An important goal of cancer immunotherapy is to generate long-lived memory T cells to provide long-term immunity against cancer. However, it is virtually unknown what controls the formation of tumor-specific memory T cells. Thus, understanding and exploiting mechanisms underlying the induction of long-lasting memory T cell immunity is crucial to the development of vaccines and immunotherapies for the prevention and treatment of cancers in humans. The objective of this application is to elucidate critical mechanisms governing the formation of long-lived, tumor-specific memory CD8 T cells. Specifically, we hypothesize that NK cells are critical for the generation of long-lived, tumor-specific CD8 memory T cells. We will test this hypothesis with four specific aims and pursue the mechanisms underlying NK cell-dependent formation of long-lived memory CD8 T cells in two different tumor models. By providing molecular and cellular basis for the formation of long- lived, tumor-specific CD8 memory T cells, these studies will substantially increase knowledge of critical factors responsible for the generation of long-lasting anti-tumor immunity. Thus, the outcomes of this proposal will have significant impact on the design of effective vaccine strategies for treating cancer and preventing relapses, leading to the potential cure of cancer. Furthermore, the principles learned here can be applied to the memory T cell field in general for the treatment of other diseases such as pathogenic infections.

Public Health Relevance

An ultimate goal of cancer immunotherapy is to generate long-lived, tumor-specific memory T cell responses to provide long-term immunity against cancer. However, it is not clear what controls the formation of long-lived tumor-specific memory T cells. The proposed work will identify critical factors governing the generation of tumor-specifi memory T cells, and in turn will help us design more effective immunotherapeutic strategies for treating cancer as well as preventing relapses, leading to potential cure of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA193167-03
Application #
9388332
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Mccarthy, Susan A
Project Start
2015-12-01
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
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
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
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