One critical mechanism of peripheral immunologic tolerance occurs through the process of T cell anergy, particularly in the tumor context. We previously have shown that upregulated expression of lipid kinases of the diacylglycerol kinase (DGK) family participate in the suppression of RasGRP-mediated Ras activation and contribute to T cell dysfunction in the anergic state. Other studies have implicated upregulation of additional negative regulatory signaling proteins, which may cooperate to maintain T cell dysfunction. Recently, through conditional knockout studies, gene expression profiling and ChIP-Seq experiments, we have identified the transcription factor EGR2 as a central regulator of expression of these negative regulatory factors in T cell anergy. Importantly, new EGR2-driven targets have emerged that are cell surface markers, which may allow flow cytometric identification of anergic cells. The major goal of this proposal is to determine the contribution o EGR2 towards peripheral tolerance to tumors.
In Specific Aim 1 we will determine the effects of conditional deletion of EGR2 in peripheral T cells in vivo. Induction of T cell anergy, generation of anti-tumor immunity, and potential for evolving autoimmunity will be assessed.
In Specific Aim 2, the relevance of a subset of EGR2- regulated genes in T cell biology will be investigated. We will focus on the secreted factor CCL1;the surface expression of CRTAM/LAG3/4-1BB;and the functional role of Semaphorin 7A. Whether combinations of these markers can identify anergic cells in the tumor microenvironment will be determined.
In Specific Aim 3, expression of EGR2 and its targets in T cells infiltrating human melanoma will be evaluated, to move towards clinical relevance. Together, these studies will substantially broaden and deepen our understanding of EGR2 and T cell anergy in vivo, and are expected to uncover strategies that can have clinical application towards immunotherapy of cancer.
Understanding mechanisms of immune evasion by tumors should highlight new therapeutic strategies for the immunotherapy of cancer. Indirect evidence has suggested a role for T cell anergy in tumor evasion from host immunity, but direct evidence has been lacking. The purpose of this proposal is to use our recent preliminary data that the transcription factor EGR2 drives T cell anergy to assess the role for EGR2 and its targets in tumor escape, and to exploit this pathway to promote improved immune-mediated tumor control.
|Williams, Jason B; Horton, Brendan L; Zheng, Yan et al. (2017) The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment. J Exp Med 214:381-400|
|Corrales, Leticia; Woo, Seng-Ryong; Williams, Jason B et al. (2016) Antagonism of the STING Pathway via Activation of the AIM2 Inflammasome by Intracellular DNA. J Immunol 196:3191-8|
|Gajewski, Thomas F (2015) The Next Hurdle in Cancer Immunotherapy: Overcoming the Non-T-Cell-Inflamed Tumor Microenvironment. Semin Oncol 42:663-71|
|Gajewski, Thomas F; Schreiber, Hans; Fu, Yang-Xin (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14:1014-22|
|Gajewski, Thomas F; Woo, Seng-Ryong; Zha, Yuanyuan et al. (2013) Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol 25:268-76|
|Zheng, Yan; Zha, Yuanyuan; Spaapen, Robbert M et al. (2013) Egr2-dependent gene expression profiling and ChIP-Seq reveal novel biologic targets in T cell anergy. Mol Immunol 55:283-91|
|Zheng, Yan; Zha, Yuanyuan; Driessens, Gregory et al. (2012) Transcriptional regulator early growth response gene 2 (Egr2) is required for T cell anergy in vitro and in vivo. J Exp Med 209:2157-63|