Reprogramming Tumor Immune Microenvironment (TIME) and Metabolism via Biomimetic Targeting Codelivery of Shikonin/JQ1.

Abstract

Remodeling tumor immune microenvironment (TIME) is an important strategy to lift the immunosuppression and achieve immune normalization. In this work, a mannosylated lactoferrin nanoparticulate system (Man-LF NPs) is developed for dual-targeting biomimetic codelivery of shikonin and JQ1 via the mannose receptor and LRP-1 that are overexpressed in both cancer cells and tumor-associated macrophages. The Man-LF NPs can serve as multitarget therapy for inducing immune cell death in the cancer cells, repressing glucose metabolism and repolarizing tumor-associated macrophages, and consequently, lead to remodeling the TIME (e.g., promotion of dendritic cell maturation and CD8+ T cell infiltration, as well as suppression of Treg). Moreover, JQ1 is a suppressor of PD-L1, and the Man-LF NPs can also work on PD-L1 checkpoint blockage. The results reveal the synergistic combination of shikonin and JQ1 and the treatment potency of the Man-LF NPs. Importantly, it is demonstrated that the interaction between the tumor metabolism and immunity plays an essential role in immunotherapy, and the developed drug combination and nanoformulation can target the multiple components in the complicated network of TIME, providing a potential therapeutic strategy.

• Authors: Hairui Wang, Yisi Tang, Yuefei Fang, Meng Zhang, Huiyuan Wang, Zhidi He, Bing Wang, Qin Xu, Yongzhuo Huang
• Journal: Nano letters (Nano Lett) Vol. 19 Issue 5 Pg. 2935-2944 (05 08 2019) ISSN: 1530-6992 [Electronic] United States
• PMID: 30950276 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (+)-JQ1 compound
• Azepines
• LRP1 protein, human
• Lectins, C-Type
• Low Density Lipoprotein Receptor-Related Protein-1
• Mannose Receptor
• Mannose-Binding Lectins
• Naphthoquinones
• Receptors, Cell Surface
• Triazoles
• shikonin
• Lactoferrin
• Mannose

Topics

• Azepines (pharmacology)
• Biomimetics
• CD8-Positive T-Lymphocytes (drug effects)
• Cell Line, Tumor
• Dendritic Cells (drug effects)
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunotherapy
• Lactoferrin (chemistry, pharmacology)
• Lectins, C-Type (chemistry, genetics)
• Low Density Lipoprotein Receptor-Related Protein-1 (genetics)
• Macrophages (drug effects)
• Mannose (chemistry)
• Mannose Receptor
• Mannose-Binding Lectins (chemistry, genetics)
• Nanoparticles (chemistry)
• Naphthoquinones (chemistry, pharmacology)
• Neoplasms (drug therapy, immunology, metabolism, pathology)
• Receptors, Cell Surface (chemistry, genetics)
• Triazoles (pharmacology)
• Tumor Microenvironment (drug effects, immunology)