Drug-loaded Microbubble Delivery System to Enhance PD-L1 Blockade Immunotherapy with Remodeling Immune Microenvironment

Abstract

Abstract Background Compared with the conventional tumor therapeutic modalities, immune checkpoint blockade (e.g., PD-1/PD-L1) immunotherapy demonstrates great promise in the treatment of metastatic cancers. Although PD-L1 blockade immunotherapy is applied to a variety of tumor types, only a small number of patients respond to this treatment. The efficacy of PD-L1 blockade immunotherapy is based on the expression of PD-L1 on tumor cells and the infiltration of T cells in tumor tissue. Herein, we reported a drug-loaded microbubble delivery system to enhance PD-L1 blockade immunotherapy. Methods Docetaxel (DTX) and imiquimod (R837)-loaded microbubbles (RD@MBs) were synthesized via a typical rotary evaporation method combined with mechanical oscillation. the targeted release of drugs was achieved by using the directional "bursting" capability of ultrasound-targeted microbubble destruction (UTMD) technology. The antitumor immune response by RD@MBs combining αPD-L1 were evaluated on 4T1 and CT26 tumor models. Results The dying tumor cells induced by DTX release TAAs, together with R837, promote the activation, proliferation and recruitment of T cells. Besides, DTX upregulates the expression of PD-L1 on tumor cells, induces the polarization of M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, and reduces the proportion of myeloid-derived suppressor cells (MDSCs). Also, R837 exhibits satisfactory copolarization effects on TAMs, which synergizes with DTX to alleviate immunosuppression. The RD@MBs + αPD-L1 synergistic therapy not only effectively inhibited the growth of primary tumors, but also significantly inhibited the mimic distant tumors as well as lung metastases. Conclusion PD-L1 blockade immunotherapy was enhanced by RD@MBs delivery system.