Glycocalyx-Mimicking Nanoparticles Improve Anti-PD-L1 Cancer Immunotherapy through Reversion of Tumor-Associated Macrophages

Abstract

Immune checkpoint blockade by anti-PD-L1 monoclonal antibody (αPD-L1) has achieved unprecedented clinical benefits in certain cancers, whereas the therapeutic efficacy is often hindered by immunosuppressive tumor microenvironment 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 methacrylate)- 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-κB phosphorylation. In vivo therapeutic studies have demonstrated that GNPs significantly enhance the therapeutic efficacy of αPD-L1 cancer therapy by reduction of tumor burden. Moreover, combination therapies with GNPs and αPD-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 αPD-L1 cancer therapy by synthetic carbohydrate-containing nanomaterials. This research highlights a promising strategy for optimizing immune checkpoint blockade in cancer immunotherapy.

Mannose‐Functionalized Nanoscaffolds for Targeted Delivery in Biomedical Applications

“…[42c, 78] In this regard, Zhang et al incorporated aPD-L1 mAb into the self-assembledm annosefunctionalized GNPs targetingT ME to restorei mmune functions in the TME by promoting the reversion of TAMs, and thus enhancet he aPD-L1 therapeutic effectb yd ecreasing tumor resistance ( Figure 5). [79] The main stimulation mechanism was confirmed as the downregulation of STAT6and NF-kBsignaling pathways.…”

“…To develop the nanostructures with better stability and functionality, mimicking glycocalyx, an important cell surface structure of polymeric sugar layer, has become a promising strategy for the rational design of targeted nanocarriers, since the architecture of glycocalyx has been found to greatly influence the sugar‐receptor interaction, as well as uptake by macrophages or cancer cells . In this regard, Zhang et al incorporated αPD‐L1 mAb into the self‐assembled mannose‐functionalized GNPs targeting TME to restore immune functions in the TME by promoting the reversion of TAMs, and thus enhance the αPD‐L1 therapeutic effect by decreasing tumor resistance (Figure ) . The main stimulation mechanism was confirmed as the downregulation of STAT6 and NF‐κB signaling pathways.…”

“…Schematic illustration of STAT6and NF-kBs ignaling pathways by GNP stimulation. [79] cell-surface glycoproteins ( Figure 6). [90] Interruptions of this sugar-lectin interaction have been considered as ap romising strategyf or the development of different anti-adhesive nanosystems.…”

The influence of microenvironment on tumor immunotherapy

“…Glycocalyx‐mimicking nanoparticles were used to reverse TAMs, which increased immunostimulatory IL‐12 secretion and reduced the level of immunosuppressive IL‐10, ARG1, and CCL22. The reversion of TAMs improved the effect of anti‐PD‐L1 cancer immunotherapy by suppressing STAT6 and/or activating nuclear factor‐κB , suggesting blockade of B7‐H4, PD1, or PD‐L1 as an approach for tumor therapy.…”

Artificial Nanoscale Erythrocytes from Clinically Relevant Compounds for Enhancing Cancer Immunotherapy

“…To this end, this paper presents a facile engineering method to continuously produce concave (fake blood cell) particles (FBCPs, for minimizing off-target release of the chemo-drug and immunogenicity of the nanosystem) from a clinically approved elastic polymer (Eudragit® [Eu] RS), which are used as a biomimetic nanosystem to efficiently carry anti-programmed death-ligand 1 (PD-L1) antibodies (aPL; a clinically approved immune checkpoint inhibitor) [6,[15][16][17]. An air-liquid two-phase electrospray is designed to fabricate Eu-FBCPs by air bubble pressing of Eu melts inside drying Eu droplets under a balance between the mechanical (capillary [Ca = μ F V F /γ air-liquid , where μ F is the viscosity of fluid, V F is the fluid velocity, and γ air-liquid is the surface tension at the air-liquid interface] and Reynolds [Re = 2ρ F r N V F /μ F , where ρ F is the density of fluid and r N is the nozzle radius] numbers) and electrical (electrical Bond number [B E = ε F E 2 r N /γ air-liquid , where ε F is the dielectric constant of fluid, and E is the electric field intensity]) parameters of the spray (Fig.…”