American And Chinese Researchers Discover CD73 As New Therapeutic Target For Triple-Negative Breast Cancer

Researchers from Northwestern University Feinberg School of Medicine, Chicago-USA, Emory University School of Medicine, Atlanta-USA and the First Affiliated Hospital of Nanjing Medical University, Nanjing-China have in a new study identified the ectoenzyme CD73 as a potential therapeutic target for triple-negative breast cancer.


 
The study also involved scientists and experts from University of Pittsburgh School of Medicine, Pittsburgh-USA., UT Southwestern Medical Center, Dallas-USA and Weill Cornell Medicine, New York- USA.
 
Despite the rapid utilization of immunotherapy, emerging challenges to the current immune checkpoint blockade need to be resolved.
 
The study team reported that elevation of CD73 levels due to its aberrant turnover is correlated with poor prognosis in immune-cold triple-negative breast cancers (TNBCs).
 
The researchers identified TRIM21 as an E3 ligase that governs CD73 destruction. Disruption of TRIM21 stabilizes CD73 that in turn enhances CD73-catalyzed production of adenosine, resulting in the suppression of CD8+ T cell function. Replacement of lysine 133, 208, 262, and 321 residues by arginine on CD73 attenuated CD73 ubiquitylation and degradation.
 
Diminishing of CD73 ubiquitylation remarkably promotes tumor growth and impedes antitumor immunity.
 
Furthermore, a TRIM21high/CD73low signature in a subgroup of human breast malignancies was associated with a favorable immune profile.
 
The study findings collectively uncover a mechanism that governs CD73 proteolysis and point to a new therapeutic strategy by modulating CD73 ubiquitylation.
 
The study findings were published in the peer reviewed journal: Science Advances.
https://www.science.org/doi/10.1126/sciadv.add6626
 
The study findings shows that targeting cellular post-transcription mechanisms in the CD73 ectoenzyme may promote anti-tumor immunity and slow cancer progression in triple-negative breast cancer.
 
The research was co-led by Dr Bin Zhang, MD, Ph.D., a Professor of Medicine in the Division of Hematology and Oncology and of Microbiology-Immunology, Northwestern University Feinberg School of Medicine and the findings suggest a new immunotherapy strategy for patients who currently lack effective treatment options.
 
Dr Zhang told Breast Cancer News, "For triple-negative breast cancer, you want to consider targeting a major immunosuppressive mechanism, and targeting CD73 has now become an emerging option in addition to other conventional checkpoint blockades.
 
TNBC or triple-negative breast cancer cells do not contain the typical hormone and protein receptors commonly found in breast cancer cells, which leaves a limited number of viable therapeutic targets.
 
Besides surgery, radiation and chemotherapy, immunotherapies such as immune checkpoint inhibitors…drugs that identify and block specific proteins or "checkpoints" produced by immune cells and cancer cells have been widely used to treat solid tumors, including TNBC.
 
However, previous clinical trials have shown that most patients with TNBC have little to no response to that kind of therapy.
 
The study team aimed to identify new therapeutic targets that can mobilize the body's immune system to overcome tumor-induced immunosuppression from TNBC cells.
 
By carefully analyzing TNBC cell lines, the study team discovered that elevated levels of the active ectoenzyme CD73 were expressed on the surface of cancer cells.
 
According to Dr Zhang, this increased expression of CD73 is abnormal, , suggesting that elevated levels of the enzyme increase immunosuppressive activity within the tumor microenvironment.
 
Utilizing advanced microscopy techniques to investigate the cancer cells further, the study team found that the ubiquitinase protein TRIM21 mediates the degradation of CD73, and disrupting TRIM21 stabilized CD73 and, in turn, suppressed CD8-positive T-cells that would have otherwise promoted an adaptive immune response against the cancer.
 
D Zhang commented, "Therefore, you can actually provide additional options to generate reagents to block the structural interaction between these two molecules.”
 
To comprehensively understand how CD73 is regulated by the ubiquitin-proteasome pathway and subsequently modulates tumor immunogenicity, the study team showed that:
 
-increased CD73 plasma presentation by inhibiting the proteasomal pathway impairs T cell survival and function using a breast cancer cell PBMC coculture system;
 
 -TRIM21, a E3 ligase, identified from a mass spectrometry screening assay, interacts with CD73 through amino acid residues 175 to 225 of CD73 to dictate its cellular quantity maintenance;
 
-knocking down TRIM21 or overexpression of ubiquitylation-deficient mutant CD73 in breast cancer cells significantly disrupts the antitumor T cell immunity and promotes tumor development;
 
-reciprocal expression of TRIM21 and CD73 is regulated by IFN-γ secreted from activated T cells; and (v) a TRIM21high/CD73low signature in a subgroup of human breast malignancies is associated with a favorable immune profile, warranting further investigations to define the functional and prognostic significance of a TRIM21-CD73 axis in breast cancer.
 
Collectively, both coculture and in vivo mouse xenograft studies offer clues into the modulation of tumor CD73 at the protein level, paving the way for potential therapeutic targets to treat the breast cancer.
 
The study team also extracted specific amino acids from CD73, which degraded essential intracellular functions of CD73, specifically ubiquitylation, and enhanced tumor growth by preventing antitumor immunity.
 
The study findings reveal a new potential therapeutic strategy in which mitigating CD73 protein levels could prevent TNBC tumor progression.
 
Furthermore, decreased levels of CD73 and increased levels of TRIM21 in cancer cells could also serve as biomarkers for identifying patients who may have a more favorable response to immunotherapy.
 
Dr Zhang added, "We think if you modulate CD73 protein levels directly, not only can you diminish the enzyme activity but also can target CD73 independent of enzyme activity function.”
 
In this study, the TRIM21-CD73-adenosine axis dictates the essential steps of the tumor immunity cycle between tumor cells and immune cells. Moreover, IFN-γ produced by effector T cells is capable of activating TRIM21-CD73 ubiquitylation to potentially amplify antitumor T cell activity, suggesting that a favorable feedback mechanism might occur whenever tumor TRIM21 is activated. Nevertheless, further work is needed to elucidate the exact mechanism of the mode of action of the TRIM21-CD73 ubiquitylation during tumor development, particularly in response to immunotherapy.
 
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