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

Shime, Hiroaki; Maruyama, Akira; Yoshida, Sumito; Takeda, Yohei; Matsumoto, Misako; Seya, Tsukasa

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

Shime, Hiroaki; Maruyama, Akira; Yoshida, Sumito et al.

Oncoimmunology, 2018, 7(1), e1373231

Permalink : https://hdl.handle.net/2115/68842

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論文情報

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アクセス権	open access
URI	https://hdl.handle.net/2115/68842
タイトル	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
著者	Shime, Hiroaki ; Maruyama, Akira ; Yoshida, Sumito ; Takeda, Yohei ; Matsumoto, Misako ; Seya, Tsukasa
e-Rad_Researcher 70372133 著者名 Shime, Hiroaki
著者名 Maruyama, Akira
著者名 Yoshida, Sumito
著者名 Takeda, Yohei
e-Rad_Researcher 30332456 著者名 Matsumoto, Misako
e-Rad_Researcher 10301805 著者名 Seya, Tsukasa
言語	英語
キーワード	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)
発行日	2018
出版者	Taylor & Francis
収録物名	Oncoimmunology
巻(号)	7(1)
ページ	e1373231
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Version of Record
権利情報	Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
PISSN	2162-402X
関連情報 (isIdenticalTo)	出版社版DOI https://doi.org/10.1080/2162402X.2017.1373231