Tumor-induced immune evasion represents one chief barrier in cancer immunotherapy. The mechanisms underlying this immune evasion include defective tumor-antigen processing and presentation, production of immune inhibitory cytokines, and induction of tumor-specific T cell tolerance mediated by CD4+CD25+ regulatory T (TReg) cells. Myeloablative chemotherapy with stem cell transplant may offer the best chance of achieving a state of minimal residual disease, and thus minimizing tumor-induced immune evasion. However, TReg-mediated tumor-specific T cell tolerance persists following transplant. We have identified that in vivo stimulation of Toll-like receptors (TLRs) of the innate immunity is required for the reversal of TReg-mediated suppression on tumor-specific CD8+ T cells post-transplant. This can be achieved by conventional dendritic cell (cDC) vaccines co-administered with a TLR9 ligand, CpG in vivo. We have also discovered that vaccinia virus (VV)-based vaccines can even more potently activate tumor-specific CD8 T cell response post-transplant due to their unique ability to activate multiple innate immune pathways in vivo: VV activates cDCs through TLR2, leading to the production of pro-inflammatory cytokines, and a TLR-independent pathway, resulting in secretion of type I interferons (IFNs);In addition, VV also activates plasmacytoid DCs (pDCs) to secrete high levels of type I IFNs in a TLR-dependent manner. Taken together, these observations suggest a central hypothesis that efficient activation of innate immune system is critical for overcoming TReg-mediated suppression on tumor- specific T cells through post-transplant vaccinations. To test this hypothesis, we propose to pursue the following 5 aims: 1) To study the biological function of pDCs in TLR-dependent augmentation of anti-tumor immunity post-transplant;2) To delineate the mechanism(s) underlying TLR-dependent reversal of TReg-mediated suppression on tumor-specific T cells post-transplant;3) To investigate the synergistic effect of multiple TLRs on the generation of anti-tumor effector and long-lived memory T cells post-transplant;4) To determine the function of TLRs in the recovery of innate immune cells post-transplant;5) To evaluate the efficacy of novel immunotherapeutic strategies for treating pre-established tumors in the setting of stem cell transplant. We expect that this work will lead to the identification of critical elements for enhancing anti-tumor T cell immunity post-transplant, and in turn will help us design new generations of effective tumor vaccines in the setting of stem cell transplant.

Public Health Relevance

One major hurdle in cancer immunotherapy even in the setting of stem cell transplantation is the presence of immunosuppressive regulatory T cells. Therefore, the key is to develop cancer vaccines capable of overcoming regulatory T cell-mediated suppression and effectively activate anti-tumor immunity. The proposed work will lead to the identification of critical factors required for overcoming regulatory T cell-mediated suppression and promoting anti-tumor T cell immunity post-transplant, and in turn will help us design new generations of effective vaccines for treating cancer in the setting of stem cell transplant.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136934-03
Application #
8014888
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Welch, Anthony R
Project Start
2009-03-01
Project End
2014-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
3
Fiscal Year
2011
Total Cost
$313,989
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Brennan, Todd V; Yang, Yiping (2017) PD-L1 serves as a double agent in separating GVL from GVHD. J Clin Invest 127:1627-1630
Yuan, Yuqing; Yang, Yiping; Huang, Xiaopei (2017) IL-21 is required for CD4 memory formation in response to viral infection. JCI Insight 2:e90652
Petty, Amy J; Yang, Yiping (2017) Tumor-associated macrophages: implications in cancer immunotherapy. Immunotherapy 9:289-302
Brandstadter, Joshua D; Chen, Huiyao; Jiang, Songfu et al. (2017) IL-18-dependent NKG2D ligand upregulation on accessory cells is mediated by the PI3K/GSK-3 pathway. J Leukoc Biol 101:1317-1323
Fortin, Carl; Yang, Yiping; Huang, Xiaopei (2017) Monocytic myeloid-derived suppressor cells regulate T-cell responses against vaccinia virus. Eur J Immunol 47:1022-1031
Zhu, Jiangao; Chen, Huiyao; Huang, Xiaopei et al. (2016) Ly6C(hi) monocytes regulate T cell responses in viral hepatitis. JCI Insight 1:e89880
Brennan, Todd V; Lin, Liwen; Brandstadter, Joshua D et al. (2016) Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation. J Clin Invest 126:207-19
Heyman, Benjamin; Yang, Yiping (2016) Mechanisms of heparanase inhibitors in cancer therapy. Exp Hematol 44:1002-1012
Huang, Xiaopei; Yang, Yiping (2016) Driving an improved CAR for cancer immunotherapy. J Clin Invest 126:2795-8
Yang, Yiping (2015) Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest 125:3335-7

Showing the most recent 10 out of 25 publications