TNFRSF25 agonists as potent cancer vaccine adjuvants (131.25)

Abstract

Abstract Signaling through TNFRSF25 by its natural ligand, TNFSF15, or agonistic antibodies enhances cytokine production and effector function by antigen-activated T cells. Paradoxically, we recently discovered that TNFRSF25 signaling induces rapid and specific proliferation of CD4+FoxP3+ regulatory T cells (Treg) in vivo in the absence of exogenous antigen. When TNFRSF25 agonistic antibody, clone 4C12, was used in combination with heat shock protein (gp96-Ig) based vaccination, 4C12 treatment led to synergistic antigen-specific CTL expansion when given together with the vaccine, which occurred simultaneously with Treg expansion in vivo. The frequency of CTL and Treg reached 65% of total CD8+ cells and 45% of total CD4+ cells, respectively, within the same tissue following combined administration of 4C12 and gp96-Ig. TNFR25 driven synergism with gp96-Ig vaccination was dependent upon mTOR signaling. In a therapeutic setting, combined administration of 4C12 and gp96-Ig enhanced rejection of established EG7, LLC and 3-MCA induced sarcoma tumors. These data indicate that TNFRSF25 agonists enhance vaccine-induced anti-tumor immunity which correlates with increased magnitude and duration of tumor-specific CTL expansion, systemically. These findings illustrate that TNFRSF25 signaling may enhance either inflammatory or regulatory immunity depending on the temporal availability of its ligand and the inflammatory milieu.