IL-36 is required for the induction of therapeutic immunity by Tbet gene-modified dendritic cells. (TUM10P.1024)

Our lab has developed a dendritic cell (DC) vaccine as a means of overcoming immune dysfunction in the tumor microenvironment (TME) and generating a therapeutic anti-tumor immune response. As protective Type 1 immune responses are characterized by intrinsic expression of the Tbet transactivator in T cells and DC, we engineered DC with Tbet cDNA (ie, DC.Tbet) and injected these cells into the TME of syngeneic tumor-bearing mice as a therapy. Treatment of MCA205 sarcomas with DC.Tbet promoted the rapid (hours) and sustained (days-weeks) infiltration of Type 1-polarized CD4+ and CD8+ TIL into the TME and led to increased TME expression of factors characteristic of ectopic lymphoid structures (ELS), such as TNFSF14, CCL19, and CCL21. DC.Tbet cells revealed a 60-fold increase in the level of IL-36gamma mRNA over mock-transduced DC and inhibition of signaling through the IL-36 receptor (IL-36R) using natural antagonist IL-1F5 abrogated the ability of DC.Tbet therapy to inhibit tumor growth in vivo , concurrent with reduced recruitment of therapy-induced CD4+ and CD8+ TIL. The efficacy of DC.Tbet therapy was similarly negated in MCA205-bearing IL-36R-/- hosts. These data suggest a mechanism whereby treatment with DC.Tbet leads to recruitment of anti-tumor TIL via an IL-36R signaling-dependent mechanism that supports the development of ELS in the TME. These findings foreshadow the clinical use of IL-36gamma in cancer vaccine formulations as a means to promote therapeutic immunity.