The role of UBR2 in triple-negative breast cancer and its implications for immune checkpoint blockade therapy
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Yanlin Jiang1, Yi Fu2, Xinyan Song3
1Department of Breast and Thyroid Surgery, The Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan, Dalian, 116001, Liaoning, China.
Objective:
UBR2 (also referred to as n-recognin 2, the E3 component of ubiquitin protein ligase) targets proteins with unstable N-terminal residues for polyubiquitination and proteasome-mediated degradation. It was initially identified as a crucial oncogene during embryonic development. Nevertheless, the function of UBR2 in triple-negative breast cancer (TNBC) and its non-ubiquitination role, particularly in suppressing antitumor immune responses, remain elusive.
Methods:
Utilizing bulk RNA and single-cell RNA sequencing datasets from the GEO and TCGA databases, differentially expressed genes (DEGs) were discerned. Moreover, the relationship between UBR2 and PD-L1 was verified via overexpression viruses, shRNA viruses, and Western blotting. In addition, the correlation between UBR2 and immunotherapy was investigated by means of flow cytometry and immune-infiltration analysis in both in vivo and in vitro experiments.
Results:
In the cohort of TNBC patients presenting an immune desert microenvironment, as well as in the group of patients responding poorly to PD-L1/PD-1 therapy, UBR2 exerted a significant impact on the establishment of an immunosuppressive microenvironment. The inhibition of UBR2 could diminish the expression of PD-L1 in TNBC cell lines. In addition, the expression level of UBR2 could act as a potential indicator for PD-L1 therapy in TNBC patients, where higher UBR2 expression suggests greater responsiveness to PD-L1 therapy. Concurrently, we screened for inhibitors (11-oxo-mogroside V) targeting the functional domain of UBR2, and concurrent inhibition of UBR2 in combination with PD-L1 therapy can reduce the tumor burden in TNBC.
Conclusion:
Our findings indicate that the inhibition of UBR2 can augment TIL infiltration by diminishing PD-L1 expression, thereby emerging as an efficacious strategy (the functional inhibitors of UBR2) to enhance the therapeutic efficacy of PD-L1/PD1 blockers, offering a novel perspective for the treatment of TNBC through combined immunotherapy.
Insights
Inhibition of UBR2 reduces PD-L1 expression, enhancing T-cell infiltration and improving immunotherapy response in triple-negative breast cancer (TNBC). This offers a new strategy for combined immunotherapy against TNBC.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- UBR2 (n-recognin 2) is an E3 ubiquitin ligase targeting proteins for degradation.
- UBR2 is an oncogene in embryonic development, but its role in triple-negative breast cancer (TNBC) and immune suppression is unclear.
Purpose of the Study:
- To investigate the function of UBR2 in TNBC.
- To explore UBR2's role in suppressing antitumor immune responses.
- To assess UBR2 as a therapeutic target for TNBC immunotherapy.
Main Methods:
- Analyzed bulk and single-cell RNA sequencing data (GEO, TCGA) for differentially expressed genes.
- Verified UBR2-PD-L1 relationship using overexpression and shRNA viruses, and Western blotting.
- Assessed UBR2's correlation with immunotherapy response via flow cytometry and immune-infiltration analysis in vivo and in vitro.
Main Results:
- UBR2 promotes an immunosuppressive microenvironment in TNBC, particularly in immune-desert tumors and non-responders to PD-L1/PD-1 therapy.
- Inhibiting UBR2 decreases PD-L1 expression in TNBC cell lines.
- UBR2 expression levels predict responsiveness to PD-L1 therapy.
- A UBR2 inhibitor (11-oxo-mogroside V) combined with PD-L1 therapy reduced tumor burden in TNBC models.
Conclusions:
- UBR2 inhibition enhances T-cell infiltration by reducing PD-L1 expression.
- Targeting UBR2 with functional inhibitors is a promising strategy to improve PD-L1/PD-1 blockade efficacy.
- Combined UBR2 inhibition and immunotherapy offers a novel therapeutic approach for TNBC.
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