Targeting posttranslational modifications of CD73 in TNBCs

靶向性CD73在TNBC中的翻译后修饰 本项目的目标是确定E3连接酶TRIM21对CD73蛋白降解调节的影响。 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 对肿瘤细胞和免疫细胞都有影响。CD73在肿瘤中的高表达与不良密切相关 各种类型的癌症，特别是三阴性乳腺癌(TNBC)的预后。此外，异常 CD73的积聚被认为干扰了化疗和免疫治疗，并有助于 肿瘤逃逸/进展/转移与耐药性。目前尚不清楚病理性堆积是否 CD73在TNBC中的缺失是由于蛋白质周转调节受损引起的。我们最近提纯了CD73蛋白 这导致了TRIM21被鉴定为一种泛素E3连接酶，它调控CD73泛素化和 退化。我们发现，TRIM21促进的CD73蛋白分解决定了一个高于阈值的丰度阈值 其中腺苷信号介导的T细胞增殖和活性调节肿瘤侵袭。在不同文化背景下 TNBC细胞和活化的CD8T细胞，TRIM21缺失或CD73稳定在TNBC细胞中导致 肿瘤微环境中腺苷的升高，导致T细胞的显著抑制 增强了T细胞的耗竭。我们进一步证明了对TRIM21介导的CD73的干扰 临床前动物模型中泛素化导致肿瘤进展与腺苷增加相关 肿瘤信号转导和抑制T细胞增殖/功能。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，以及对CD73周转的操纵可能 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。 在这项建议中，我们的目标是确定CD73泛素化的TRIM21在TNBC中的病理生理学作用 肿瘤免疫调节的研究进展及检测TRIM21-CD73的临床意义 Axis在TNBC治疗中的应用。我们将测试TRIM21介导的CD73降解的丢失影响 肿瘤免疫促进TNBC肿瘤逃逸/进展，抑制肿瘤治疗效果 调节TRIM21-CD73轴将在TNBC中逆转这些过程。我们提出了以下具体建议 目的是验证这一假说：(1)确定TRIM21调节CD73介导的肿瘤的机制 免疫；(2)确定CD73泛素化与TRIM21调控肿瘤的生理相关性 以及(3)确定TRIM21-CD73轴在抗TNBC治疗中的相关性。 临床前动物模型。

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.