Tumor repolarization by an advanced liposomal drug delivery system provides a potent new approach for chemo-immunotherapy.

L Ringgaard,T B Engel,D R Elema,R Eliasen,R I Jølck,K Kristensen,F P Fliedner,F Melander,A Kjaer,M Bak,T L Andresen,A E Hansen,J R Henriksen

doi:10.1126/sciadv.aba5628

L Ringgaard, T B Engel + Show 11 more

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https://doi.org/10.1126/sciadv.aba5628

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Abstract

Immunosuppressive cells in the tumor microenvironment allow cancer cells to escape immune recognition and support cancer progression and dissemination. To improve therapeutic efficacy, we designed a liposomal oxaliplatin formulation (PCL8-U75) that elicits cytotoxic effects toward both cancer and immunosuppressive cells via protease-mediated, intratumoral liposome activation. The PCL8-U75 liposomes displayed superior therapeutic efficacy across all syngeneic cancer models in comparison to free-drug and liposomal controls. The PCL8-U75 depleted myeloid-derived suppressor cells and tumor-associated macrophages in the tumor microenvironment. The combination of improved cancer cell cytotoxicity and depletion of immunosuppressive populations of immune cells is attractive for combination with immune-activating therapy. Combining the PCL8-U75 liposomes with a TLR7 agonist induced immunological rejection of established tumors. This combination therapy increased intratumoral numbers of cancer antigen-specific cytotoxic T cells and Foxp3- T helper cells. These results are encouraging toward advancing liposomal drug delivery systems with anticancer and immune-modulating properties into clinical cancer therapy.

Highlights

Cancer cells have effective immunoediting abilities that are central for establishing the immunosuppressive tumor microenvironment (TME)
Proteases expressed in the TME cleaves the PEGylated cleavable lipopeptide (PCL) peptide motif and thereby dePEGylates and destabilizes the liposome, which improves cell interactions and drug release (Fig. 1, A to D)
The PCL-functionalized liposomes resulted in improved cytotoxicity compared to stealth liposomes in all cell lines tested, and the most optimal composition in terms of potency was the PCL8-U75 liposomes containing 8% PCL and 7.5% unsaturated cationic lipids (POPC:Cholesterol:dioleoyl-3-trimethylammonium- propane (DOTAP):PCL 52.5:32.0:7.5:8.0 molar ratio; Fig. 1, E to G)

Summary

Introduction

Cancer cells have effective immunoediting abilities that are central for establishing the immunosuppressive tumor microenvironment (TME). These properties allow cancer cells to escape immune recognition and support the cancer progression and dissemination [1]. Monocytic myeloid-derived suppressor cells (Mo-MDSCs) represent a central immunosuppressive population with potent protumorigenic properties and inhibitory activities on cytotoxic (cT) T cells and natural killer cell effector function [6,7,8]. They are progenitors to protumorigenic tumor-associated macrophages (TAMs) [9, 10].

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