A Novel Immunomodulator Delivery Platform Based on Bacterial Biomimetic Vesicles for Enhanced Antitumor Immunity.

ABSTRACT

T cell activation-induced cell death (AICD) during tumor pathogenesis is a tumor immune escape process dependent on dendritic cells (DCs). Proper immune-modulatory therapies effectively inhibit tumor-specific CD8+ T cell exhaustion and enhance antitumor immune responses. Here, high-pressure homogenization is utilized to drive immunomodulator IL10-modified bacteria to extrude through the gap and self-assemble into bacterial biomimetic vesicles exposing IL10 (IL10-BBVs) on the surface with high efficiency. IL10-BBVs efficiently target DCs in tumor-draining lymph nodes and thus increase the interaction between IL10 on BBVs and IL10R on DCs to suppress AICD and mitigate CD8+ T cell exhaustion specific to tumor antigens. Two subcutaneous peripheral injections of IL10-BBVs 1 week apart in tumor-bearing mice effectively increase systemic and intratumoral proportions of CD8+ T cells to suppress tumor growth and metastasis. Tumor-specific antigen E7 is enclosed into the periplasm of IL10-BBVs (IL10-E7-BBVs) to realize concurrent actions of the immunomodulator IL10 and the tumor antigen human papillomavirus (HPV) 16E7 in lymph nodes, further enhancing the antitumor effects mediated by CD8+ T cells. The development of this modified BBV delivery platform will expand the application of bacterial membranes and provide novel immunotherapeutic strategies for tumor treatment.