肿瘤细胞靶向性光动力疗法联合SIRPα抗体导向的TRAIL对抗“冷”肿瘤的作用及机制

“冷”肿瘤对T细胞免疫检查点抑制剂反应低，急需建立新的免疫疗法。巨噬细胞和中性粒细胞可吞噬肿瘤，但吞噬强度取决于肿瘤受损程度和瘤内CD47-SIRPα信号强弱。诱导吞噬细胞浸入瘤内，同时加重肿瘤损伤并削弱CD47-SIPRα信号，可能高效对抗“冷”肿瘤。项目前期发现，光动力疗法PDT损伤结直肠癌瘤体，不仅大量诱导SIPRα阳性巨噬细胞和中性粒细胞浸入瘤内，还显著提高肿瘤对TRAIL的敏感性；PDT联合Anti-SIRPα-TRAIL蛋白清除了较大瘤体，提示加重损伤并促进吞噬对“冷”肿瘤可能切实有效。若PDT能广泛、大量诱导吞噬细胞浸入“冷”肿瘤并提高肿瘤对TRAIL的敏感性，PDT联合Anti-SIRPα-TRAIL蛋白极有可能成为新型、高效、广谱抗“冷”肿瘤免疫疗法。因此，本项目拟用多种“冷”肿瘤模型，评价联合方案的抗肿瘤效果和安全性，探索作用机制，可望为“冷”肿瘤免疫治疗提供新选择。

Due to the lack of pre-infiltrated T cells, ‘cold’ tumors showed low response to present immune checkpoint inhibitors for T cells. It is urgently required to explore novel immunotherapies for ‘cold’ tumors. SIPRα-expressing macrophages and neutrophils could attack tumor cells by direct phagocytosis, which might be amplified by exaggerating injury for tumor cells combined with blocking the CD47-SIPRα pathway in tumor. Inducing infiltration of phagocytes, followed by enhancing tumor cell injury and pro-phagocytosis by blocking CD47-SIPRα pathway might exert great antitumor effect in ‘cold’ tumors. In previous works by the applicant, it was found that photodynamic therapy (PDT) induced infiltration of numerous SIRPα-expressing macrophages and neutrophils in tumor grafts of colorectal cancer cells in mice lacking T cells, which is closely associated with the damage of tumor tissues. And PDT-treated tumor cells were more sensitive to TRAIL. Administration of the fusion protein comprising TRAIL and antibody against SIRPα (Anti-SIRPα-TRAIL) after PDT eliminated large (>100mm3) tumor grafts, suggesting that amplifying injury of tumor cells by using TRAIL, and simultaneously prompting phagocytosis of macrophages and neutrophils by using antibody against SIPRα after PDT might be potent for ‘cold’ tumor. If PDT could induce infiltration of macrophages and neutrophils in a wide range of ‘cold’ tumors, and if PDT could sensitize these tumor cells to TRAIL, the strategy, i.e. PDT combined with Anti-SIRPα-TRAIL fusion protein, might be highly effective against broad ‘cold’ tumors. In this project, several types of ‘cold’ tumor models would be constructed at first. Subsequently, the antitumor effect, mechanism and safety of the PDT and Anti-SIRPα-TRAIL combination strategy would be investigated in detail. It is hopeful to develop a novel immunotherapy that is highly effective against broad ‘cold’ tumors.