Abstract：
Multiple oxaliplatin-resistance mechanisms have been proposed such as increase of anti-inflammatory M2 macrophages and lack of cytotoxic T-cells. Thereby oxaliplatin chemotherapy promotes an immunosuppressive tumor microenvironment and inhibits anti-tumor efficacy. It has been shown that toll-like receptor (TLR) agonists are capable of triggering broad inflammatory responses, which may potentially reduce oxaliplatin-resistance and improve the efficacy of chemotherapy. In this study, we established colorectal tumor-bearing zebrafish and mice, and investigated the effects of TLR agonists and oxaliplatin in macrophage function and anti-tumor T cell immunity as well as tumor growth control in vivo. To increase the potential of this strategy as well minimize side effects, neutral liposomes carrying oxaliplatin and cationic liposomes co-loaded with TLR agonists Poly I:C and R848 were employed for maximum immune activation. Both of two liposomal systems exhibited good physicochemical properties and excellent biological activities in vitro. The combination strategy delivered by liposomes showed more pronounced tumor regression and correlated with decreased M2 macrophage numbers in both zebrafish and mice. Increasing numbers of dendritic cells, DC maturation and T cell infiltration mediated via immunogenic cell death were observed in treated mice. Our study offers valuable insights into the potential of liposomal combination therapy to improve cancer treatment by reprogramming the tumor microenvironment and enhancing immune responses.
摘要：
已经提出了多种奥沙利铂耐药机制，例如抗炎M2巨噬细胞的增加和细胞毒性T细胞的缺乏。从而奥沙利铂化疗促进免疫抑制肿瘤微环境并抑制抗肿瘤功效。研究表明，toll样受体（TLR）激动剂能够引发广泛的炎症反应，这可能会降低奥沙利铂耐药并提高化疗疗效。在这项研究中,我们建立了结直肠荷瘤斑马鱼和小鼠，并研究了TLR激动剂和奥沙利铂在体内巨噬细胞功能和抗肿瘤T细胞免疫以及肿瘤生长控制中的作用。为了增加这种策略的潜力，同时尽量减少副作用，携带奥沙利铂的中性脂质体和共负载有TLR激动剂的阳离子脂质体聚I:C和R848用于最大免疫激活。两种脂质体系统均表现出良好的理化性质和优异的体外生物活性。通过脂质体递送的组合策略显示出更明显的肿瘤消退，并且与斑马鱼和小鼠的M2巨噬细胞数量减少相关。越来越多的树突状细胞,在处理的小鼠中观察到由免疫原性细胞死亡介导的DC成熟和T细胞浸润。我们的研究为脂质体联合治疗通过重新编程肿瘤微环境和增强免疫反应来改善癌症治疗的潜力提供了有价值的见解。
