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.
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.
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