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Research
Hanbo Wang
Department of Urology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
Corresponding Author
ORCiD: https://orcid.org/0000-0002-6095-8611
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This work is licensed under a CC BY 4.0 License. Read Full License
Background: 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. Here, 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.
Methods: The effect of TFE3 expression on ccRCC proliferation had been evaluated. The regulation of TFE3 on PD-L1 was assessed by qPCR and western blots in human primary clear cell lines and ccRCC specimens. The regulation of Sun on TFE3 and PD-L1 was assessed by western blots and flow cytometry. The therapeutic efficacy of Sun plus PD-L1 blockade was evaluated in xenograft mouse model.
Results: In this study, we propose that TFE3 but not TFEB is essential for tumor survival and more importantly it is more of a promotor of cell proliferation which was associated with the poorer survival of cancer patients. We also found a positive correlation between TFE3 and PD-L1 expression in clear cell RCC 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 tumor suppression in a xenografted mouse model.
Conclusions: Our data provides a strong rationale to apply Sun and PD-L1 inhibition jointly as a novel immunotherapeutic approach for ccRCC treatment.
Keywords
clear cell renal cell carcinoma, TFE3, PD-L1, sunitinib
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This is a preprint. It has not completed peer review.
Research
Hanbo Wang
Department of Urology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
Corresponding Author
ORCiD: https://orcid.org/0000-0002-6095-8611
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 04 Aug, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Translational Medicine
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: 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. Here, 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.
Methods: The effect of TFE3 expression on ccRCC proliferation had been evaluated. The regulation of TFE3 on PD-L1 was assessed by qPCR and western blots in human primary clear cell lines and ccRCC specimens. The regulation of Sun on TFE3 and PD-L1 was assessed by western blots and flow cytometry. The therapeutic efficacy of Sun plus PD-L1 blockade was evaluated in xenograft mouse model.
Results: In this study, we propose that TFE3 but not TFEB is essential for tumor survival and more importantly it is more of a promotor of cell proliferation which was associated with the poorer survival of cancer patients. We also found a positive correlation between TFE3 and PD-L1 expression in clear cell RCC 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 tumor suppression in a xenografted mouse model.
Conclusions: Our data provides a strong rationale to apply Sun and PD-L1 inhibition jointly as a novel immunotherapeutic approach for ccRCC treatment.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
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