2011 Fiscal Year Final Research Report
Analysis of Myeloid-derived suppressor cell-induced functional defects of CD4+T cells in tumor-bearing animals
| Project/Area Number |
22700897
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Tumor immunology
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| Research Institution | Kumamoto University |
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Principal Investigator |
AWAI Hirotake 熊本大学, 大学院・生命科学研究部, 助教 (10433020)
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| Project Period (FY) |
2010 – 2011
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| Keywords | 免疫抑制 / CD4^+T細胞 / ミエロイド系抑制性細胞 |
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| Research Abstract |
Collaborative action between host-derived immune-suppressor cells and tumor cells abrogate the efficient T cell-mediated attack against the tumor cells. Myeloid-derived suppressor cells(MDSC) accumulated in most cancer patients are potent inhibitors of T cell-mediated anticancer immunity. While their inhibitory action on primary T cell activation was well established, their influence on secondary T cell responses or differentiation remains to be investigated. Here, we demonstrated that CD4^+T cell differentiation into effector Th1 cells were suppressed by systemic IL-6 trans-signaling in tumor bearing mice. Moreover, we found that we IL-6 was produced by Gr-1^+MDSC in tumor bearing mice, which was consistent with the fact that the ability to produce IFN-was attenuated in effector T cells co-cultured with MDSC in vitro in an IL-6-dependent manner. Transfer experiments demonstrated that MDSC-sensitized effector CD4^+T cells were less potent to mount anti-tumor CD8^+T cell responses and to induce subsequent tumor regression. IL-6^<+/+> MDSC but not IL-6^<-/-> MDSC dampened the efficient induction of antigen-specific Th1 effector T cells in response to active immunization with antigenic peptide pulsed-DC in vivo, and counteracted CD4^+T cell-mediated anti-tumor immunity. These finding suggest that MDSC-derived IL-6 inhibited functional differentiation into anti-tumor effector CD4^+T cells in tumor-bearing mice. We provide the evidence for a novel mode of MDSC-mediated induction of effector CD4^+T cell tolerance in tumor-bearing animals, which should be considered for a rational design of effective T cell-mediated antitumor therapies.
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