Induction of type I IFN is required for overcoming tumor-specific T-cell tolerance after stem cell transplantation

被引:12
|
作者
Horkheimer, Ian [1 ]
Quigley, Michael [2 ]
Zhu, Jiangao [1 ]
Huang, Xiaopei [1 ]
Chao, Nelson J. [1 ,2 ]
Yang, Yiping [1 ,2 ]
机构
[1] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
[2] Duke Univ, Med Ctr, Div Immunol, Durham, NC 27710 USA
基金
美国国家卫生研究院;
关键词
BONE-MARROW-TRANSPLANTATION; DENDRITIC CELLS; TRANSGENIC MICE; PERIPHERAL TOLERANCE; METASTATIC MELANOMA; ANTIGEN-4; BLOCKADE; IMMUNE-RESPONSES; REGULATORY CELLS; CANCER VACCINES; TGF-BETA;
D O I
10.1182/blood-2008-05-155150
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Tumor-specific T-cell tolerance represents one major mechanism of tumor-induced immune evasion. Myeloablative chemotherapy with stem cell transplantation may offer the best chance of achieving a state of minimal residual disease and, thus, minimize tumor-induced immune evasion. However, studies have shown that tumor-specific T-cell tolerance persists after transplantation. Here, we showed that CD4(+)CD25(+) regulatory T (T-Reg) cells play a critical role in tumor-specific CD8(+) T-cell tolerance after trans-plantation. Removal of T-Reg cells from the donor lymphocyte graft did not overcome this tolerance because of rapid conversion of donor CD4(+)CD25(-) T cells into CD4(+)CD25(+)Foxp3(+) T-Reg cells in recipients after transplantation, and depletion of T-Reg cells in recipients was necessary for the reversal of tumor-specific tolerance. These results suggest that strategies capable of overcoming T-cell tolerance in recipients are required to promote antitumor immunity after transplantation. Toward this goal, we showed that dendritic cell (DC) vaccines coadministered with the TLR9 ligand, CpG could effectively overcome tumor-specific tolerance, leading to significant prolongation of tumor-free survival after transplantation. We further showed that CpG-induced type I interferon was critical for the reversal of tumor-specific tolerance in vivo. Collectively, these results may suggest effective immunotherapeutic strategies for treating cancer after stem cell transplantation. (Blood. 2009; 113: 5330-5339)
引用
收藏
页码:5330 / 5339
页数:10
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