CXCL14 is an essential modulator of TLR9 agonist-induced antitumor immune responses.

Abstract

Cancer immunotherapeutic CpG oligodeoxynucleotide (ODN) is an agonist for TLR9 and a potent inducer of inflammatory cytokines and type I interferon. Clinical trials of CpG ODNs highlight the urgent need for effective TLR9 agonist CpG ODNs in humans. Here, we developed a highly potent CpG ODN, A602, which induces antitumor immune responses in combination with CXCL14. A602 induced secretion of interferon-α by human peripheral blood mononuclear cells. In mouse macrophages, dendritic cells, and human plasmacytoid dendritic cell lines, CXCL14 enhanced cellular uptake of A602, thereby promoting TLR9-mediated immune responses. Importantly, A602 exhibited strong antitumor activity in syngeneic mouse models of colorectal cancer-derived CT26, B lymphoma-derived A20, and melanoma-derived B16F10 cells. Because the antitumor effect of A602 against B16F10 cells was negated in Cxcl14 knockout mice, endogenously expressed CXCL14 is required for the A602-mediated tumor suppression. Thus, modulation of CXCL14 during the A602-induced immune responses shall unveil an innovative new approach for the antitumor immune therapy.