Myeloid-derived suppressor cell-targeted virus-like particles synergistically activate innate immune response for cancer immunotherapy

Abstract

The importance of the tumor microenvironment in dynamically modulating neoplastic process, fostering proliferation, survival and migration is now widely appreciated. Therapeutics directed to various components of tumor microenvironment, especially tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs), have become an attractive avenue for cancer immunotherapy. Virus-like particles (VLPs) derived from cowpea chlorotic mottle viruses (CCMV) have been used extensively in biotechnology and are ideal platforms for the targeted delivery of therapeutic drugs for cancer immunotherapy. Here, oxidative dsDNAs, which have excellent immunostimulatory effects, are encapsulated into CCMV (CPD VLPs). CPD VLPs could be effectively taken up by macrophages and subsequently trigger Cyclic GMP-AMP synthase-stimulator of interferon genes pathway and NLRP3/Caspase-1/Gasdermin D -dependent pyroptosis pathway. To increase tumor-targeting specificity and reduce toxicity in bystander healthy tissues, peptides targeting MDSCs are conjugated to the exterior surfaces of the CPD VLPs named CPD-TP VLPs. CPD-TP VLPs can home to tumor side and induce a robust antitumor response by reprogramming tumor microenvironment. Notably, CPD-TP VLPs administration is also efficacious against lung metastasis from breast cancer. Moreover, the combination of CPD-TP VLPs with programmed cell death protein 1 (PD-1) blockade could improve therapeutic response of PD-1 antibody treatment in “immune-cold” mouse tumor models. Therefore, this study presents a novel design for VLP-based cancer vaccine.