Synergy of Immunostimulatory Genetherapy with Immune Checkpoint Blockade Motivates Immune Response to Eliminate Cancer

Abstract Normalizing the tumor‐induced immune deficiency in the immunosuppressive tumor microenvironment (TME) through increasing the efficient infiltration and activation of antitumoral immunity in TME is the core of promising immunotherapy. Herein, a Cyclo(Arg‐Gly‐Asp‐ d ‐Phe‐Lys) (RGD) peptides‐modified combinatorial immunotherapy system based on the self‐assembly of the nanoparticles named RGD‐DMA composed of RGD‐PEG‐PLA, methoxy poly(ethylene glycol)‐poly(lactide) (MPEG‐PLA) and 1,2‐Dioleoyl‐3‐trimethylammonium‐propane (DOTAP) is used to codeliver the immunostimulatory chemokine CCL19‐encoding plasmid DNA (CCL19 pDNA) and immune checkpoint ligand PD‐L1 inhibitor (BMS‐1). The RGD‐DMA/pCCL19‐BMS‐1 system not only exhibited significant inhibition of tumor progression but also induced locally high concentrations of immunostimulatory cytokines at tumor sites without causing an obviously systemic inflammatory response. The immunosuppressive TME is efficaciously reshaped by the coadministration of RGD‐DMA/pCCL19 and BMS‐1, as indicated by the activated T lymphocytes, increased intratumoral‐infiltration of mature dendritic cells (DCs), and the repolarization of macrophages from pro‐tumoral M2‐phenotype toward tumoricidal M1‐phenotype. The upregulated PD‐L1 expression at tumor sites caused by the increased IFN‐γ levels after immunostimulatory gene therapy further demonstrated the synergistic effects of BMS‐1 in counteracting the inhibitory role of PD‐L1 expression in antitumor immunity. Therefore, the combination of immunostimulating therapy and immune checkpoint inhibitor that synergistically target multiple immune regulatory pathways demonstrates significant potential as a novel immunotherapy approach.