Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA.
Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA.
J Immunother Cancer. 2024 Aug 28;12(8):e008977. doi: 10.1136/jitc-2024-008977.
Immune checkpoint protein V-domain immunoglobulin suppressor of T cell activation (VISTA) controls antitumor immunity and is a valuable target for cancer immunotherapy. Previous mechanistic studies have indicated that VISTA impairs the toll-like receptor (TLR)-mediated activation of myeloid antigen-presenting cells, promoting the expansion of myeloid-derived suppressor cells, and suppressing tumor-reactive cytotoxic T cell function.
The aim of this study was to develop a dual-action lipid nanoparticle (dual-LNP) coloaded with VISTA-specific siRNA and TLR9 agonist CpG oligonucleotide. We used three murine preclinical tumor models, melanoma YUMM1.7, melanoma B16F10, and colon carcinoma MC38 to assess the functional synergy of the two cargoes of the dual LNP and therapeutic efficacy.
The dual-LNP synergistically augmented antitumor immune responses and rejected large established tumors whereas LNPs containing VISTA siRNA or CpG alone were ineffective. In comparison with therapies using the soluble CpG and a VISTA-specific monoclonal antibody, the dual-LNP demonstrated superior therapeutic efficacy yet with reduced systemic inflammatory cytokine production. In three murine models, the dual-LNP treatment achieved a high cure rate. Tumor rejection was associated with influx of immune cells to tumor tissues, augmented dendritic cell activation, production of proinflammatory cytokines, and improved function of cytotoxic T cells.
Our studies show the dual-LNP ensured codelivery of its synergistic cargoes to tumor-infiltrating myeloid cells, leading to simultaneous silencing of VISTA and stimulation of TLR9. As a result, the dual-LNP drove a highly potent antitumor immune response that rejected large aggressive tumors, thus may be a promising therapeutic platform for treating immune-cold tumors.
免疫检查点蛋白 V 结构域免疫球蛋白抑制 T 细胞活化（VISTA）控制抗肿瘤免疫，是癌症免疫治疗的有价值靶点。先前的机制研究表明，VISTA 损害了 Toll 样受体（TLR）介导的髓样抗原呈递细胞的激活，促进了髓源性抑制细胞的扩增，并抑制了肿瘤反应性细胞毒性 T 细胞的功能。
本研究旨在开发一种共载有 VISTA 特异性 siRNA 和 TLR9 激动剂 CpG 寡核苷酸的双重作用脂质纳米颗粒（dual-LNP）。我们使用三种小鼠临床前肿瘤模型，黑色素瘤 YUMM1.7、黑色素瘤 B16F10 和结肠癌细胞 MC38，评估双重 LNP 的两种货物的功能协同作用和治疗效果。
双重-LNP 协同增强了抗肿瘤免疫反应，并排斥了已建立的大型肿瘤，而单独含 VISTA siRNA 或 CpG 的 LNPs 则无效。与使用可溶性 CpG 和 VISTA 特异性单克隆抗体的治疗相比，双重-LNP 表现出更好的治疗效果，同时减少了全身炎症细胞因子的产生。在三种小鼠模型中，双重-LNP 治疗实现了高治愈率。肿瘤排斥与免疫细胞涌入肿瘤组织、树突状细胞激活增强、促炎细胞因子产生和细胞毒性 T 细胞功能改善有关。
我们的研究表明，双重-LNP 确保了其协同货物递送到肿瘤浸润的髓样细胞中，同时沉默 VISTA 并刺激 TLR9。结果，双重-LNP 引发了强烈的抗肿瘤免疫反应，排斥了大型侵袭性肿瘤，因此可能是治疗免疫冷肿瘤的有前途的治疗平台。
