Abstract
BackgroundMyeloid-derived suppressor cells (MDSCs) are among the major obstacles that adjuvants for cancer vaccines have to overcome. These cells cross-present tumor-associated antigens (TAA) to naive T lymphocytes with a tolerogenic outcome. Very Small Size Proteoliposomes (VSSP) is used as adjuvant by four therapeutic cancer vaccines currently in Phase I and II clinical trials. We previously found that VSSP reduces the suppressive function of MDSCs, then activating antigen-specific CTL responses in tumor-bearing (TB) mice, with the consequent reduction of tumor growth. However the mechanistic explanation for the immunomodulatory effect of this adjuvant in TB hosts has not been addressed before.MethodsTB mice were inoculated with VSSP and MDSCs isolated and characterized by their expression of Arg1 and Nos2 genes by RT-PCR. The effect of VSSP on antigen cross-presentation by MDSCs, regulatory T cells (Tregs) expansion and MDSCs differentiation towards dendritic cells (DCs) was analyzed by FACS. Student’s t test or ANOVA and Tukey’s tests were used for statistical analyses.ResultsAfter inoculating VSSP into TB mice, a significant reduction of Arg1 and Nos2 gene expression was observed in recovered MDSCs. Concurrently the ability of these cells to induce down-regulation of CD3ζ chain on T cells was lost. Likewise in mice inoculated with the adjuvant lower percentages of Tregs were detected. In vitro, VSSP treatment was enough to differentiate MDSCs into phenotypically mature DCs, eliminating the former suppressive effect. Noteworthy, in vivo administration of VSSP to OVA-expressing (EG.7) TB mice abrogated this model antigen cross-presentation by splenic MDSCs. Similar results were obtained even when OVA antigen was administered into these TB mice formulated in VSSP. On the contrary, immunization with the same protein in polyI:C did not change the percentage of MDSCs expressing SIINFEKL/H-2Kb complexes, whereas a concomitant injection of VSSP aborted the limitations of polyI:C in this setting.ConclusionsAltogether, these results indicate that VSSP has the peculiar capacity of inhibiting TAA cross-presentation and certain suppressive mechanisms on MDSCs which in turn, combined with the ability to induce differentiation of these cells into antigen-presenting cells (APCs), sustains this adjuvant as an ideal immunomodulator for cancer immunotherapy.
Highlights
Myeloid-derived suppressor cells (MDSCs) are among the major obstacles that adjuvants for cancer vaccines have to overcome
To understand the mechanisms associated with the antitumor effect of Very Small Size Proteoliposomes (VSSP), we began by studying the effector T cell responses in these mice
When TB mice injected with OVA/polyI:C received three doses of VSSP alone, the detected antigen-specific CTL response was significantly higher than in TB mice non-treated with the adjuvant and even superior than in tumor-free mice vaccinated with OVA/polyI:C (Figure 1A and Additional file 1: Figure S1A)
Summary
Myeloid-derived suppressor cells (MDSCs) are among the major obstacles that adjuvants for cancer vaccines have to overcome. These cells cross-present tumor-associated antigens (TAA) to naive T lymphocytes with a tolerogenic outcome. We previously found that VSSP reduces the suppressive function of MDSCs, activating antigen-specific CTL responses in tumor-bearing (TB) mice, with the consequent reduction of tumor growth. MDSCs and tumor-associated macrophages have been recognized as the main inhibitory populations recruited by tumors with relevant contribution to the dampening of antitumor immune response [1,2,3]. It has been shown that splenic MDSCs can cross-present tumor antigens to CD8+ T cells, which leads to tolerance induction [15]. The immunosuppressive network associated to cancer is reinforced by MDSCs that expand Tregs [16,17] but can differentiate into tumor-associated macrophages within the tumor microenvironment [18,19]
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