Abstract
Despite the FDA approval of mTOR inhibitors (mTORi) for the treatment of renal cell carcinoma (RCC), the benefits are relatively modest and the few responders usually develop resistance. We investigated whether the resistance to mTORi is due to upregulation of PD-L1 and the underlying molecular mechanism. The effects of transcription factor EB (TFEB) on RCC proliferation, apoptosis, and migration were evaluated. Correlation of TFEB with PD-L1 expression, as well as effects of mTOR inhibition on TFEB and PD-L1 expression, was assessed in human primary clear cell RCCs. The regulation of TFEB on PD-L1 was assessed by chromatin immunoprecipitation and luciferase reporter assay. The therapeutic efficacies of mTORi plus PD-L1 blockade were evaluated in a mouse model. The function of tumor-infiltrating CD8+ T cells was analyzed by flow cytometry. TFEB did not affect tumor cell proliferation, apoptosis, and migration. We found a positive correlation between TFEB and PD-L1 expression in RCC tumor tissues, primary tumor cells, and RCC cells. TFEB bound to PD-L1 promoter in RCCs and inhibition of mTOR led to enhanced TFEB nuclear translocation and PD-L1 expression. Simultaneous inhibition of mTOR and blockade of PD-L1 enhanced CD8+ cytolytic function and tumor suppression in a xenografted mouse model of RCC. These data revealed that TFEB mediates resistance to mTOR inhibition via induction of PD-L1 in human primary RCC tumors, RCC cells, and murine xenograft model. Our data provide a strong rationale to target mTOR and PD-L1 jointly as a novel immunotherapeutic approach for RCC treatment.
Highlights
Renal cell carcinoma (RCC) encompasses a heterogeneous group of cancers derived from renal tubular epithelial cells [1]
These data revealed that transcription factor EB (TFEB) mediates resistance to mTOR inhibition via induction of PD-L1 in human primary renal cell carcinoma (RCC) tumors, RCC cells, and murine xenograft model
We found that TFEB directly regulates PD-L1 expression in RCC cell lines and primary human RCC cells, despite no effect on tumor cell biology
Summary
Renal cell carcinoma (RCC) encompasses a heterogeneous group of cancers derived from renal tubular epithelial cells [1]. Patients with localized RCC after partial or radical nephrectomy often go on to develop metastatic disease, which requires systemic therapies that are rarely curative [2, 3]. The mTOR is a serine/ threonine kinase that forms two complexes mTORC1 and mTORC2 [4, 5]. Inhibitors of mTOR, everolimus, and temsirolimus that are derived from rapamycin have been approved by the FDA to treat advanced metastatic renal cancers [8, 9]. Despite initial excitement of mTOR inhibitors for the treatment of RCC, mTOR inhibitors rarely achieve complete responses and most patients develop resistance to mTOR inhibitor therapy [10, 11]. The underlying mechanisms by which the RCC resists mTOR inhibition are elusive
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