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Toll-like receptor 2 ligand and interferon-γ suppress anti-tumor T cell responses by enhancing the immunosuppressive activity of monocytic myeloid-derived suppressor cells

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Title: Toll-like receptor 2 ligand and interferon-γ suppress anti-tumor T cell responses by enhancing the immunosuppressive activity of monocytic myeloid-derived suppressor cells
Authors: Shime, Hiroaki Browse this author →KAKEN DB
Maruyama, Akira Browse this author
Yoshida, Sumito Browse this author
Takeda, Yohei Browse this author
Matsumoto, Misako Browse this author →KAKEN DB
Seya, Tsukasa Browse this author →KAKEN DB
Keywords: Inducible NO synthase (iNOS/NOS2)
interferon-γ (IFN-γ)
macrophages
monocytic MDSCs (M-MDSCs)
myeloid-derived suppressor cells (MDSCs)
nitric oxide (NO)
toll-like receptor 2 (TLR2)
Issue Date: 2018
Publisher: Taylor & Francis
Journal Title: Oncoimmunology
Volume: 7
Issue: 1
Start Page: e1373231
Publisher DOI: 10.1080/2162402X.2017.1373231
Abstract: CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) suppress activation/proliferation of cytotoxic T cells, thereby hindering cancer immunotherapy. MDSCs are increased after adjuvant therapy with toll-like receptor (TLR) 2 ligands, such as Pam2CSK4, in tumor-bearing mice. However, it remains unknown if the activation of TLR2 in MDSCs affects their function and the therapeutic efficacy of TLR2 ligand. Here, we show that TLR2 signaling in CD11b+Ly6G-Ly6Chigh monocytic MDSCs (M-MDSCs), but not CD11b+Ly6G+Ly6Clow granulocytic MDSCs (G-MDSCs), enhances their immunosuppressive activity, thereby limiting anti-tumor T cell responses induced by TLR2-activated dendritic cells (DCs). iNOS induction was critical for Pam2CSK4-enhanced T cell suppression by M-MDSCs. iNOS was expressed in M-MDSC-derived macrophages, but not undifferentiated M-MDSCs, in cocultures with CD8+ T cells, CD11c+ DCs, antigen peptide and Pam2CSK4. Pam2CSK4 increased the differentiation frequency of M-MDSCs to macrophages, and iNOS expression required interferon-γ (IFN-γ) production by CD8+ T cells that had been transiently stimulated by M-MDSC-derived macrophages in an antigen/TLR2-dependent manner. Although Pam2CSK4 triggered DC maturation and tumor regression via induction of tumor antigen-specific cytotoxic T lymphocyte (CTL) responses in tumor-bearing mice, Pam2CSK4 plus antigen increased the frequency of iNOS+ macrophages in the tumor. Treatment with iNOS inhibitor enhanced the therapeutic efficacy of Pam2CSK4. Hence, the results suggest that TLR2 ligand and T cell-derived IFN-γ enhance M-MDSC-mediated immunosuppression, which may negatively regulate anti-tumor CTL response.
Rights: http://creativecommons.org/licenses/by-nc-nd/4.0/
Type: article
URI: http://hdl.handle.net/2115/68842
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 瀬谷 司

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