| Project/Area Number |
22700897
|
|---|
| Research Category |
Grant-in-Aid for Young Scientists (B)
|
| Allocation Type | Single-year Grants |
|---|
| Research Field |
Tumor immunology
|
|---|
| Research Institution | Kumamoto University |
|---|
Principal Investigator |
AWAI Hirotake 熊本大学, 大学院・生命科学研究部, 助教 (10433020)
|
|---|
| Project Period (FY) |
2010 – 2011
|
| Project Status |
Completed (Fiscal Year 2011)
|
| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2010: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
|
|---|
| Keywords | 免疫抑制 / CD4^+T細胞 / ミエロイド系抑制性細胞 / がん / T細胞 / 免疫制御 / MDSC |
|---|
| 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.
|
