Locoregional Immune Checkpoint Blockade and Remodeling of Lymph Nodes by Engineered Dendritic Cell-Derived Exosomes for Suppressing Tumor Progression and Metastasis.

Abstract

Tumor-draining lymph nodes (TDLNs) are the primary sites of eliciting anti-tumor immunity, which play an important role in controlling tumor progression and metastasis. However, the immunosuppressive microenvironment of TDLNs propels the formation of pre-metastatic niche, in which the immunocytes are dysfunctional, and the high expression of programmed death-ligand 1 (PD-L1) on dendritic cells (DCs) restricts the activation of cytotoxic T lymphocytes. Herein, engineered exosomes (EmDEX@GA) are developed for locoregional immunomodulation of TDLNs. EmDEX@GA possess CC-chemokine receptor 7 (CCR7) -dependent LN homing capacity and over-expressed programmed cell death protein 1 (PD-1) for immune checkpoint blockade (ICB). The loaded stimulator of interferon genes (STING) agonist can reinforce anti-tumor immunity through STING pathway activation. In orthotopic breast cancer mouse model, local administration of EmDEX@GA remodels the immunosuppressive microenvironment of TDLNs and elicits potent anti-tumor immunity, resulting in the suppression of tumor as well as the reduction of lymph node metastasis and distant metastasis. Compared with systemic ICB, local immunotherapy with EmDEX@GA has better therapeutic efficacy on suppressing distant metastasis. Moreover, the study suggests that the occurrences of distant metastasis are associated with the immunosuppressive microenvironment rather than the metastasis in TDLNs, indicating that targeted immunomodulation of TDLNs is necessary.