Blockade of neutrophil recruitment to tumor sites based on sialic acid-modified nanoplatforms enhances the efficacy of checkpoint blockade immunotherapy

Abstract

Checkpoint inhibitors are designed to rejuvenate depleted or suppressed T cells in the tumor microenvironment, relying on the immune system to control and kill tumors. However, accumulating evidence indicates that tumor-infiltrating neutrophils impede the proliferation and activation of T cells and determine the resistance to checkpoint blockade and chemotherapy. In this study, sialic acid ligand-modified colchicine derivative phospholipid complexes specifically targeted tumor-associated neutrophils in the peripheral blood, blocked neutrophil accumulation in tumors, and attenuated the inhibitory effect of infiltrating neutrophils on T cells. Neutrophil blocking therapy enhanced the immunotherapy effect of the PD-L1 antibody in S180 advanced tumors and 4T1 breast cancer. Our study found that PD-L1 antibody monotherapy increased the tumor infiltration of immunosuppressive neutrophils. Combination therapy with neutrophil blocking can greatly reduce tumor-infiltrating neutrophils and increase the proliferation of cytotoxic CD8+ T lymphocytes in the tumor. The combination therapy significantly improved the survival rate of mice with advanced S180 tumors and increased the sensitivity of immune checkpoint inhibitors to 4T1 cold tumors.

Keywords

• Neutrophil blockade
• Combination immunotherapy
• Sialic acid