Myeloid-derived suppressor cells attenuate TH1 development through IL-6 production to promote tumor progression

Collaborative action between tumor cells and host-derived suppressor cells leads to peripheral tolerance of T cells to tumor antigens. Here, we showed that in tumor-bearing mice, generation of tumor antigen-specific effector T-helper cells (TH1) was significantly attenuated, and impaired TH1 differe...

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Published in:Cancer immunology research 2013-07, Vol.1 (1), p.64-76
Main Authors: Tsukamoto, Hirotake, Nishikata, Ryutaro, Senju, Satoru, Nishimura, Yasuharu
Format: Article
Language:English
Subjects:
Animals
CD4-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - immunology
Cell Differentiation - immunology
Disease Progression
Interleukin-6 - biosynthesis
Interleukin-6 - immunology
Melanoma, Experimental - immunology
Melanoma, Experimental - therapy
Mice
Mice, Inbred C57BL
Myeloid Cells - immunology
Sarcoma, Experimental - immunology
Sarcoma, Experimental - therapy
Th1 Cells - immunology
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container_title Cancer immunology research
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creator Tsukamoto, Hirotake
Nishikata, Ryutaro
Senju, Satoru
Nishimura, Yasuharu
description Collaborative action between tumor cells and host-derived suppressor cells leads to peripheral tolerance of T cells to tumor antigens. Here, we showed that in tumor-bearing mice, generation of tumor antigen-specific effector T-helper cells (TH1) was significantly attenuated, and impaired TH1 differentiation was restored by the temporal blockade of interleukin (IL)-6 activity at the T-cell priming phase. Furthermore, we found that Gr-1(+) myeloid-derived suppressor cells (MDSC) served as a source of IL-6 in tumor-bearing mice. Adoptive transfer of effector CD4(+) T cells revealed that MDSC-sensitized effector CD4(+) T cells were less potent in mounting antitumor immune responses, although effector T cells generated together with Gr-1(+) cells from tumor-free mice eradicated established tumors. CD8(+) T cells, IFN-γ, and MHC-class II expression in host mice were indispensable for the antitumor activity initiated by effector CD4(+) T cells. Despite comparable suppressive activity of IL-6(+/+) and IL-6(-/-) MDSC on primary T-cell activation, transfer of IL-6(+/+) MDSC, but not IL-6(-/-) MDSC, dampened the efficient induction of effector TH1 cells and counteracted CD4(+) T cell-mediated antitumor immunity including cognate help for CD8(+) T cells in vivo. These findings suggest that, apart from the inhibitory effects on primary T-cell activation, MDSC promote tumor progression by attenuating functional differentiation of tumor-specific CD4(+) T cells into effector TH1 cells through IL-6 production to promote tumor progression. This novel mode of MDSC-induced tolerance of effector CD4(+) T cells should be considered as the basis for the rational design of effective T cell-mediated antitumor therapies.
doi_str_mv 10.1158/2326-6066.cir-13-0030
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source Free E-Journal (出版社公開部分のみ）
subjects Animals
CD4-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - immunology
Cell Differentiation - immunology
Disease Progression
Interleukin-6 - biosynthesis
Interleukin-6 - immunology
Melanoma, Experimental - immunology
Melanoma, Experimental - therapy
Mice
Mice, Inbred C57BL
Myeloid Cells - immunology
Sarcoma, Experimental - immunology
Sarcoma, Experimental - therapy
Th1 Cells - immunology
title Myeloid-derived suppressor cells attenuate TH1 development through IL-6 production to promote tumor progression
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