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.
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.
|Brennan, Todd V; Lin, Liwen; Huang, Xiaopei et al. (2018) Generation of Luciferase-expressing Tumor Cell Lines. Bio Protoc 8:|
|Dredge, Keith; Brennan, Todd V; Hammond, Edward et al. (2018) A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours. Br J Cancer 118:1035-1041|
|Heyman, Benjamin; Yang, Yiping (2018) New developments in immunotherapy for lymphoma. Cancer Biol Med 15:189-209|
|Hammond, Edward; Haynes, Nicole M; Cullinane, Carleen et al. (2018) Immunomodulatory activities of pixatimod: emerging nonclinical and clinical data, and its potential utility in combination with PD-1 inhibitors. J Immunother Cancer 6:54|
|Barbas, Andrew S; Lin, Liwen; McRae, MacKenzie et al. (2018) Heparan sulfate is a plasma biomarker of acute cellular allograft rejection. PLoS One 13:e0200877|
|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|
Showing the most recent 10 out of 30 publications