Co-immunizing with PD-L1 induces CD8+ DCs-mediated anti-tumor immunity in multiple myeloma

Abstract

Tumor therapeutic vaccines have faced a challenge for effective protection against malignant tumors by inducing tumor-specific CD8⁺ T cell responses. Here, we designed a DNA vaccine containing a tumor-specific antigen of Dickkopf-1 (DKK-1) and an immune checkpoint of programmed death ligand 1 (PD-L1) delivered by PLGA/PEI nanoparticle-mediated delivery system for multiple myeloma therapy. Murine subcutaneous tumor model established with human DKK1 (hDKK-1)-SP2/0 cells were intramuscularly immunized with PLGA/PEI-pPD-L1/pDDK-1 vaccine and equal amount of control 3 times at 10 day-intervals. Compared with PLGA/PEI-pDKK1 immunization group, PLGA/PEI-pPD-L1/pDKK-1 co-immunization enhanced the induction and mature of CD11c⁺ DCs and CD8⁺CD11c⁺ DCs, and promoted antigen-specific Th1 responses and cytotoxic T lymphocyte (CTL) responses. The reduced tumor volume and weight as well as increased tumor inhibition rate were observed in PLGA/PEI-pPD-L1/pDKK-1 vaccine co-immunization group, indicated that the vaccine could effectively inhibit the tumor growth of multiple myeloma. The anti-tumor activity of PLGA/PEI-pPD-L1/pDKK-1 vaccine was abrogated by CD8 cell depletion accompanied with the reduced percentages of CD8⁺CD11c⁺ DCs and CD8⁺ T cells in the spleen and TILs. These results indicated that the anti-tumor efficacy of PLGA/PEI-pPD-L1/pDKK-1 vaccine was required for CD8⁺CD11c⁺ DCs-mediated CD8⁺ T cell immunity responses. This vaccine strategy may represent a potential and promising approach for hematological malignancy treatment.

Keywords: CD8(+) CD11c(+) DCs; DKK-1; PD-L1; PLGA/PEI nanoparticles; Tumor therapeutic vaccine.