IFN-alpha and 5-Aza-2-deoxycytidine enhance the anti-tumor efficacy of a dendritic-cell targeting MIP3alpha-Gp100-Trp2 DNA vaccine by affecting T-cell recruitment and tumor microenvironment gene expression
Background: The chemokine MIP-3α (CCL20) binds to CCR6 found on immature dendritic cells. DNA vaccines fusing MIP-3α to melanoma-associated antigens have shown improved efficacy and immunogenicity in the B16F10 model. To optimize the therapy, our laboratory has added agents designed to overcome immunoregulatory mechanisms of the tumor microenvironment. Here, we report that the combination of type-I interferon therapy (IFNα) with 5-Aza-2-deoxycitidine (Aza) profoundly enhanced the therapeutic anti-melanoma efficacy of a MIP-3α-Gp100-Trp2 DNA vaccine. Methods: The current studies utilize the B16F10 syngeneic mouse melanoma model. The vaccine is administered intramuscularly (i.m.) followed by i.m. electroporation. Vaccinations are given thrice at one-week intervals beginning day 5 with CpG adjuvant given two days later as noted. Aza is given i.p. at 1mg/kg on days 5 and 12. IFNα therapy is given in a series of one high followed by three low doses, beginning on days 5 and 12. Tumor sizes, growth, and survival were all assessed. Tumor microenvironment gene expression levels were explored by qRT-PCR. Tumor-infiltrating lymphocytes (TILs) were assessed by stimulating the purified lymphocyte fraction of tumors with vaccine antigens followed by intracellular cytokine staining flow cytometry. Results: We demonstrate that the addition of IFNα and Aza treatments to mice vaccinated with the MIP-3α-Gp100-Trp2 vaccine has led to significantly reduced tumor burden and overall increases in mouse survival, increasing median survival by 39% over vaccine and 86% over controls. Importantly, this increase in efficacy was dependent on the presence of all three components: vaccine, IFNα, and Aza. The addition of Aza and IFNα to the vaccine increased T-cell tumor infiltration and altered the proportion of CD8+T-cells. Also, IFNα and vaccine induced durable changes in IFNα-stimulated gene transcription. Conclusions: Efficient targeting of antigen to immature dendritic cells with a chemokine-fusion vaccine offers a potential alternative approach to classic and dendritic cell based vaccines currently undergoing clinical investigation. Combining this approach with IFNα and Aza combination treatment significantly improved vaccine efficacy, with efficacy correlating with changes in TILs and in IFNα -stimulated gene expression. Further potential therapy optimization currently undergoing investigation offers promise for this line of investigation to become a novel melanoma therapy.
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