Sunday, June 1, 2025
6/1/2025
Targeting posttranslational modifications of CD73 in TNBCs - 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.
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