Journal
BIOMACROMOLECULES
Volume 19, Issue 6, Pages 2098-2108Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.biomac.8b00305
Keywords
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Funding
- National Natural Science Foundation of China [21504016, 91527305]
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Immune checkpoint blockade by anti-PD-L1 monoclonal antibody (alpha PD-L1) has achieved unprecedented clinical benefits in certain cancers, whereas the therapeutic efficacy is often hindered by immunosuppressive tumor micro environment mediated by tumor-associated macrophages (TAMs), which leads to innate resistance to this approach. To improve checkpoint blockade efficacy, the amphiphilic diblock copolymers poly(mannopyranoside/galactopyranoside methacry-late)-block-polystyrene are prepared by RAFT polymerization, which are sequentially self-assembled into glycocalyx-mimicking nanoparticles (GNPs) to neutralize TAMs. It is shown that GNPs can be specifically internalized by TAMs via lectin receptors, which results in upregulation of immunostimulatory IL-12 and downregulation of immunosuppressive IL-10, arginase 1, and CCL22, indicating functional reversion of protumor TAMs toward antitumor phenotype. The reversion of TAMs is proved to be mainly controlled by suppressing STAT6 and activating NF-kappa B phosphorylation. In vivo therapeutic studies have demonstrated that GNPs significantly enhance the therapeutic efficacy of alpha PD-L1 cancer therapy by reduction of tumor burden. Moreover, combination therapies with GNPs and alpha PD-L1 greatly improve immunosuppressive tumor microenvironment by reciprocal modulation of tumor-infiltrating effector and regulatory T cells. Notably, for the first time, our results demonstrate the reversion of TAMs and improvement of alpha PD-L1 cancer therapy by synthetic carbohydrate-containing nanomaterials. This research highlights a promising strategy for optimizing immune checkpoint blockade in cancer immunotherapy.
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