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mTOR Inhibition Increases Transcription Factor E3 (TFE3) Activity and Modulates Programmed Death-Ligand 1 (PD-L1)

Hyun Jung Lee1, Dong Hoon Shin1, Ji Sun Song2

  • 1Department of Pathology, School of Medicine, Pusan National University, Yangsan, Republic of Korea; The Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea.

The American Journal of Pathology
|August 6, 2021
PubMed

Insights

Transcription factor E3 (TFE3) drives PD-L1 expression in renal cell carcinoma (RCC). mTOR inhibition boosts PD-L1 via TFE3, suggesting combination therapy for translocation RCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • The efficacy of PD-L1/PD-1 blockade in renal cell carcinoma (RCC) is unknown.
  • mTOR inhibitors' effects and resistance mechanisms in RCC require further investigation.
  • Understanding cancer cell-intrinsic mTOR pathways is crucial for effective RCC treatment.

Purpose of the Study:

  • To investigate if transcription factor E3 (TFE3) regulates PD-L1 expression and the tumor microenvironment in RCC.
  • To explore the effects of a mammalian target of rapamycin (mTOR) inhibitor on translocation RCC.
  • To assess the potential of combination therapy involving mTOR inhibition and PD-L1 blockade.

Main Methods:

  • Overexpression of TFE3 in clear cell RCC cell lines.
  • Analysis of PD-L1 expression using Western blot.
  • TFE3 knockdown and mTOR inhibitor treatment in translocation RCC.
  • Correlation with gene expression profiles via digital multiplex analysis.

Main Results:

  • TFE3 and PD-L1 expression are positively correlated in RCC cells.
  • TFE3 overexpression is associated with PD-L1 expression in RCC.
  • mTOR inhibition enhances PD-L1 expression through TFE3 activation in translocation RCC.

Conclusions:

  • TFE3 plays a significant role in regulating PD-L1 expression in RCC.
  • mTOR inhibition can increase PD-L1 expression, offering a potential therapeutic target.
  • Combination therapy with mTOR inhibitors and PD-L1 blockade is a promising strategy for translocation RCC.

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