Effector T cells mediate protective tumor immunity. The goal of tumor immune therapy including check-point blockade and immune vaccination and adoptive effector T cell is to engender long-term protective effector T cell immunity, and cause tumor eradiation in patients with cancer. To this end, effector T cells must traffic into and retai within the tumor microenvironment. Interestingly, the central scientific efforts in the field of tuor immunology are focused on exploring, designing and determining the functional potency and therapeutic efficacy of effector T cells. However, our current knowledge of effector T cell tumor trafficking and retention, and its underlying molecular mechanisms remain poorly understood in patients with cancer. This inadvertent deficiency significantly tempers our efforts toward understanding basic human effector T cell biology, establishing and evaluating immune therapeutic regimens and tumor vaccines in treating patients with cancer. It is essential to conduct comprehensive molecular and functional research on the nature of effector T cell tumor trafficking in the human tumor microenvironment. Th1-type chemokines CXCL9 and CXCL10 mediate effector T cell migration. CXCL9 and CXCL10 have been shown to be correlated with T cell density in human tumor and are associated positively with cancer patient survival. It is well known that IFN? stimulates the production of CXCL9 and CXCL10 in variety of cells. However, it is poorly understood how Th1-type chemokine expression is regulated in the human cancer microenvironment, and in turn how effector T cell tumor trafficking are controlled. Epigenetic silencing including histone modifications is important tumorigeneic mechanism in cancer. However, its role in tumor immunity remains to be defined. Using human primary ovarian cancer as a model, our preliminary studies demonstrated that a polycomb complex 2 (PRC2) protein, enhancer of zeste 2 (EZH2)-based histone H3 lysine 27 trimethylation (H3K27me3) was selectively involved in the regulation of the tumor production of Th1-type chemokines CXCL9 and CXCL10, and might subsequently determine effector T cell trafficking to the tumor microenvironment. Based on this surprising and novel finding, we hypothesize that tumor epigenetic silencing is not only a crucial carcinogeneic mechanism, but also key circuits controlling Th1-type chemokine expression and consequently impact effector T cell tumor trafficking and tumor therapy. We propose two specific aims to mechanistically, functionally and clinically test our central hypothesis.
Aim 1 is to test our hypothesis that PRC2-signaling circuit controls Th1-type chemokine production in the tumor microenvironment.
Aim 2 is to test our hypothesis that PRC2-signaling circuit clinically and therapeutically associates with effector T cell tumor trafficking and tumor immunity.
In this proposal we focus on the patients with ovarian cancer. We study the immunological mechanisms by which effector T cell trafficking into the tumor. The study will potentially lead to the development of preventive or therapeutic agents for patients with cancer.
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