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CD73的翻译后修饰 该项目的目的是确定E3连接酶TRIM21在 乳腺癌的发生和作为乳腺癌的治疗靶标。 CD73是一种多功能的骨酶 影响肿瘤细胞和免疫细胞。 CD73的肿瘤表达升高与较差 各种类型的癌症的预后，尤其是三阴性乳腺癌（TNBC）。此外，异常 CD73的积累被认为会干扰化疗和免疫疗法，并有助于 肿瘤逃避/进展/转移和耐药性。目前尚不清楚病理积累是否 TNBC中CD73的of是由蛋白质周转的调节受损引起的。我们最近纯化了CD73蛋白 复合物，导致TRIM21鉴定为泛素E3连接酶，该连接酶控制CD73泛素化和 降解。我们发现CD73的TRIM21-促进蛋白水解决定了以上的丰度阈值 腺苷信号介导的T细胞增殖和活性调节肿瘤侵袭。在共同文化中 TNBC细胞和活化的CD8+ T细胞，TRIM21的耗竭或TNBC细胞中CD73的稳定导致 肿瘤微环境中腺苷的升高，导致T细胞膨胀的显着抑制 并增强了T细胞耗尽。我们进一步证明了TRIM21介导的CD73的破坏 临床前动物模型中的泛素化导致肿瘤进展与腺苷的增加有关 通过肿瘤和T细胞增殖/功能的抑制信号传导。这些数据表明TRIM21是关键 确定CD73介导的肿瘤逃避和入侵的玩家以及CD73失误的操纵可能 成为一种新型的治疗策略，可以与当前FDA批准的TNBC治疗方案结合使用。 在此提案中，我们旨在确定TRIM21在TNBC中CD73泛素化的病理生理作用 通过调节肿瘤免疫的进展，并检查TRIM21-CD73的临床相关性 TNBC治疗中的轴。我们将检验以下假设：TRIM21介导的CD73降解影响会影响 肿瘤免疫可促进TNBC肿瘤逃避/进展并抑制癌症治疗疗效，并 调节TRIM21-CD73轴将在TNBC中逆转这些过程。我们提出以下特定 旨在检验此假设：（1）确定TRIM21调节CD73介导的肿瘤的机制 免疫; （2）确定TRIM21在调节肿瘤中CD73泛素化的生理相关性 免疫; （3）确定TRIM21-CD73轴在抗TNBC处理中的相关性 临床前动物模型。