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

Kosuke Tanegashima1, Eiji Esashi2, Koji Ishida2

  • 1Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan.

Journal of Immunology (Baltimore, Md. : 1950)
|May 22, 2025
PubMed

Insights

A novel CpG oligodeoxynucleotide (ODN), A602, enhances antitumor immunity by working with CXCL14. This combination therapy shows potent anti-cancer effects in mouse models, highlighting a new approach for cancer immunotherapy.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • CpG oligodeoxynucleotides (ODNs) are agonists for Toll-like receptor 9 (TLR9) and potent inducers of inflammatory cytokines and type I interferon.
  • Clinical trials indicate a need for more effective human TLR9 agonist CpG ODNs for cancer immunotherapy.

Purpose of the Study:

  • To develop a potent CpG ODN (A602) that induces antitumor immune responses.
  • To investigate the role of CXCL14 in enhancing the efficacy of CpG ODN A602.

Main Methods:

  • A602 was developed and its ability to induce interferon-alpha was tested in human peripheral blood mononuclear cells.
  • The effect of CXCL14 on cellular uptake of A602 and TLR9-mediated immune responses was assessed in various immune cell lines.
  • Antitumor activity of A602, alone and in combination with CXCL14, was evaluated in syngeneic mouse models of colorectal cancer, B lymphoma, and melanoma.
  • The necessity of endogenous CXCL14 was determined using CXCL14 knockout mice.

Main Results:

  • A602 induced interferon-alpha secretion from human peripheral blood mononuclear cells.
  • CXCL14 enhanced the cellular uptake of A602 in immune cells, boosting TLR9-mediated responses.
  • A602 demonstrated significant antitumor activity against CT26, A20, and B16F10 cancer cells in mouse models.
  • The antitumor effect of A602 against B16F10 melanoma was abolished in CXCL14 knockout mice, confirming the requirement of endogenous CXCL14.

Conclusions:

  • The novel CpG ODN A602, in combination with CXCL14, effectively induces antitumor immune responses.
  • Endogenous CXCL14 is crucial for the tumor-suppressive effects mediated by A602.
  • Modulating CXCL14 presents a promising innovative strategy for developing new antitumor immunotherapies.
Keywords:
CXCL14CpG oligodeoxynucleotidesTLR9anti-tumor immune responses

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