TLR7/8 Agonist and SHP2 Inhibitor Loaded Nanoparticle Enhances Macrophage Immunotherapy Efficacy,Advanced Therapeutics

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TLR7/8 Agonist and SHP2 Inhibitor Loaded Nanoparticle Enhances Macrophage Immunotherapy Efficacy
Advanced Therapeutics ( IF 3.7 ) Pub Date : 2021-07-22 , DOI: 10.1002/adtp.202100086
Vaishali Malik _{1,

2} , Anujan Ramesh _{1,

3} , Ashish A. Kulkarni _{1,

2,

3,

4}

Affiliation

Tumor-associated macrophages (TAMs) are among the most abundant immune cells in the solid tumor microenvironment, making them an attractive target for cancer immunotherapy. However, there are two important challenges. First, tumors repolarize the TAMs predominantly to M2 tumor-aiding phenotype by secreting various immunosuppressive cytokines. Second, CD47 on cancer cells interacts with signal-regulating protein a (SIRPa) expressed on macrophages. This crosstalk provides a downregulatory signal in the form of activation of SHP1/2 that inhibits cancer cell phagocytosis. These challenges can be overcome by engineering a nanoparticle that can deliver a rationale combination of immunomodulatory agents to the TAMs that can repolarize the M2 macrophages to M1 phenotype efficiently and concurrently block CD47-SIRPa interactions by inhibiting SHP2 signaling. A lipid nanoparticle (LNP) system loaded with amphiphilic R848-cholesterol (TLR7/8 agonist) and SHP099 (SHP2 inhibitor) in a predefined ratio has been designed. In vitro studies show that the LNPs system repolarized to M2 macrophages to M1 phenotype and expressed co-stimulatory molecules while enhancing phagocytic potential. In vivo efficacy studies in 4T1 tumor-bearing mice show that LNPs exhibit superior anti-tumor efficacy than other treatments. Thus, the lipid nanoparticle-mediated co-delivery of a rational combination of TLR7/8 agonist and SHP2 inhibitor in the TAMs can enhance macrophage immunotherapy.

中文翻译：

TLR7/8 激动剂和 SHP2 抑制剂负载纳米颗粒增强巨噬细胞免疫治疗效果

肿瘤相关巨噬细胞 (TAM) 是实体瘤微环境中最丰富的免疫细胞之一，使其成为癌症免疫治疗的有吸引力的靶点。然而，有两个重要的挑战。首先，肿瘤通过分泌各种免疫抑制细胞因子，主要将 TAM 重新极化为 M2 肿瘤辅助表型。其次，癌细胞上的 CD47 与巨噬细胞上表达的信号调节蛋白 a (SIRPa) 相互作用。这种串扰以激活 SHP1/2 的形式提供下调信号，从而抑制癌细胞的吞噬作用。这些挑战可以通过设计一种纳米颗粒来克服，该纳米颗粒可以向 TAM 提供免疫调节剂的合理组合，可以有效地将 M2 巨噬细胞重新极化为 M1 表型，同时通过抑制 SHP2 信号传导阻断 CD47-SIRPa 相互作用。设计了一种以预定比例装载两亲性 R848-胆固醇（TLR7/8 激动剂）和 SHP099（SHP2 抑制剂）的脂质纳米颗粒 (LNP) 系统。体外研究表明，LNPs 系统重新极化为 M2 巨噬细胞至 M1 表型，并在增强吞噬潜力的同时表达共刺激分子。4T1 荷瘤小鼠体内疗效研究表明，LNPs 表现出优于其他治疗的抗肿瘤疗效。因此，

更新日期：2021-08-25

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