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:
- 金额:$ 41.01万
- 依托单位:
- 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:
- 关键词:BindingCAR T cell therapyCD8-Positive T-LymphocytesCD8B1 geneCRISPR/Cas technologyCancer ModelCarcinoembryonic AntigenCell TherapyCell physiologyCellsClinical TrialsColon CarcinomaComplexDissectionEquilibriumEventFamilyFunctional disorderGene Expression ProfileImmuneImmune checkpoint inhibitorInterferonsMC38MediatingMolecularMusPathway interactionsPatientsPlayPost-Translational Protein ProcessingRegulationRoleSolid NeoplasmSumoylation PathwayT cell responseT cell therapyTestingTumor ImmunityTumor-Infiltrating LymphocytesUbiquitinationanti-CTLA4 antibodiesanti-PD-1cancer therapychimeric antigen receptorchimeric antigen receptor T cellsexhaustexhaustionimproved outcomemembernovelpatient derived xenograft modelpreventprogrammed cell death protein 1promoterprotein complexprotein degradationtherapeutic evaluationtherapeutic targettranscription factortumortumor growthtumor microenvironmentubiquitin 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
项目成果
期刊论文数量(0)
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Venuprasad K Poojary其他文献
Venuprasad K Poojary的其他文献
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{{ truncateString('Venuprasad K Poojary', 18)}}的其他基金
Znf740 in the regulation of CD8+T cell exhaustion
Znf740 调节 CD8 T 细胞耗竭
- 批准号:
10715852 - 财政年份:2023
- 资助金额:
$ 41.01万 - 项目类别:
Regulation of RORγt in Th17-mediated inflammation
RORγt 在 Th17 介导的炎症中的调节
- 批准号:
10509373 - 财政年份:2022
- 资助金额:
$ 41.01万 - 项目类别:
Regulation of RORγt in Th17-mediated inflammation
RORγt 在 Th17 介导的炎症中的调节
- 批准号:
10646293 - 财政年份:2022
- 资助金额:
$ 41.01万 - 项目类别:
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
- 批准号:
10377321 - 财政年份:2021
- 资助金额:
$ 41.01万 - 项目类别:
Regulation of ROR-gt in colonic inflammation
ROR-gt 在结肠炎症中的调节
- 批准号:
9886237 - 财政年份:2018
- 资助金额:
$ 41.01万 - 项目类别:
Regulation of ROR-gt in colonic inflammation
ROR-gt 在结肠炎症中的调节
- 批准号:
10113592 - 财政年份:2018
- 资助金额:
$ 41.01万 - 项目类别:
Role of TIEG1 in Foxp3+Treg development and tumor progression
TIEG1 在 Foxp3 Treg 发育和肿瘤进展中的作用
- 批准号:
7830845 - 财政年份:2009
- 资助金额:
$ 41.01万 - 项目类别:
Role of TIEG1 in Foxp3+Treg development and tumor progression
TIEG1 在 Foxp3 Treg 发育和肿瘤进展中的作用
- 批准号:
7943954 - 财政年份:2009
- 资助金额:
$ 41.01万 - 项目类别:
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