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Mutual Exclusion Analysis Shows that DUSP9 Negatively Regulates PD-L1 Expression and Acts as a Target to Enhance
Yuzhe Hu1,2, Ling Tang1,2, Zheng Kuang1,2
1Department of Immunology, NHC Key Laboratory of Medical Immunology (Peking University), Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
Abstract:
The expression level of PD-L1 is one of the most widely used predictive markers of immune checkpoint blockade (ICB) efficacy in the clinic, suggesting the importance of regulating PD-L1 expression. However, no published reports have addressed the systematic exploration of the regulation of immune checkpoint molecules from the perspective of mutual exclusion (ME) in gene expression. The ME analysis, based on gene plasticity, provides a novel perspective on the intergenic regulatory paradigm. Here, multiple negative regulators of PD-L1 expression are identified, and dual-specificity phosphatase 9 (DUSP9) is selected for intensive study. DUSP9 negatively regulates PD-L1 expression in multiple tumor cells, and mechanistically, DUSP9 dephosphorylates STAT3 to mediate the inhibitory role. In syngeneic tumor models, the combination of DUSP9 targeting and PD-1 antibody can enhance therapeutic sensitivity. The clinical data demonstrated that elevated DUSP9 expression is correlated with diminished PD-1/PD-L1 antibody response rates. Consequently, DUSP9 emerges as a promising target for enhancing treatment response in combination with PD-1 antibody, and functions as a potential marker for predicting the efficacy of tumor immunotherapy. This research demonstrates an efficient method for identifying negative regulators of highly plastic genes (HPGs), which can predict immunotherapy responses and identify new targets for combination therapy with ICB.
Insights
Dual-specificity phosphatase 9 (DUSP9) was identified as a negative regulator of PD-L1 expression. Targeting DUSP9 combined with PD-1 antibodies may enhance cancer immunotherapy efficacy and predict patient response.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Programmed death-ligand 1 (PD-L1) expression is a key predictor of immune checkpoint blockade (ICB) therapy efficacy.
- Systematic exploration of PD-L1 regulation using mutual exclusion (ME) gene expression analysis is lacking.
Purpose of the Study:
- To identify novel negative regulators of PD-L1 expression using ME analysis.
- To investigate the role of dual-specificity phosphatase 9 (DUSP9) in regulating PD-L1 and its potential as a therapeutic target in cancer immunotherapy.
Main Methods:
- Mutual exclusion (ME) gene expression analysis to identify negative regulators of PD-L1.
- In vitro studies in tumor cells to elucidate the mechanism of DUSP9 action.
- Syngeneic tumor models and analysis of clinical data to evaluate therapeutic efficacy and predictive potential.
Main Results:
- Multiple negative regulators of PD-L1 were identified, with DUSP9 selected for further study.
- DUSP9 was found to negatively regulate PD-L1 expression in tumor cells by dephosphorylating STAT3.
- Combination therapy targeting DUSP9 and PD-1 antibody enhanced therapeutic sensitivity in preclinical models.
- Elevated DUSP9 expression correlated with reduced response rates to PD-1/PD-L1 antibody treatment in clinical data.
Conclusions:
- DUSP9 acts as a negative regulator of PD-L1 expression via STAT3 dephosphorylation.
- DUSP9 is a potential therapeutic target for enhancing ICB efficacy and a predictive biomarker for immunotherapy response.
- The ME analysis approach is effective for identifying negative regulators of highly plastic genes and potential targets for combination immunotherapy.
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