Submitted May 2, 2008
Accepted March 9, 2009
Induction of type I IFN is required for overcoming tumor-specific T cell tolerance following stem cell transplantation
Ian Horkheimer, Michael Quigley, Jiangao Zhu, Xiaopei Huang, Nelson J Chao, and Yiping Yang*
Department of Medicine, Duke University Medical Center, Durham, NC, United States
Department of Immunology, Duke University Medical Center, Durham, NC, United States
* Corresponding author; email: yang0029{at}mc.duke.edu.
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 following transplantation. Here we showed that CD4+CD25+ regulatory T (TReg) cells play a critical role in tumor-specific CD8+ T cell tolerance post-transplant. Removal of TReg cells from the donor lymphocyte graft did not overcome this tolerance due to rapid conversion of donor CD4+CD25- T cells into CD4+CD25+Foxp3+ TReg cells in recipients post-transplant, and depletion of TReg cells in recipients was necessary for the reversal of tumor-specific tolerance. There results suggest that strategies capable of overcoming T cell tolerance in recipients are required to promote anti-tumor immunity post-transplant. Towards this goal, we demonstrated that DC vaccines co-administered with the TLR9 ligand, CpG could effectively overcome tumor-specific tolerance, leading to significant prolongation of tumor-free survival post-transplant. We further demonstrated 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 following stem cell transplantation.
