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 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.
Authors' Affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Hirotake
H
Tsukamoto
Ryutaro
R
Nishikata
Satoru
S
Senju
Yasuharu
Y
Nishimura
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D018450:Disease Progression; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D012513:Sarcoma, Experimental / Q000276:immunology / Q000628:therapy; D018417:Th1 Cells / Q000276:immunology*
D015850:Interleukin-6