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

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TFEB Mediates Immune Evasion and Resistance to Mtor Inhibition of Renal Cell Carcinoma Via Induction of PD-L1 Published OnlineFirst August 5, 2019; DOI: 10.1158/1078-0432.CCR-19-0733 Translational Cancer Mechanisms and Therapy Clinical Cancer Research TFEB Mediates Immune Evasion and Resistance to mTOR Inhibition of Renal Cell Carcinoma via Induction of PD-L1 Cai Zhang1, Yaqi Duan2,3, Minghui Xia1, Yuting Dong2,3, Yufei Chen1, Lu Zheng4, Shuaishuai Chai5, Qian Zhang2,3, Zhengping Wei1, Na Liu1, Jing Wang1, Chaoyang Sun6, Zhaohui Tang7, Xiang Cheng8, Jie Wu9, Guoping Wang2,3, Fang Zheng1, Arian Laurence10, Bing Li5, and Xiang-Ping Yang1 Abstract Purpose: Despite the FDA approval of mTOR inhibitors Results: TFEB did not affect tumor cell proliferation, (mTORi) for the treatment of renal cell carcinoma (RCC), the apoptosis, and migration. We found a positive correlation benefits are relatively modest and the few responders usually betweenTFEBandPD-L1expressioninRCCtumor develop resistance. We investigated whether the resistance to tissues, primary tumor cells, and RCC cells. TFEB bound mTORi is due to upregulation of PD-L1 and the underlying to PD-L1 promoter in RCCs and inhibition of mTOR molecular mechanism. led to enhanced TFEB nuclear translocation and PD-L1 Experimental Design: The effects of transcription factor EB expression. Simultaneous inhibition of mTOR and þ (TFEB) on RCC proliferation, apoptosis, and migration were blockade of PD-L1 enhanced CD8 cytolytic function evaluated. Correlation of TFEB with PD-L1 expression, as well and tumor suppression in a xenografted mouse model as effects of mTOR inhibition on TFEB and PD-L1 expression, of RCC. was assessed in human primary clear cell RCCs. The regulation Conclusions: These data revealed that TFEB mediates of TFEB on PD-L1 was assessed by chromatin immunopre- resistance to mTOR inhibition via induction of PD-L1 in cipitation and luciferase reporter assay. The therapeutic effi- human primary RCC tumors, RCC cells, and murine xeno- cacies of mTORi plus PD-L1 blockade were evaluated in a graft model. Our data provide a strong rationale to target þ mouse model. The function of tumor-infiltrating CD8 T cells mTOR and PD-L1 jointly as a novel immunotherapeutic was analyzed by flow cytometry. approach for RCC treatment. Introduction 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 1Department of Immunology, School of Basic Medicine, Tongji Medical College, often go on to develop metastatic disease, which requires systemic Huazhong University of Science and Technology (HUST), Wuhan, China. therapies that are rarely curative (2, 3). The mTOR is a serine/ 2Department of Pathology, School of Basic Medicine, Tongji Medical College, HUST, Wuhan, China. 3Institute of Pathology, Tongji Hospital, Tongji Medical threonine kinase that forms two complexes mTORC1 and College, HUST, Wuhan, China. 4Department of Neurobiology, School of Basic mTORC2 (4, 5). These sense the availability of nutrition, growth Medicine, Tongji Medical College, HUST, Wuhan, China. 5Department of Urology, factors, and energy levels to regulate cell growth, proliferation, Union Hospital, Tongji Medical College, HUST, Wuhan, China. 6Department of and differentiation. Dysregulation of mTOR pathways and muta- Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, HUST, tions of mTOR pathway–related genes are often associated with 7 Wuhan, China. Department of Surgery, Tongji Hospital, HUST, Wuhan, China. tumor growth in a variety of cancers (6, 7). Inhibitors of mTOR, 8Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College, HUST, Wuhan, China. 9Department of Cardio- everolimus, and temsirolimus that are derived from rapamycin vascular Surgery, Union Hospital, Tongji Medical College, HUST, Wuhan, China. have been approved by the FDA to treat advanced metastatic renal 10Department of Haematology, University College Hospital, London, England. cancers (8, 9). Despite initial excitement of mTOR inhibitors for Note: Supplementary data for this article are available at Clinical Cancer the treatment of RCC, mTOR inhibitors rarely achieve complete Research Online (http://clincancerres.aacrjournals.org/). responses and most patients ultimately develop resistance to mTOR inhibitor therapy (10, 11). However, the underlying C. Zhang and Y. Duan contributed equally to this article. mechanisms by which the RCC resists mTOR inhibition are Corresponding Author: Xiang-Ping Yang, Tongji Medical College, Huazhong elusive. University of Science and Technology, No.13, Hangkong Road, Wuhan 430030, The transcription factor EB (TFEB) is a member of the micro- China. Phone: 8627-8369-2600; Fax: 8627-8369-2608; E-mail: [email protected] phthalmia family of basic helix-loop-helix-leucine-zipper (bHLH-Zip) transcription factors (MiT family), which binds to Clin Cancer Res 2019;XX:XX–XX the coordinated lysosomal expression and regulation (CLEAR) doi: 10.1158/1078-0432.CCR-19-0733 consensus motif and plays important functions in regulation of Ó2019 American Association for Cancer Research. lysosome biogenesis, autophagy, and metabolism (12, 13). TFEB www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst August 5, 2019; DOI: 10.1158/1078-0432.CCR-19-0733 Zhang et al. efficacy in a mouse RCC xenograft model. Thus, our data provide Translational Relevance evidence and rationale to support the combination of mTORi and Despite the significant progress achieved by targeting mTOR PD-L1 blockade as a potential therapeutic approach to treat RCC. in renal cell carcinoma (RCC), the effects of mTOR inhibitors are modest and patients often develop resistance. The lack of understanding of cancer cell–intrinsic mTOR-mediated path- Materials and Methods ways remains a major hurdle for the development of effective Cell culture therapies. Here, we uncovered that TFEB expression is posi- Cells were cultured at 37 C and 5% CO2 in a humidified tively correlated with PD-L1 expression in RCC cells. Further- incubator. 786-O, ACHN, H1975, A549, H2126, HCT116, LoVo, more, inhibition of mTOR in RCC enhances TFEB nuclear SW480, and Renca cells were from ATCC; 769-P, OS-RC-2, and localization and expression that subsequently drives PD-L1 Caki-1 cells were from and authenticated by Cell Repository, expression and immune evasion in RCC cell lines and primary Chinese Academy of Sciences (Shanghai, China). 786-O, ACHN, tumors. Simultaneously targeting mTOR and PD-L1 enhanced OS-RC-2, 769-P, and Caki-1 cells were authenticated by STR the efficacy in a mouse RCC xenograft model. Thus, our data profiling and authentication of other cell lines was not routinely provide rationale for a combinational strategy that targets performed. All of the cell lines were passaged less than 2 months mTOR and PD-1/PD-L1 axis jointly as a novel approach for after each thaw and tested to be free of mycoplasma contamina- patients with RCC. tion (D101, Vazyme). Transient transfection and generation of stable cell lines 769-P, HEK 293T, and Renca cells were transfected with can be phosphorylated by mTORC1 and GSK3b at serine 211; either pcDNA3.1 control plasmid (EV) or pcDNA3.1 encoding serine phosphorylated TFEB interacts with 14-3-3 and is seques- the constitutively active form of TFEB S211A (TFEB) using tered within cytoplasm (14, 15). Mutation of serine 211 to lipofectamine 2000 (11668019, Invitrogen) as described by alanine (S211A) results in a loss of phosphorylation of TFEB by the manufacturer. TFEB mutant of TFEB-S211A was generated mTORC1 and leads to its constitutively nuclear localization (14). by site-directed point mutagenesis using MutanBEST kit (D401, TFEB can bind to the Tfeb promoter and induces its own expres- Takara). Transfected 769-P and Renca cells were selected with sion (16). The levels of the TFEB and its activity are elevated in G418 (A2513, APExBIO) for 3 weeks and subcloned by dilu- multiple types of human cancers and associated with prolifera- tion at 1 cell/well in 96-well microliter plates. 786-O cells were tion and motility of cancer cells (17). Furthermore, TFEB fusion transduced with control lentivirus expressing a scrambled and overexpression caused by chromosomal translocation events shRNA or lentiviral particles encoding two TFEB short hairpin are linked with a poor prognosis in a subset of patients with RCC RNAs (shRNAs) as follows. ShTFEB-1 (forward): 50-CCGG- with elevated recurrence and metastasis (18, 19). CCCACTTTGGTGCTAATAGCTCTCGAGAGCTATTAGCACCAA- Cancer cells are subject to immune surveillance by which AGTGGGTTTTTG-30, ShTFEB-1 (reverse): 50-AATTCAAAAACC- cytotoxic T cells are able to recognize and kill tumor cells. RCC CACTTTGGTGCT AATAGCTCTCGAGAGCTATTAGCACCAAA- tumors are characterized by an inflammatory infiltrate and the GTGGG-30. ShTFEB-2 (forward): 50-CCGGCGATGTCCTTGGC- T-cell growth cytokine IL2 has long been used to treat RCC (20). TACATCAACTCGAGTTGATGTAGCCAAGGACATCGTTTTTG-30, To evade the immune system, tumor cells express coinhibitory ShTFEB-2 (reverse): 50-AATTCAAAAACGATGTCCTTGG CTAC- molecules, of which PD-L1 has attracted great interest (21). PD-L1 ATCAACTCGAGTTGATGTAGCCAAGGACATCG-30. Cells were expressed by the tumor cells binds to the inhibitory coreceptor selected with puromycin (HY-B1743, MCE) for 3 weeks and PD-1 on the surface of tumor-infiltrating T cells to suppress T-cell subcloned by dilution at 1 cell/well in 96-well microtiter plates. function.
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