Non-responsiveness to therapeutic tumor vaccination is overcome by functional modulation of myeloid derived suppressor cells

Abstract

Therapeutic tumor vaccination represents a promising strategy to induce anti-tumor activity in cancer patients. However, usually only a subpopulation of patients benefits from tumor vaccines, whereas others display continuous tumor growth and metastatic spreading. Here we report a similar observation in a B16 melanoma model. Vaccinating these mice with a model tumor antigen and a combination of adjuvants, i.e. TLR-9-ligand CpG and NKT-cell ligand α-galactosylceramide, controlled the tumor in most animals (High-Responders), whereas others showed no clear benefit from the treatment (Non-Responders). No differences in numbers of B, NK or T cells were detected between both groups. However, Non-Responders showed significantly increased numbers of CD11b+Gr-1+myeloid-derived-suppressor-cells (MDSCs). Treatment with all-trans-retinoic-acid (atRA), which has been described to modulate MDSCs, effectively restored the tumor control in Non-responders. Frequencies neither of regulatory T cells nor MDSCs differed after treatment with atRA, but those cells from atRA-treated animals with a phenotype of monocytic MDSCs (CD11b+Ly6ChighLy6G–cells) had lost their suppressive capacity and displayed upregulation of MHC-Class-II, indicating acquisition of immune-stimulatory properties. Concomitantly, IFNγ production by CD8+ T cells was significantly higher in atRA-treated mice.