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Regulation of Zbtb44-Eomes complex in CD8+T cells and anti-tumor immunity

CD8 T 细胞中 Zbtb44-Eomes 复合物的调节和抗肿瘤免疫

基本信息

批准号：
10574602
负责人：
Venuprasad K Poojary
金额：
$ 41.01万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-24 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10574602
关键词：
Binding CAR T cell therapy CD8-Positive T-Lymphocytes CD8B1 gene CRISPR/Cas technology Cancer Model Carcinoembryonic Antigen Cell Therapy Cell physiology Cells Clinical Trials Colon Carcinoma Complex Dissection Equilibrium Event Family Functional disorder Gene Expression Profile Immune Immune checkpoint inhibitor Interferons MC38 Mediating Molecular Mus Pathway interactions Patients Play Post-Translational Protein Processing Regulation Role Solid Neoplasm Sumoylation Pathway T cell response T cell therapy Testing Tumor Immunity Tumor-Infiltrating Lymphocytes Ubiquitination anti-CTLA4 antibodies anti-PD-1 cancer therapy chimeric antigen receptor chimeric antigen receptor T cells exhaust exhaustion improved outcome member novel patient derived xenograft model prevent programmed cell death protein 1 promoter protein complex protein degradation therapeutic evaluation therapeutic target transcription factor tumor tumor growth tumor microenvironment ubiquitin ligase

项目摘要

ABSTRACT CAR-T cell therapy is an emerging option for cancer treatment, but its efficacy is limited, especially in solid tumors because the effector CD8+T cells become dysfunctional and exhausted in the tumor microenvironment (TME). However, the key pathways that define the delicate balance between the effector vs exhausted state of CD8+T cells remain unclear. Our preliminary studies demonstrate that sumoylation of the T-box transcription factor, Eomesodermin (Eomes), facilitates its association with Zbtb44, a member of the ThPOK family of transcription factors. The Zbtb44-Eomes complex promotes the effector function and anti-tumor activity of CD8+ tumor infiltrated lymphocytes (TILs). In exhausted CD8+ TILs, the ubiquitin ligase Trim47 targets Zbtb44 for degradation and disrupts the Zbtb44-Eomes complex. Furthermore, CRISPR-Cas9-mediated inhibition of Trim47 rescues exhausted CD8+ TILs and restores their effector function. These preliminary findings led us to hypothesize that ubiquitination and sumoylation of the Zbtb44/Eomes complex are critical molecular events that dictate the effector vs exhaustion of CD8+ TILs which can be therapeutically targeted. In Aim1, we will determine the mechanism by which the Zbtb44-Eomes complex promotes effector CD8+T cell function and anti-tumor immunity. We will use newly generated Zbtb44-/- mice to investigate how sumoylation of Eomes at Lys(K)-446 facilitates the formation of the Zbtb44-Eomes complex via the SUMO interacting motif (SIM) within Zbtb44. Further, we will delineate the mechanism by which the Zbtb44-Eomes complex cooperatively binds to and transactivates the IFN- promoter. In Aim 2, we will determine the mechanism by which Trim47-mediated ubiquitination of Zbtb44 leads to dysfunction of CD8+T cells. We will investigate how Trim47, which is upregulated in exhausted (PD1+Tim3+) CD8+ TILs, targets Zbtb44 for ubiquitination at K139 and promotes its degradation. Using newly generated Trim47-/- mice, we will determine how disruption of the Zbtb44- Eomes complex leads to the inhibitory transcriptional profile of exhausted CD8+T cells. In Aim 3, we will target the Zbtb44-Trim47 pathway to promote anti-tumor immunity. We will test the therapeutic potential of blocking Zbtb44 ubiquitination in CAR-T cells against carcinoembryonic antigen (CEA) in the MC38 and in a patient- derived xenograft (PDX) colon cancer model. Completion of these studies will lead to: 1) dissection of the novel Zbtb44-Eomes complex that is critical for effector CD8+ T cell function, 2) determination of how Trim47-mediated ubiquitination disrupts this complex leading to alternate transcription profile in exhausted CD8+ TILs, and 3) evaluate the means to target the Zbtb44- Trim47 pathway to overcome the current limitations of CAR-T cell therapy for solid tumors.

摘要