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

Adv Mater. 2021 Oct;33(43):e2103923. doi: 10.1002/adma.202103923. Epub 2021 Sep 12.

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.

Keywords: activation-induced T cell death; antitumor immunity; bacterial vesicles; cytokines; immunomodulators.

MeSH terms

  • Animals
  • Biomimetic Materials* / chemistry
  • Biomimetic Materials* / pharmacology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Dendritic Cells / immunology
  • Humans
  • Immunologic Factors / chemistry
  • Immunologic Factors / pharmacology
  • Immunotherapy
  • Interleukin-10* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms / drug therapy
  • Neoplasms / immunology
  • Neoplasms / therapy

Substances

  • Interleukin-10
  • Immunologic Factors