Targeting posttranslational modifications of CD73 in TNBCs

针对 TNBC 中 CD73 的翻译后修饰

基本信息

批准号：
10523388
负责人：
Yong Wan
金额：
$ 66.4万
依托单位：
EMORY UNIVERSITY
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：
2021-11-09 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10523388
关键词：
Adenosine Affect Animal Model Breast Cancer Cell Breast Cancer Treatment Breast Cancer therapy Breast Carcinogenesis CD8-Positive T-Lymphocytes Cells Coculture Techniques Data Development Drug resistance FDA approved Feedback Future Goals Human Immune Immune Evasion Immune response Immunocompetent Immunotherapy Impairment In Vitro Interferon Type II Malignant Neoplasms Mammary Neoplasms Mediating Modeling Molecular Mus Neoplasm Metastasis Oncogenic Pathologic Pathway interactions Physiological Post-Translational Protein Processing Process Prognosis Proteolysis Regulation Regulation of Proteolysis Role S-Phase Fraction Signal Transduction T-Cell Depletion T-Cell Proliferation T-Lymphocyte Testing The Cancer Genome Atlas Treatment Efficacy Treatment Protocols Tumor Cell Invasion Tumor Escape Tumor Immunity Ubiquitin Ubiquitination Work breast cancer progression cancer type chemotherapy clinically relevant exhaustion in vivo in vivo Model malignant breast neoplasm multicatalytic endopeptidase complex neoplastic cell new therapeutic target novel therapeutic intervention novel therapeutics patient derived xenograft model pre-clinical protein complex protein degradation targeted cancer therapy therapeutic development therapeutic target triple-negative invasive breast carcinoma tumor tumor microenvironment tumor progression tumor-immune system interactions ubiquitin-protein ligase

项目摘要

Targeting posttranslational modification of CD73 in TNBC The goal of this project is to determine the impact of proteolytic regulation of CD73 by the E3 ligase TRIM21 in breast carcinogenesis and as a therapeutic target in breast cancer. CD73 is a multifunctional ectoenzyme affecting both tumor cells and immune cells. Elevated tumor expression of CD73 is tightly correlated to poor prognosis in various types of cancers, especially triple-negative breast cancer (TNBC). Furthermore, abnormal accumulation of CD73 is thought to interfere with both chemotherapy and immunotherapy, and contribute to tumor evasion/progression/metastasis and drug resistance. It is unclear whether the pathological accumulation of CD73 in TNBC is caused by impaired regulation of protein turnover. We recently purified the CD73 protein complex, which led to the identification of TRIM21 as a ubiquitin E3 ligase that governs CD73 ubiquitylation and degradation. We found that TRIM21-facilitated proteolysis of CD73 determines an abundance threshold above which adenosine signal-mediated T cell proliferation and activity regulates tumor invasion. In co-cultures of TNBC cells and activated CD8+ T cells, depletion of TRIM21 or stabilization of CD73 in TNBC cells led to elevation of adenosine in the tumor microenvironment, resulting in significant suppression of T cell expansion and enhanced T cell exhaustion. We further demonstrated that disruption of TRIM21-mediated CD73 ubiquitylation in a preclinical animal model led to tumor progression associated with an increase in adenosine signaling by the tumor and inhibition of T cell proliferation/function. These data suggest that TRIM21 is a critical player that determines CD73-mediated tumor evasion and invasion, and that manipulation of CD73 turnover may be a novel therapeutic strategy that could be combined with current FDA-approved TNBC treatment regimens. In this proposal, we aim to determine the pathophysiological role of CD73 ubiquitylation by TRIM21 in TNBC progression through modulation of tumor immunity, and to examine the clinical relevance of the TRIM21-CD73 axis in TNBC therapy. We will test the hypothesis that loss of TRIM21-mediated CD73 degradation affects tumor immunity to promote TNBC tumor evasion/progression and inhibit cancer therapeutic efficacy, and that modulating the TRIM21-CD73 axis will reverse these processes in TNBC. We propose the following specific aims to test this hypothesis: (1) Determine the mechanism by which TRIM21 regulates CD73-mediated tumor immunity; (2) Determine the physiological relevance of CD73 ubiquitylation by TRIM21 in regulating tumor immunity; and (3) Determine the relevance of the TRIM21-CD73 axis in anti-TNBC treatment in various preclinical animal models.

TNBC 中 CD73 的靶向翻译后修饰该项目的目标是确定 E3 连接酶 TRIM21 对 CD73 蛋白水解调节的影响乳腺癌的发生和作为乳腺癌的治疗靶点。 CD73是一种多功能胞外酶同时影响肿瘤细胞和免疫细胞。 CD73 的肿瘤表达升高与肿瘤的不良表达密切相关。各种癌症的预后，特别是三阴性乳腺癌（TNBC）。此外，异常 CD73 的积累被认为会干扰化疗和免疫治疗，并有助于肿瘤逃避/进展/转移和耐药性。目前尚不清楚是否存在病理性积累 TNBC 中 CD73 的减少是由蛋白质周转调节受损引起的。我们最近纯化了CD73蛋白复合物，这导致 TRIM21 被鉴定为控制 CD73 泛素化的泛素 E3 连接酶，降解。我们发现 TRIM21 促进的 CD73 蛋白水解决定了高于其中腺苷信号介导的 T 细胞增殖和活性调节肿瘤侵袭。在共培养中 TNBC 细胞和活化的 CD8+ T 细胞、TRIM21 的耗竭或 TNBC 细胞中 CD73 的稳定化导致肿瘤微环境中腺苷的升高，导致 T 细胞扩增的显着抑制并增强 T 细胞耗竭。我们进一步证明 TRIM21 介导的 CD73 的破坏临床前动物模型中的泛素化导致与腺苷增加相关的肿瘤进展肿瘤信号传导和 T 细胞增殖/功能抑制。这些数据表明 TRIM21 是一个关键的决定 CD73 介导的肿瘤逃逸和侵袭的参与者，并且 CD73 周转的操纵可能是一种新颖的治疗策略，可以与 FDA 目前批准的 TNBC 治疗方案相结合。在本提案中，我们的目标是确定 TRIM21 对 CD73 泛素化在 TNBC 中的病理生理学作用通过调节肿瘤免疫来进展，并检查 TRIM21-CD73 的临床相关性 TNBC 治疗中的轴。我们将测试 TRIM21 介导的 CD73 降解的缺失会影响这一假设肿瘤免疫促进TNBC肿瘤逃避/进展并抑制癌症治疗效果，并且调制 TRIM21-CD73 轴将逆转 TNBC 中的这些过程。我们提出以下具体建议旨在检验这一假设：（1）确定TRIM21调节CD73介导的肿瘤的机制免疫; (2)确定TRIM21对CD73泛素化调节肿瘤的生理相关性免疫; (3) 确定 TRIM21-CD73 轴在各种抗 TNBC 治疗中的相关性临床前动物模型。