Targeting posttranslational modifications of CD73 in TNBCs

针对 TNBC 中 CD73 的翻译后修饰

• 批准号: 10359179
• 负责人: Yong Wan
• 金额: --
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-09 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359179
• 关键词: Adenosine; Affect; Animal Model; Breast Cancer Cell; Breast Cancer Treatment; Breast Cancer therapy; Breast Carcinogenesis; CD8-Positive T-Lymphocytes; Cell secretion; 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; Invaded; 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; Signal Transduction; T-Cell Proliferation; T-Lymphocyte; Testing; The Cancer Genome Atlas; Treatment Efficacy; Treatment Protocols; Tumor Cell Invasion; Tumor Escape; Tumor Immunity; Tumor Promotion; 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

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.

靶向TNBC中CD 73的翻译后修饰 本项目的目的是确定E3连接酶TRIM 21对CD 73蛋白水解调节的影响， 乳腺癌发生和作为乳腺癌的治疗靶点。CD 73是一种多功能胞外酶 影响肿瘤细胞和免疫细胞。CD 73的肿瘤表达升高与肿瘤细胞的恶性程度密切相关。 在各种类型的癌症，特别是三阴性乳腺癌（TNBC）的预后。此外，异常 CD 73的积累被认为会干扰化疗和免疫治疗， 肿瘤逃避/进展/转移和耐药性。目前尚不清楚病理性积聚是否 TNBC中CD 73的表达是由蛋白质周转调节受损引起的。我们最近纯化了CD 73蛋白 复合物，这导致TRIM 21被鉴定为一种泛素E3连接酶，它控制CD 73泛素化， 降解我们发现TRIM 21促进的CD 73蛋白水解决定了高于 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CD 8 + T细胞中，TNBC细胞中TRIM 21的耗尽或CD 73的稳定导致TNBC细胞中的TRIM 21的减少或CD 73的稳定。 肿瘤微环境中腺苷的升高，导致T细胞扩增的显著抑制 增强T细胞耗竭。我们进一步证明了TRIM 21介导的CD 73 在临床前动物模型中，泛素化导致与腺苷增加相关的肿瘤进展， 通过肿瘤的信号传导和抑制T细胞增殖/功能。这些数据表明，TRIM 21是一个关键的 决定CD 73介导的肿瘤逃避和侵袭的参与者，并且CD 73周转的操纵可能 这是一种新的治疗策略，可以与目前FDA批准的TNBC治疗方案相结合。 在这个建议中，我们的目的是确定CD 73泛素化的病理生理作用的TRIM 21在TNBC 通过调节肿瘤免疫进展，并检查TRIM 21-CD 73的临床相关性， 轴TNBC治疗。我们将检验TRIM 21介导的CD 73降解的缺失影响CD 73表达的假设。 促进TNBC肿瘤逃避/进展和抑制癌症治疗功效的肿瘤免疫，并且 调节TRIM 21-CD 73轴将逆转TNBC中的这些过程。我们提出以下具体建议： 目的：（1）确定TRIM 21调节CD 73介导的肿瘤的机制 （2）通过TRIM 21确定CD 73泛素化在调节肿瘤中的生理相关性 （3）确定TRIM 21-CD 73轴在各种肿瘤的抗TNBC治疗中的相关性。 临床前动物模型。