Abstract
Tumor microenvironment (TME) is characterized by multiple immune suppressive mechanisms able to suppress anti-tumor effector cell immunity. Combinatorial strategies, including vaccine and immunomodulatory drugs, need to be developed for improved immunotherapy efficacy.A novel combinatorial approach was assessed in C57BL/6 mice injected with mouse melanoma B16F10 cells. A multi-peptide vaccine (PEPT) was combined with a low dose metronomic chemotherapy (MCT) and an anti-PD-1 checkpoint inhibitor (CI). Statistical analysis were performed with the unpaired two-sided Student’s t-test and ANOVA.Animals treated with the multi-peptide vaccine combined with MCT or CI showed remarkable delay in tumor growth and prolonged survival as compared to control groups. The multi-pronged combination including PEPT+MCT+CI was able to prolong survival in all mice and inhibit tumor growth in 66.6% of mice. All animals which did not show tumor growth were re-challenged with the same melanoma cells and one of them showed complete tumor growth inhibition. The anti-tumor effect was associated with strong T cell immune response to vaccine mutated peptides and significant reduction of regulatory T cells.The combination of a vaccine with MCT and CI was highly efficient in potentiating the vaccine’s anti-tumor effects. The approach is highly promising to be moved into clinical trial.
Highlights
Anti-tumor immunity is severely hindered by multiple immune suppressive mechanisms characterizing the tumor microenvironment (TME)
The results showed that all the combinatorial strategies induced a significant delay in tumor growth when compared to control and peptide vaccination only (p < 0.01) (Figure 1A)
The results showed a significant delay in tumor growth in animals coming from the multi-peptide vaccine (PEPT)+metronomic chemotherapy (MCT) group and even more significantly in those coming from the PEPT+MCT+checkpoint inhibitor (CI) group, when compared to animals originally treated with PEPT (p < 0.01) (Figure 6A)
Summary
Anti-tumor immunity is severely hindered by multiple immune suppressive mechanisms characterizing the tumor microenvironment (TME). Tregs are able to lower antitumor immunity by suppressing NK and effector T cell responses [1,2,3,4] Their percentage is inversely correlated with tumor progression and poor prognosis www.impactjournals.com/oncotarget [5,6,7,8]. The binding of PD-L1 to programmed death 1 (PD-1) receptor on the surface of activated T and B cells, induces inhibitory pathways and generates a net immunosuppressive effect. This allows tumor evading cell killing [9]. Different tumors express PD-L1 molecules and, in recent years, treatment with blocking monoclonal antibodies has been shown to induce tumor regression in significant percentage of cancer patients (reviewed in [10, 11])
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