Renal cell carcinoma (RCC) has become the most malignant tumour of kidneys in worldwide. 1 Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCCs, representing approximately 70% of all adult renal carcinomas. The other histologies mainly encompass papillary and chromophobe RCC. 2 The prognosis of ccRCC is poor: 30% of patients are metastatic at diagnosis and almost 30% of the remaining patients will develop metastasis detected during the follow-up. 3 With the continuous development of medicine, the treatment and management of ccRCC, particularly metastatic RCC, have radically changed over the past few decades. 4 Initially, first-generation immunotherapy with cytokines: interleukins or interferon represented standard approaches but with poor results. 5,6 In recent years, 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 TKI that is registered for the treatment of advanced or metastatic RCC. 8,9 Currently, the emergence of immune checkpoint inhibitors (ICI) showed promising results in RCC treatment. 10-12 Programmed cell death 1 (PD-1), programmed death ligand-1 (PD-L1)

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.