Vaccination with irradiated granulocyte macrophage-colony stimulating factor (GM-CSF)-transduced autologous tumor cells (GVAX) has been shown to induce therapeutic antitumor immunity. However, its effectiveness is limited. We aimed to improve the antitumor effect by identifying key pathways in GM-CSF-sensitized dendritic cells (GM-DCs) in the tumor-draining lymph nodes (TDLNs). First we confirmed that syngeneic mice injected subcutaneously (s.c.) with poorly immunogenic Lewis lung carcinoma (LLC) cells transduced with Sendai virus encoding GM-CSF (LLC/SeV/GM) rejected the transduced tumor cells. Using cDNA microarrays, we found that the expression levels of type I interferons (IFNs)-related genes, predominantly expressed in plasmacytoid DCs (pDCs) were significantly upregulated in TDLNs-derived GM-DCs. Indeed, effective stimulation of GM-CSF-induced antitumor immunity was observed in immunocompetent mice treated with LLC/SeV/GM cells, and the effect was significantly attenuated when pDCs-depleted or IFN- receptor knockout (IFNRA-/-) mice were used. Importantly, in both LLC and CT26 colon cancer-bearing mice, the combined regimen of synthetic TLR7 ligand imiquimod with autologous GVAX therapy overcame the refractoriness to GVAX monotherapy accompanied by tolerability. Mechanistically, mice treated with the combined vaccination displayed increased expression levels of CD86, CD9, and Siglec-H, which correlate with an antitumor phenotype in pDCs, but decreased the frequency of CD4+CD25+FoxP3+ regulatory T cells in the TDLNs. Together, these findings indicate that the addition of imiquimod to activate pDCs with type I IFN production, as a positive regulator of T-cell priming, could enhance the antitumor immune effects of GVAX therapy, adding to the understanding of and treatment with GM-CSF-based cancer immunotherapy.
- Received September 5, 2013.
- Revision received February 5, 2014.
- Accepted March 3, 2014.
- Copyright © 2014, American Association for Cancer Research.