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TFE3-PD-L1 axis is pivotal for sunitinib resistance in clear cell renal cell carcinoma.

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.

SUBMITTER: Guo X

PROVIDER: S-EPMC7753981 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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TFE3-PD-L1 axis is pivotal for sunitinib resistance in clear cell renal cell carcinoma.

Guo Xudong X Li Ruxia R Bai Qiulei Q Jiang Shaobo S Wang Hanbo H

Journal of cellular and molecular medicine 20201103 24

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 t ...[more]

PMID: 33145941

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Project description:(1). Background: Immunohistochemical (IHC) evaluation of programmed death-1 (PD-1) and its ligand (PD-L1) is being used to evaluate advanced malignancies with potential response to immune checkpoint inhibitors. We evaluated both plasma and tissue expression of PD-1 and PD-L1 in the same cohort of patients, including non-metastatic and metastatic clear cell renal cell carcinoma (CCRCC). Concomitant plasma and tissue expression of PD-1 and PD-L1 was evaluated with emphasis on diagnostic and prognostic implications. (2) Methods: we analyzed PD-1 and PD-L1 IHC expression in tumor tissues and soluble forms (sPD-1 and sPD-L1) in plasma from 89 patients with CCRCC, of which 23 were metastatic and 16 received systemic therapy. The primary endpoint was evaluation of overall survival using Kaplan-Meier analysis and the Cox regression model. Plasma samples from healthy volunteers were also evaluated. (3) Results: Interestingly, sPD-1 and sPD-L1 levels were lower in cancer patients than in controls. sPD-1 and sPD-L1 levels and their counterpart tissue expression both at the tumor center and infiltrating front were not associated. Higher expression of both PD-1 and PD-L1 were associated with tumor grade, necrosis and tumor size. PD-1 was associated to tumor stage (pT) and PD-L1 to metastases. sPD-1 and sPD-L1 were not associated with clinico-pathological parameters, although both were higher in patients with synchronous metastases compared to metachronous ones and sPD-L1 was also higher for metastatic patients compared to non-metastatic patients. sPD-1 was also associated with the International Metastatic Renal Cell Cancer Database Consortium (IMDC) prognostic groups in metastatic CCRCC and also to the Morphology, Attenuation, Size and Structure (MASS) response criteria in metastatic patients treated with systemic therapy, mainly tyrosine-kinase inhibitors. Regarding prognosis, PD-L1 immunostaining at the tumor center with and without the tumor front was associated with worse survival, and so was sPD-L1 at a cut-off >793 ng/mL. Combination of positivity at both the tissue and plasma level increased the level of significance to predict prognosis. (4) Conclusions: Our findings corroborate the role of PD-L1 IHC to evaluate prognosis in CCRCC and present novel data on the usefulness of plasma sPD-L1 as a promising biomarker of survival in this neoplasia.

Dataset Information

TFE3-PD-L1 axis is pivotal for sunitinib resistance in clear cell renal cell carcinoma.

Publications

TFE3-PD-L1 axis is pivotal for sunitinib resistance in clear cell renal cell carcinoma.

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