Efficacy of anti-programmed cell death protein 1 monoclonal antibody combined with bevacizumab and/or Pseudomonas aeruginosa injection in transplanted tumor of mouse forestomach carcinoma cell gastric cancer in mice and its mechanism in regulating tumor immune microenvironment

Abstract

Tumor immunotherapy represented by 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 MFC GC cells into 615 mice. Interventions were conducted with normal saline, anti-PD-1 monoclonal antibody (mAb), bevacizumab, 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 up-regulate the number of Th1-type cells, CD8+T cells and type I TAMs, while down-regulate the number of Th2-type cells, MDSCs, Tregs 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 anti-tumor effect of anti-PD-1 mAb.

Research progress and future directions of immune checkpoint inhibitor combination therapy in advanced gastric cancer

“…Anti-PD-1 monoclonal antibody combined with bevacizumab and PA-MSHA could significantly upregulate the number of T helper 1 cells, CD8 + T cells, and Type I tumor-associated macrophages (TAMs), while downregulate the number of Th2-type cells, myeloid-derived suppressor cells, Treg cells, and Type II TAMs. 81 …”