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TFE3-PD-L1 axis is pivotal for sunitinib resistance in clear cell renal cell carcinoma
Xudong Guo1, Ruxia Li1, Qiulei Bai1
1Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Abstract:
The microphthalmia of bHLH-LZ transcription factor (MiT/TFE) family chromosomal translocation or overexpression is linked with a poor prognosis in clear cell renal cell carcinoma (ccRCC) with elevated recurrence and drug resistance, but the molecular mechanism is not fully understood. Here, we investigated whether the resistance to sunitinib (Sun), the standard treatment for metastatic ccRCC, is due to up-regulation of programmed death ligand 1 (PD-L1) by the transcription factor E3 (TFE3). In this study, we propose that TFE3 but not TFEB is essential for tumour survival which was associated with the poorer survival of cancer patients. We also found a positive correlation between TFE3 and PD-L1 expression in ccRCC cells and tissues. Sun treatment led to enhanced TFE3 nuclear translocation and PD-L1 expression. Finally, we observed the therapeutic benefit of Sun plus PD-L1 inhibition which enhanced CD8+ cytolytic activity and thus tumour suppression in a xenografted mouse model. These data revealed that TFE3 is a potent tumour promoting gene and it mediates resistance to Sun by induction of PD-L1 in ccRCC. Our data provide a strong rationale to apply Sun and PD-L1 inhibition jointly as a novel immunotherapeutic approach for ccRCC treatment.
Insights
Transcription factor E3 (TFE3) drives resistance to sunitinib in clear cell renal cell carcinoma (ccRCC) by increasing PD-L1. Combining sunitinib with PD-L1 inhibitors offers a promising new immunotherapy for ccRCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Chromosomal translocations or overexpression of the MiT/TFE family transcription factors are associated with poor prognosis in clear cell renal cell carcinoma (ccRCC).
- The precise molecular mechanisms underlying drug resistance and recurrence in ccRCC, particularly concerning sunitinib (Sun), remain incompletely understood.
- Programmed death ligand 1 (PD-L1) is implicated in immune evasion and therapeutic resistance in various cancers.
Purpose of the Study:
- To investigate the role of transcription factor E3 (TFE3) in mediating sunitinib resistance in ccRCC.
- To determine if TFE3 up-regulates programmed death ligand 1 (PD-L1) expression, contributing to sunitinib resistance.
- To evaluate the therapeutic potential of combining sunitinib with PD-L1 inhibition in ccRCC.
Main Methods:
- Analysis of TFE3 and PD-L1 expression correlation in ccRCC tissues and cells.
- Assessment of TFE3 nuclear translocation and PD-L1 expression following sunitinib treatment.
- Evaluation of combination therapy (sunitinib + PD-L1 inhibition) efficacy in a ccRCC xenograft mouse model, including assessment of CD8+ T cell activity.
Main Results:
- TFE3, but not TFEB, was found to be essential for tumor survival and associated with poorer patient outcomes in ccRCC.
- A positive correlation between TFE3 and PD-L1 expression was observed in ccRCC cells and patient tissues.
- Sunitinib treatment enhanced TFE3 nuclear translocation and subsequent PD-L1 expression.
- Combined treatment with sunitinib and PD-L1 inhibition demonstrated therapeutic benefits, enhancing CD8+ cytolytic activity and suppressing tumor growth in vivo.
Conclusions:
- TFE3 acts as a potent tumor-promoting gene in ccRCC.
- TFE3 mediates resistance to sunitinib by inducing PD-L1 expression.
- Combination therapy of sunitinib and PD-L1 inhibition represents a novel and effective immunotherapeutic strategy for ccRCC treatment.
