IMMUNOADJUVANT INTERLEUKIN 33 INDUCES ANTIGEN-SPECIFIC TUMOR AND VIRAL IMMUNITY
Daniel Villarreal1, Megan Wise1, Jewell Walters1, Jian Yan2, Matthew Morrow2, David Weiner1.
1University of Pennsylvania, Philadelphia, PA, 2Inovio Pharmaceuticals, Plymouth Meeting, PA.
Recent studies are beginning to show that IL-33 cytokine activities exceed those of the Th2 immunity, and can promote Th1 immune responses. However, the potential ability of IL-33 to act as vaccine adjuvant to influence the CD4 Th1 and CD8 T cell immune responses has not been well defined. Here we examine IL-33 for its immunoadjuvant effects in an HPV-associated cancer immune therapy model in which cell-mediated immunity is critical for protection. To this end, we developed a highly optimized DNA-vector encoding IL-33 and evaluated its adjuvant properties in combination with a DNA fusion HPV 16 E6/E7 construct in vivo. We showed that IL-33 was capable of enhancing potent antigen (Ag)-specific effector and memory T cell immunity in vivo in a DNA vaccine setting. Additionally, IL-33 augmented vaccine-induced Ag-specific polyfunctional CD4+ and CD8+ T-cell responses, with a large proportion of CD8+ T cells undergoing cytolytic plurifunctional degranulation. Therapeutic studies indicated that established TC-1-bearing mice underwent rapid and complete regression after therapeutic vaccination with IL-33 in conjunction with an HPV DNA vaccine. Furthermore, we show that IL-33 can significantly expand the magnitude of Ag-specific CD8+ T-cell responses and elicit effector-memory CD8+ T cells. Given these significant findings, we also explored IL-33 adjuvant effects in conjunction with an HIV DNA vaccine and demonstrated that IL-33 also can increase the antigen-specific HIV T-cell immune responses. Overall, these results lay the groundwork for IL-33 as an immunoadjuvant candidate in future vaccination in the context of both antitumor and antiviral immunotherapy.