Abstract
Our evolving understandings of cell-material interactions provide insights for using polymers to modulate cell behaviour that may lead to therapeutic applications. It is known that in certain cancers, myeloid-derived suppressor cells (MDSCs) play vital roles in promoting tumour progression, chiefly because of their ‘alternatively activated’ (or M2) phenotype that orchestrates immunosuppression. In this study, we demonstrated that two cationic polymers – cationic dextran (C-dextran) and polyethyleneimine (PEI) – could directly remodel these cells into an anti-tumour, ‘classically activated’ (or M1) phenotype, thereby stimulating these cells to express tumouricidal cytokines, reactivating the T cell functions, and prolonging the lifespan of the mice model. Our investigations with knock-out mice further indicate that the functions of these cationic polymers require the involvement of toll-like receptor 4-mediated signalling. Taken together, our study suggests that these cationic polymers can effectively and directly re-polarize MDSCs from an immunosuppressive characteristic to an anti-tumour phenotype, leading to successful restoration of immune surveillance in the tumour microenvironment and elimination of tumour cells. Our findings may have immediate impact on further development of polymer-based therapeutics for cancer immunotherapy.
Highlights
Cationic polymers may possess the potential to re-polarize myeloid-derived suppressor cells (MDSCs) for two reasons
We treated MDSCs with dextran, C-dextran or PEI, and determined the concentrations of IL-12, TNF-α, IL-10 and TGF-β in the supernatant and the mRNA levels of iNOS and Arg I. We found that both cationic polymers, C-dextran and PEI, stimulated the cells to secrete IL-12 and TNF-α (Fig. 1A) and increased the transcriptional level of iNOS (Fig. 1D)
To determine the percentage of MDSCs re-polarized from M2- to M1-like phenotype by the cationic polymers, we analysed by flow cytometry the ability of these cells to produce IL-12 and TNF-α
Summary
Several studies have demonstrated that modulation of the toll-like receptors (TLRs) signalling in MDSCs could re-activate immunosurveillance against tumour and thereby enhance immunotherapy[22,23,24,25]. Our previous studies reported that two cationic polymers, namely cationic dextran (C-dextran) and polyethyleneimine (PEI), stimulated macrophages to produce immune-activating cytokine IL-12 via toll-like receptor 4 (TLR4) signalling[27], and re-directed tumour-associated macrophages (TAM) from a immunosuppressive to tumour-killing phenotype[29]. We hypothesized that cationic polymers could re-polarize MDSCs via TLR4 signalling, triggering desired immune responses and restoring cancer immunosurveillance. We demonstrated for the first time that these cationic polymers could reverse the M2-like phenotype of MDSCs and reduce their immunosuppressive functions via TLR4 signalling
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