Nano-Liposome Co-Loaded with C-X-C Chemokine Ligand 12/CXCR4 Pathway Inhibitor Synergistically Increases the Immune Efficacy of Anti-PD-L1 and Increase Anti-Tumor Activity of Effector T Cells

Abstract

Blockade of the immune checkpoint programmed cell death receptor-1 (PD-1) or programmed death receptor ligand-1 (PD-L1) enhances the antitumor activity of effector T cells. However, many patients lack response to PD-1/PD-L1 therapy. Enhancing the efficacy of immune checkpoint inhibitors by improving the immunosuppressive tumor microenvironment (TME) has emerged as a promising cancer treatment strategy. In this study, a new nano-liposome (PD-L1/siCXCL12-Lp) of C-X-C chemokine ligand 12 (CXCL12) siRNA and anti-PD-L1 peptide (PD-L1/siCXCL12-Lp) responsive to matrix metalloproteinases (MMPs) was constructed, combined with siCXCL12. The regulation of TME and the immunomodulatory effect of anti-PD-L1 peptide to synergistically enhance the antitumor immune response. The animal experiment protocol was reviewed and approved by the Biomedical Ethics Committee of Peking University. This study showed that PD-L1/siCXCL12-Lp directly downregulated CXCL12 expression in vitro (33.8%) and in vivo (15.5%), and effectively increased the CD8+/Treg ratio (20.0%), which favored anti-PD-L1 peptides better exert its immune function. Combination therapy significantly inhibited tumor growth (52.08%) with good safety, exploring new ideas for cancer immunotherapy.