Extranodal induction of therapeutic immunity in the tumor microenvironment after intratumoral delivery of Tbet gene-modified dendritic cells

Murine dendritic cells (DC) transduced to express the Type-1 transactivator T-bet (i.e. mDC.Tbet) and delivered intratumorally (i.t.) as a therapy are superior to control wild-type DC in slowing the growth of established subcutaneous (s.c.) MCA205 sarcomas in vivo. Optimal anti-tumor efficacy of mDC.Tbet-based gene therapy was dependent on host NK cells and CD8(+) T cells, and required mDC.Tbet expression of MHC class I molecules, but was independent of the capacity of the injected mDC.Tbet to produce pro-inflammatory cytokines (IL-12 family members or IFN-γ) or to migrate to tumor-draining lymph nodes (TDLN) based on CCR7 ligand chemokine recruitment. Conditional (CD11c-DTR) or genetic (BATF3(−/−)) deficiency in host antigen crosspresenting DC did not diminish the therapeutic action of i.t.-delivered wild-type mDC.Tbet. Interestingly, we observed that i.t delivery of mDC.Tbet (versus control mDC.Null) promoted the acute infiltration of NK cells and naïve CD45RB(+) T cells into the tumor microenvironment (TME) in association with elevated expression of NK- and T cell-recruiting chemokines by mDC.Tbet. When taken together, our data support a paradigm for extranodal (cross)priming of therapeutic Type-1 immunity in the TME after i.t. delivery of mDC.Tbet-based gene therapy.