Macrophages reprogramming improves immunotherapy of IL-33 in peritoneal metastasis of gastric cancer

Peritoneal metastasis (PM) has a suppressive tumor immune microenvironment (TIME), which limits the effects of immunotherapy. This study aims to investigate the immunomodulatory effects of intraperitoneal administration of IL-33 on PM-associated TIME. Immunocompetent mice were used to investigate the role of IL-33 in development of abdominal dissemination and host outcome. Murine (m) and human (h) gastric cancer cells were tested for their response to IL-33 by qRT-PCR, flow cytometry, and immunofluorescence. Survival was significantly prolonged in patients with high Il-33 mRNA expression. Intraperitoneal administration of IL-33 could induce the celiac inflammatory environment, activate immunologic effector cells and reverse the immunosuppressive tumor microenvironment, which delayed tumor progression and peritoneal metastasis of gastric cancer. Mechanistically, IL-33 could induce M2 polarization by activating p38-GATA-binding protein 3 (GATA3) signaling pathway. IL-33 combined with anti-CSF1R or p38 inhibitor to regulate tumor-associated macrophages (TAMs) showed synergistic anti-tumor effect. Intraperitoneal administration of IL-33 inducing local inflammatory milieu provided a novel approach for the treatment of metastatic peritoneal malignancies, which combined with TAMs reprogramming to reshape TIME could achieve better treatment efficacy. Overall design: To investigate the immunomodulatory effects of intraperitoneal administration of IL-33 on peritoneal metastasis-associated tumor immune microenvironment, we established abdominal dissemination tumor model by challenging 615-line mice with mouse forestomach carcinoma cells.

腹膜转移（Peritoneal Metastasis, PM）具有免疫抑制性肿瘤免疫微环境（Tumor Immune Microenvironment, TIME），该微环境会限制免疫治疗的疗效。本研究旨在探讨腹腔给予白细胞介素-33（Interleukin-33, IL-33）对腹膜转移相关肿瘤免疫微环境的免疫调节作用。研究采用免疫健全小鼠，探究IL-33在腹腔播散性肿瘤发生发展及宿主预后中的调控作用。通过实时荧光定量聚合酶链反应（qRT-PCR）、流式细胞术（Flow Cytometry）与免疫荧光染色（Immunofluorescence），检测小鼠（m）及人（h）胃癌细胞对IL-33的应答反应。临床数据显示，IL-33 mRNA高表达的患者生存期显著延长。腹腔给予IL-33可诱导腹腔炎症微环境，激活免疫效应细胞，逆转免疫抑制性肿瘤微环境，进而延缓胃癌的肿瘤进展与腹膜转移。机制层面，IL-33可通过激活p38-GATA结合蛋白3（GATA3）信号通路诱导M2极化。IL-33联合抗CSF1R或p38抑制剂以调控肿瘤相关巨噬细胞（Tumor-Associated Macrophages, TAMs），可展现出协同抗肿瘤效应。腹腔给予IL-33诱导局部炎症微环境的策略，为转移性腹膜恶性肿瘤的治疗提供了全新思路；联合肿瘤相关巨噬细胞重编程以重塑肿瘤免疫微环境，可获得更优异的治疗效果。总体实验设计：为探究腹腔给予IL-33对腹膜转移相关肿瘤免疫微环境的免疫调节作用，本研究通过向615系小鼠接种小鼠前胃癌细胞，构建腹腔播散性肿瘤模型。