TFEB Mediates Immune Evasion and Resistance to mTOR Inhibition of Renal Cell Carcinoma via Induction of PD-L1

Abstract

Purpose: 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.Experimental Design: 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 þ T cells was analyzed by flow cytometry.Results: 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 þ cytolytic function and tumor suppression in a xenografted mouse model of RCC.Conclusions: 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.

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

“…As a result, knockdown of TFEB did not affect cell proliferation. This is consistent with previous report [23]. But interestingly, knockdown of TFE3 signi cantly inhibited cell proliferation ( Fig 1F).…”

“…Identi cation the TFE3 regulated genes in ccRCC cells can provide better understanding of TFE3 functions in the regulation ccRCC tumorigenesis and the interaction between ccRCC cells and the immune microenvironment. Recent study showed that TFEB can mediate immune evasion by positively regulation the expression of PD-L1 in RCC [23]. Given the similar roles of TFE3 and TFEB in the crossregulation of cellullar functions, we tested the expression of typical immune checkpoints, and interestingly we found that TFE3 can also regulate the expression of many immune checkpoints including CD273 (PD-L2) CD274 (PD-L1) CD275 (ICOSL) and CD270 (HVEM).…”

“…Among all the four members of the MiT/TFE family, TFEB and TFE3 show a more ubiquitous pattern of expression and their functions has been widely investigated including proliferation, metabolism, and autophagy [20,24]. The tight connection of TFEB and TFE3 with renal cell carcinoma has been reported, especially in translocation renal cell carcinoma (tRCC) [21][22][23]. But its biological function is not clearly investigated.…”

“…The levels of TFEB and TFE3 are elevated in multiple types of human cancers and have been linked with both occurrence and poor prognosis [20][21][22]24]. Recent study claimed that TFEB has little effect on RCC proliferation [23]. To clarify the role of TFEB and TFE3 in ccRCC, we rst analyzed the publicly available Kaplan Meier plotter and The Cancer Genome Atlas (TCGA) database on the expression of TFEB and TFE3.…”

“…But the molecular mechanism is not fully understood. Recently, XP Yang, et al reported that TFEB mediates immune evasion and resistance to mTOR inhibition of renal cell carcinoma via induction of PD-L1 [23]. These studies have shown that the MiT-TFE family plays an important role not only in the progression, but also chemotherapy resistance of RCC tumors.…”