Memory CD8+ T cells are one of the most important players in mediating protective tumor immunity. The major goal of tumor immune therapy and immune vaccination including adoptive effector T cell and dendritic cell transfusion is to engender long-term protective memory CD8+ T cell immunity, and in turn results in tumor eradiation in patients with cancer. However, our current knowledge of memory T cells arises almost exclusively from studies of infectious disease models. The induction of memory T cells in cancer is often inadvertently thought of as being analogous to that observed in chronic infections. It is evident that the generation and function of memory T cells are dramatically impacted by the tumor microenvironment. We recently performed preliminary studies on the phenotype, functionality and epigenetic of memory CD8+ T cell subsets in human tumors. We have observed multiple phenotypically and functionally distinct memory CD8+ T cell subsets in ovarian cancer microenvironment. A number of unique clusters of genes were identified along with these memory CD8+ T cell subsets. Among these genes, the expression patterns of the polycomb group (PcG) protein like Enhancer of zeste homolog 2 (Ezh2), Ezh2-dependent trimethylation gene H3K27 (H3K27me3) and the target genes like Ezh2/Ink4a/Arf pathway are associated with particular CD8+ memory T cell subsets. Recent studies have revealed that Ezh2-dependent H3K27 trimethylation (H3K27me3) represses target genes like Ink4a/Arf to control growth, survival and renewal of cancer cells, cancer stem cells, ? cells and embryonic fibroblasts. However, the expression, regulation and role of Ezh2/Ink4a/Arf pathway have not been explored in immune cells including humans and mice. Our work suggests that epigenetic regulation plays a role in controlling memory T cell "stemness" (proliferation, renewal and survival) and effector function of CD8+ memory T cell subsets in the tumor.
Our specific aims are:
Aim 1 is to test our hypothesis that ABCG2+CD8+ memory T cells exhibit the stem-like properties (stemness) in the OC microenvironment.
Aim 2 is to test our hypothesis that distinct epigenetic histone profiles are linked to specific CD8+ memory T cell subsets in the OC microenvironment.
Aim 3 is to test our hypothesis that the Ezh2/Ink4a/Arf pathway importantly determines the fate of CD8+ memory T cells, and that reprogramming this pathway engenders potent long-term anti-tumor immunity.

Public Health Relevance

Our understanding of memory CD8+ T cells in human tumor microenvironment lags much behind the more comprehensive analyses of these cells in infectious disease models. This deficiency significantly tempers our efforts toward understanding basic human memory T cell biology and potential application. The application takes a comprehensive approach by combining basic immunological methods, genetic and epigenetic research, and clinical and comparative analyses to address the nature of memory CD8+ T cells in the human tumor microenvironment. The application is conceptually and applicably significant, and will generate novel insight into new approaches in cancer immune therapy and vaccination.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA152470-02
Application #
8293069
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2011-07-01
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$393,042
Indirect Cost
$140,282
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Wan, Shanshan; Zhao, Ende; Kryczek, Ilona et al. (2014) Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147:1393-404
Kryczek, Ilona; Lin, Yanwei; Nagarsheth, Nisha et al. (2014) IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L. Immunity 40:772-84
Crespo, Joel; Sun, Haoyu; Welling, Theodore H et al. (2013) T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol 25:214-21
Cui, Tracy X; Kryczek, Ilona; Zhao, Lili et al. (2013) Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. Immunity 39:611-21
Zhao, Ende; Xu, Huanbin; Wang, Lin et al. (2012) Bone marrow and the control of immunity. Cell Mol Immunol 9:11-9