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.
Highlights
The microphthalmia of bHLH-LZ transcription factors (MiT/TFE) family chromosomal translocation or overexpression is linked with a poor prognosis in clear cell renal cell carcinoma with elevated recurrence and drug resistance, but the molecular mechanism is not fully understood
We found that the basal expression of transcription factor E3 (TFE3) is higher than that of The transcription factor EB (TFEB) in clear cell renal cell carcinoma (ccRCC) specimens and tumor cell lines by The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) (Fig 1B)
This indicated that TFE3 can be at least another potent tumor promotor beyond TFEB in specifc tumor types such as ccRCC
Summary
The microphthalmia of bHLH-LZ transcription factors (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. We investigated whether the resistance to sunitinib malate (Sun), the standard treatment for metastatic RCC, is due to upregulation of programmed death ligand 1 (PD-L1) by the transcription factor E3 (TFE3) in ccRCC. The development of tyrosine kinase inhibitors (TKI), mainly targeted to vascular endothelial growth factor receptor, largely improved the prognosis of both overall survival (OS) and progression free survival (PFS) [7]. Sunitinib malate (Sun) is an oral multi-targeting tyrosine kinase inhibitor that is registered for the treatment of advanced or metastatic renal cell carcinoma [8, 9]. Blockade the PD-1/PD-L1 axis has been of benefit in the treatment of many different types of cancers including RCC [14, 15]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
