MSHA can transform the tumor immunosuppressive microenvironment into a supportive immune microenvironment, thus maximizing the antitumor effect of anti-PD-1 mAb.
肿瘤免疫治疗以程序性死亡蛋白 1（PD-1）抑制剂为代表，被认为是最有前途的癌症治疗方法，并已广泛应用于晚期胃癌（GC）的治疗。然而，PD-1 抑制剂单药治疗的有效率较低。本研究通过将小鼠前胃癌细胞（MFC）GC 细胞接种于 615 只小鼠中构建 GC 小鼠移植瘤模型。分别用生理盐水、抗 PD-1 单克隆抗体（mAb）、贝伐珠单抗、铜绿假单胞菌甘露糖敏感血凝素（PA-MSHA）、抗 PD-1 mAb 联合贝伐珠单抗、抗 PD-1 mAb 联合 PA-MSHA、贝伐珠单抗联合 PA-MSHA、抗 PD-1 mAb 联合贝伐珠单抗和 PA-MSHA 进行干预，绘制肿瘤生长曲线。TUNEL 检测、western blot 和免疫组化检测肿瘤增殖和凋亡。流式细胞术和 ELISA 检测肿瘤浸润淋巴细胞和细胞因子的表达。本研究发现，抗 PD-1 mAb 单独应用不能显著抑制小鼠移植瘤的生长。抗 PD-1 mAb 联合贝伐珠单抗、抗 PD-1 mAb 联合 PA-MSHA、抗 PD-1 mAb 联合贝伐珠单抗和 PA-MSHA 均可显著抑制小鼠肿瘤生长，三药联合组肿瘤抑制率最高。抗 PD-1 mAb 联合贝伐珠单抗和 PA-MSHA 可显著上调 Th1 型细胞、CD8+T 细胞和 I 型肿瘤相关巨噬细胞（TAMs）的数量，下调 Th2 型细胞、髓源性抑制细胞、调节性 T 细胞和 II 型 TAMs 的数量。因此，我们得出结论，抗 PD-1 mAb 联合贝伐珠单抗和/或 PA-MSHA 具有协同作用。贝伐珠单抗和 PA-MSHA 可以将肿瘤免疫抑制微环境转化为支持性免疫微环境，从而最大限度地发挥抗 PD-1 mAb 的抗肿瘤作用。
