Type-1 polarized dendritic cells primed for high IL-12 production show enhanced activity as cancer vaccines
- 293 Downloads
While multiple pathways of dendritic cell (DC) maturation result in transient production of IL-12, fully mature DCs show reduced ability to produce IL-12p70 upon a subsequent interaction with Ag-specific T cells, limiting their in vivo performance as vaccines. Such “DC exhaustion” can be prevented by the presence of IFNγ during the maturation of human DCs (type-1-polarization), resulting in improved induction of tumor-specific Th1 and CTL responses in vitro. Here, we show that type-1 polarization of mouse DCs strongly enhances their ability to induce CTL responses against a model tumor antigen, OVA, in vivo, promoting the induction of protective immunity against OVA-expressing EG7 lymphoma. Interestingly, in contrast to the human system, the induction of mouse DC1s requires the participation of IL-4, a nominal Th2-inducing cytokine. The current data help to explain the previously reported Th1-driving and anti-tumor activities of IL-4, and demonstrate that type-1 polarization increases in vivo activity of DC-based vaccines.
KeywordsDendritic cells Vaccines Lymphoma Mouse IL-12 IL-4
The authors thank Dr. Pia Bjork for stimulating discussions and Erik Berk for critically reading the manuscript. This work was supported by the NIH grants CA095128 and CA101944.
- 3.Biedermann T, Zimmermann S, Himmelrich H, Gumy A, Egeter O, Sakrauski AK, Seegmuller I, Voigt H, Launois P, Levine AD, Wagner H, Heeg K, Louis JA, Rocken M (2001) IL-4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c mice. Nat Immunol 2:1054–1060PubMedCrossRefGoogle Scholar
- 4.Chan SH, Perussia B, Gupta JW, Kobayashi M, Pospisil M, Young HA, Wolf SF, Young D, Clark SC, Trinchieri G (1991) Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med 173:869–879PubMedCrossRefGoogle Scholar
- 5.De Vries IJ, Krooshoop DJ, Scharenborg NM, Lesterhuis WJ, Diepstra JH, Van Muijen GN, Strijk SP, Ruers TJ, Boerman OC, Oyen WJ, Adema GJ, Punt CJ, Figdor CG (2003) Effective migration of antigen-pulsed dendritic cells to lymph nodes in melanoma patients is determined by their maturation state. Cancer Res 63:12–17PubMedGoogle Scholar
- 6.Fallarino F, Uyttenhove C, Boon T, Gajewski TF (1999) Improved efficacy of dendritic cell vaccines and successful immunization with tumor antigen peptide-pulsed peripheral blood mononuclear cells by coadministration of recombinant murine interleukin-12. Int J Cancer 80:324–333PubMedCrossRefGoogle Scholar
- 15.Kalinski P, Schuitemaker JH, Hilkens CM, Wierenga EA, Kapsenberg ML (1999) Final maturation of dendritic cells is associated with impaired responsiveness to IFN-gamma and to bacterial IL-12 inducers: decreased ability of mature dendritic cells to produce IL-12 during the interaction with Th cells. J Immunol 162:3231–3236PubMedGoogle Scholar
- 25.Mailliard RB, Egawa S, Cai Q, Kalinska A, Bykovskaya SN, Lotze MT, Kapsenberg ML, Storkus WJ, Kalinski P (2002) Complementary dendritic cell-activating function of CD8+ and CD4+ T cells: helper role of CD8+ T cells in the development of T helper type 1 responses. J Exp Med 195:473–483PubMedCrossRefGoogle Scholar
- 30.Nakamura Y, Watchmaker P, Urban J, Sheridan B, Giermasz A, Nishimura F, Sasaki K, Cumberland R, Muthuswamy R, Mailliard RB, Larregina AT, Falo LD, Gooding W, Storkus WJ, Okada H, Hendricks RL, Kalinski P (2007) Helper function of memory CD8+ T cells: heterologous CD8+ T cells support the induction of therapeutic cancer immunity. Cancer Res 67:10012–10018PubMedCrossRefGoogle Scholar