Biphasic function of TLR3 adjuvant on tumor and spleen dendritic cells promotes tumor T cell infiltration and regression in a vaccine therapy

Successful cancer immunotherapy necessitates T cell proliferation and infiltration into tumor without exhaustion, a process closely links optimal maturation of dendritic cells (DC), and adjuvant promotes this process as an essential prerequisite. Poly(I:C) has contributed to adjuvant immunotherapy that evokes an antitumor response through the Toll-loke receptor 3 (TLR3)/TICAM-1 pathway in DC. However, the mechanism whereby Poly(I:C) acts on DC for T cell proliferation and migration remains undetermined. Subcutaneous injection of Poly(I:C) regressed implant tumors (WT1-C1498 or OVA-EG7) in C57BL/6 mice, which coincided with tumor-infiltration of CD8 + T cells. Epitope-specific cytotoxic T lymphocytes (CTLs) were increased in spleen by challenge with Poly(I:C)+Db126 WT-1 peptide but not Poly(I:C) alone, suggesting the need of an exogenous Ag density for cross-priming. In tumor, CXCR3 ligands were upregulated by Poly(I:C), which facilitated recruitment of CTL to the tumor. Thus, Poly(I:C) acts on splenic CD8α + DC to cross-prime T cells and on intratumor cells to attract CTLs. Besides CD8 + T cell cross-priming, T cell recruitment into tumor was significantly dampened in Batf3 −/− mice, reflecting the importance of tumor Batf3-dependent DC rather than macrophages in T cell recruitment. Poly(I:C)-induced XCR1 hi CD8α + DC with high TLR3 levels were markedly decreased in Batf3 −/− mice, which hampered the production of IL-12 and IL-12-mediated CD4 + /CD8 + T cell proliferation. Subcutaneous administration of Poly(I:C) and adoptive transfer of wild-type CD8α + DC largely recovered antitumor response in those Batf3 −/− mice. Collectively, Poly(I:C) tunes up proper maturation of CD8α + DC to establish TLR3-mediated IL-12 function and cross-presentation in spleen and lymphocyte-attractive antitumor microenvironment in tumor.