Pseudoneutrophil Cytokine Sponges Disrupt Myeloid Expansion and Tumor Trafficking to Improve Cancer Immunotherapy

Abstract

Myeloid-derived suppressor cells (MDSCs) promote tumor immune escape through multiple mechanisms including suppressing antitumor activities of T lymphocytes. However, therapeutic abrogation of MDSCs often causes severe adverse effects, compensatory recruitment of alternative cell populations, and the multiplicity and complexity of relevant cytokines/receptors. Alternatively, suppressing the expansion and tumor trafficking of MDSCs may be a proficient and safe way for cancer treatment. Here we report that pseudoneutrophil cytokine sponges (pCSs) can disrupt expansion and tumor trafficking of MDSCs and reverse immune tolerance. Coated with plasma membranes of neutrophils phenotypically and morphologically similar to polymorphonuclear MDSCs (PMN-MDSCs), the nanosized pCSs inherited most membrane receptors from the “parental” neutrophils, enabling the neutralization of MDSC-related cytokines. Upon pCSs administration, the expansion of MDSCs and their enrichment in peripheral lymphoid organs and tumors were reduced without the compensatory influx of alternative myeloid subsets. In murine breast cancer and melanoma syngeneic models, pCSs treatment dramatically increased the number of tumor-infiltrating T lymphocytes and restored their antitumor functions. In addition, when pCSs were combined with the programmed cell death protein 1 (PD-1), the immune checkpoint blockade synergistically suppressed tumor progression and prolonged animal survival. Overall, the pseudocell nanoplatform opens up new paths toward effective cancer immunotherapy.

Inspired Epigenetic Modulation Synergy with Adenosine Inhibition Elicits Pyroptosis and Potentiates Cancer Immunotherapy

“…Also, tumor growth inhibition accompanied with reduced levels of GM‐CSF, chemokine ligand 1 (CXCL1), and CXCL2 may also contributed to the reduced infiltration of MDSC in the tumor. [ 37 ] Keep this in mind, more investigation will in fact be necessary on MDSC infiltration to refine these findings.…”

Cell‐Based Delivery Systems: Emerging Carriers for Immunotherapy

“…To leverage neutrophils as delivery systems, drugs or drug‐loaded carriers are often conjugated to the surface of neutrophils or internalized by neutrophils through co‐culture methods. [ 60 ] Another strategy to engineer neutrophils as delivery carriers is called neutrophil hitchhiking, in which nanocarriers bind to neutrophils to form an assembly through functionalization of nanocarriers with neutrophil‐targeting ligands. [ 61 ]…”

Recent Advancements in Nanomedicine for ‘Cold’ Tumor Immunotherapy

“…As expected, several nanotechnology-based strategies have been developed for MDSC-targeting therapies, such as gemcitabine-loaded nanocarriers to eliminate MDSCs [ 205 , 300 – 303 ] (Fig. 11 ), hypoxia alleviation-mediated MDSC elimination by platelet membrane-based co-encapsulation of metformin and IR780 [ 304 ], phosphoinositide-3-kinase-γ (PI3K-γ) inhibition-mediated MDSC remodeling by IPI-549-loaded targeted polymeric nanoparticles [ 305 ], disruption of MDSC expansion by pseudoneutriphil cytokine sponges [ 306 ], co-delivery of RNAi and chemokines in polyarginine nanocapsules for MDSC modulation [ 307 ], and inhibition of MDSC recruitment by micellar hypotoxic low molecular weight heparin-tocopherol succinate nanoparticles [ 308 ].

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