Figure 7.

ISCOMATRIX vaccines are dependent on a MyD88-signaling axis in vivo (a) CD8⁺ T-cell responses were compared in wild type (WT) and MyD88-deficient mice (MyD88 KO) vaccinated with an ISCOMATRIX vaccine on day −7, 0, with the magnitude of the CD8⁺ T-cell response shown relative to WT mice. (b, c) Same as in (a) except the CD8⁺ T-cell response was evaluated in TRIF or TLR4-deficient mice. (d) Purified CD8 and MigDCs from wild type or MyD88-deficient (KO) mice were isolated from the DLN 24 h after vaccine administration. MHC class I cross-presentation was assessed by co-culturing each population with 5 × 10⁴ CFSE-labeled OT-1 cells and quantifying proliferation 60 h later, as described. (e) CD40, CD80 and CD86 expression (black lines) was assessed for CD8 DCs isolated from the DLN of WT or MyD88 KO mice dosed with ISCOMARTIX adjuvant, compared with CD8 DCs from untreated WT mice (gray lines). Dashed lines illustrate the median fluorescence for each marker. (f) Schematic illustrating the interaction between DCs, T cells and NK cells in the DLN following ISCOMATRIX vaccine delivery. ISCOMATRIX vaccines initiate a localized inflammatory response at the subcutaneous injection site, and efficient DC activation and MHC class I cross-presentation in the DLN (MyD88-independent). Although the precise DC activation signal(s) is currently unknown, a distinct pro-inflammatory milieu was detected locally and systemically following ISCOMATIRX adjuvant administration. In the DLN, NK cell activation and CD8⁺ T-cell cross-priming was dependent on DCs, as well as an intact MyD88 signaling network. Cross-primed CD8⁺ T cells exhibit potent antitumor activity in prophylactic tumor challenge models. However, in the case of pre-established tumor burden, the effectiveness of the vaccine is likely to be blunted by immune suppressive networks, such as myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg) and tumor-derived factors that prevent complete tumor eradication.