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Current Cancer Drug Targets

Author(s): Jinhuan Wei, Jun Lu, Yun Cao, Gaosheng Yao, Yong Huang, Hongwei Zhao, Yihui Pan, Zihao Feng, Zhenhua Chen, Wei Chen, Junhang Luo* and Jiazheng Cao*

DOI: 10.2174/1568009621666210811115054

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DDX39B Predicts Poor Survival and Associated with Clinical Benefit of Anti-PD-L1 Therapy in ccRCC

Page: [849 - 859] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Background: Immune checkpoint inhibitors (ICI) have been shown to improve overall survival (OS) in clear cell renal cell carcinoma (ccRCC) patients. However, less than half of the ccRCC patients have objective response to ICI.

Objective: We aim to assess the role of DDX39B in predicting ccRCC patients'OS and ICI therapy response.

Methods: DDX39B was detected by immunohistochemistry in a tissue microarray of 305 ccRCC patients. DDX39B and its relationship with the prognosis of ccRCC were also evaluated in TCGA set and a RECA-EU set. The expression of DDX39B and patients survival was also analysed in two datasets of ccRCC patients treated with ICI.

Results: Overexpression of DDX39B predicted poor OS of ccRCC patients in SYSU set, TCGA set, and a RECA-EU set. DDX39B expression was significantly positive with the expression of PD-L1 and other immunomodulators., DDX39B negatively correlated with cytotoxic T-lymphocyte and HDAC10 exon 3 inclusion in ccRCC. DDX39B knockdown decreased the expression of PD-L1 and increased the expression of HDAC10 exon 3 in renal cancer ACHN cells. Patients of ccRCC with lower levels of HDAC10 exon 3 inclusion have higher TNM stage, higher Fuhrman grade and poor OS. There was a tendency that patients with DDX39B high expression had longer OS and PFS than patients with DDX39B low expression in ccRCC patients treated with ICI.

Conclusion: DDX39B gene is highly expressed in ccRCC and is closely related to patients' OS. DDX39B might increase PD-L1 expression via the enhancement of HDAC10 exon 3 skipping, thereby promoting the ICI therapy response.

Keywords: DDX39B, anti-PD-L1 therapy, clear cell renal cell carcinoma, HDAC10, alternative splicing, prognosis.

Graphical Abstract

[1]
Bedke, J.; Stühler, V.; Stenzl, A.; Brehmer, B. Immunotherapy for kidney cancer: Status quo and the future. Curr. opin. urol., 2018, 28(1), 8-14.
[http://dx.doi.org/10.1097/MOU.0000000000000466] [PMID: 29120911]
[2]
Flippot, R.; Escudier, B.; Albiges, L. Immune checkpoint inhibitors: Toward new paradigms in renal cell carcinoma. Drugs, 2018, 78(14), 1443-1457.
[http://dx.doi.org/10.1007/s40265-018-0970-y] [PMID: 30187355]
[3]
Herbst, R.S.; Soria, J.C.; Kowanetz, M.; Fine, G.D.; Hamid, O.; Gordon, M.S.; Sosman, J.A.; McDermott, D.F.; Powderly, J.D.; Gettinger, S.N.; Kohrt, H.E.; Horn, L.; Lawrence, D.P.; Rost, S.; Leabman, M.; Xiao, Y.; Mokatrin, A.; Koeppen, H.; Hegde, P.S.; Mellman, I.; Chen, D.S.; Hodi, F.S. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature, 2014, 515(7528), 563-567.
[http://dx.doi.org/10.1038/nature14011] [PMID: 25428504]
[4]
Zhang, X.; Wang, C.; Wang, J.; Hu, Q.; Langworthy, B.; Ye, Y.; Sun, W.; Lin, J.; Wang, T.; Fine, J.; Cheng, H.; Dotti, G.; Huang, P.; Gu, Z. PD-1 blockade cellular vesicles for cancer immunotherapy. Adv. Mater., 2018, 30(22), e1707112.
[http://dx.doi.org/10.1002/adma.201707112] [PMID: 29656492]
[5]
Pryor, A.; Tung, L.; Yang, Z.; Kapadia, F.; Chang, T.H.; Johnson, L.F. Growth-regulated expression and G0-specific turnover of the mRNA that encodes URH49, a mammalian DExH/D box protein that is highly related to the mRNA export protein UAP56. Nucleic acids res., 2004, 32(6), 1857-1865.
[http://dx.doi.org/10.1093/nar/gkh347] [PMID: 15047853]
[6]
Shen, H. UAP56- a key player with surprisingly diverse roles in pre-mRNA splicing and nuclear export. BMB Rep., 2009, 42(4), 185-188.
[http://dx.doi.org/10.5483/BMBRep.2009.42.4.185] [PMID: 19403039]
[7]
Jurewicz, M.M.; Stern, L.J. Class II MHC antigen processing in immune tolerance and inflammation. Immunogenetics, 2019, 71(3), 171-187.
[http://dx.doi.org/10.1007/s00251-018-1095-x] [PMID: 30421030]
[8]
Allcock, R.J.; Williams, J.H.; Price, P. The central MHC gene, BAT1, may encode a protein that down-regulates cytokine production. Genes Cells, 2001, 6(5), 487-494.
[http://dx.doi.org/10.1046/j.1365-2443.2001.00435.x] [PMID: 11380625]
[9]
Mendonça, V.R.; Souza, L.C.; Garcia, G.C.; Magalhães, B.M.; Lacerda, M.V.; Andrade, B.B.; Gonçalves, M.S.; Barral-Netto, M. DDX39B (BAT1), TNF and IL6 gene polymorphisms and association with clinical outcomes of patients with Plasmodium vivax malaria. Malar. J., 2014, 13, 278.
[http://dx.doi.org/10.1186/1475-2875-13-278] [PMID: 25038626]
[10]
Wong, A.M.; Allcock, R.J.; Cheong, K.Y.; Christiansen, F.T.; Price, P. Alleles of the proximal promoter of BAT1, a putative anti-inflammatory gene adjacent to the TNF cluster, reduce transcription on a disease-associated MHC haplotype. Genes Cells, 2003, 8(4), 403-412.
[http://dx.doi.org/10.1046/j.1365-2443.2002.00641.x] [PMID: 12653967]
[11]
Ryan, M.; Wong, W.C.; Brown, R.; Akbani, R.; Su, X.; Broom, B.; Melott, J.; Weinstein, J. TCGASpliceSeq a compendium of alternative mRNA splicing in cancer. nucleic acids res., 2016, 44(D1), D1018-D1022.
[http://dx.doi.org/10.1093/nar/gkv1288] [PMID: 26602693]
[12]
Yu, G.; Wang, L.G.; Han, Y.; He, Q.Y. clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS, 2012, 16(5), 284-287.
[http://dx.doi.org/10.1089/omi.2011.0118] [PMID: 22455463]
[13]
Terranova-Barberio, M.; Thomas, S.; Ali, N.; Pawlowska, N.; Park, J.; Krings, G.; Rosenblum, M.D.; Budillon, A.; Munster, P.N. HDAC inhibition potentiates immunotherapy in triple negative breast cancer. Oncotarget, 2017, 8(69), 114156-114172.
[http://dx.doi.org/10.18632/oncotarget.23169] [PMID: 29371976]
[14]
Woods, D.M.; Sodré, A.L.; Villagra, A.; Sarnaik, A.; Sotomayor, E.M.; Weber, J. HDAC Inhibition Upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 Blockade. Cancer Immunol. Res., 2015, 3(12), 1375-1385.
[http://dx.doi.org/10.1158/2326-6066.CIR-15-0077-T] [PMID: 26297712]
[15]
Jiang, P.; Gu, S.; Pan, D.; Fu, J.; Sahu, A.; Hu, X.; Li, Z.; Traugh, N.; Bu, X.; Li, B.; Liu, J.; Freeman, G.J.; Brown, M.A.; Wucherpfennig, K.W.; Liu, X.S. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat. Med., 2018, 24(10), 1550-1558.
[http://dx.doi.org/10.1038/s41591-018-0136-1] [PMID: 30127393]
[16]
Miao, D.; Margolis, C.A-O.; Gao, W.; Voss, M.H.; Li, W.; Martini, D.J.; Norton, C.; Bossé, D.; Wankowicz, S.M.; Cullen, D.; Horak, C.; Wind-Rotolo, M.; Tracy, A.; Giannakis, M.; Hodi, F.S.; Drake, C.G.; Ball, M.W.; Allaf, M.E.; Snyder, A.; Hellmann, M.D.; Ho, T.; Motzer, R.J.; Signoretti, S.; Kaelin, W.G., Jr; Choueiri, T.K.; Van Allen, E.M. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science, 2018, 359(6377), 801-806.
[http://dx.doi.org/10.1126/science.aan5951] [PMID: 29301960]
[17]
Braun, D.A-O.; Hou, Y.; Bakouny, Z.; Ficial, M.; Sant’ Angelo, M.; Forman, J.; Ross-Macdonald, P.; Berger, A.C.; Jegede, O.A.; Elagina, L.; Steinharter, J.; Sun, M.; Wind-Rotolo, M.; Pignon, J.C.; Cherniack, A.D.; Lichtenstein, L.; Neuberg, D.; Catalano, P.; Freeman, G.J.; Sharpe, A.H.; McDermott, D.F.; Van Allen, E.M.; Signoretti, S.; Wu, C.J.; Shukla, S.A.; Choueiri, T.K. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat. med., 2020, 26(6), 909-918.
[http://dx.doi.org/10.1038/s41591-020-0839-y] [PMID: 32472114]
[18]
Walbrecq, G.; Lecha, O.; Gaigneaux, A.; Fougeras, M.R.; Philippidou, D.; Margue, C.; Tetsi Nomigni, M.; Bernardin, F.; Dittmar, G.; Behrmann, I.; Kreis, S. Hypoxia-induced adaptations of mirnomes and proteomes in melanoma cells and their secreted extracellular vesicles. Cancers (Basel), 2020, 12(3), 692.
[http://dx.doi.org/10.3390/cancers12030692] [PMID: 32183388]
[19]
Gu, H.Y.; Zhang, C.; Guo, J.; Yang, M.; Zhong, H.C.; Jin, W.; Liu, Y.; Gao, L.P.; Wei, R.X. Risk score based on expression of five novel genes predicts survival in soft tissue sarcoma. Aging (Albany NY), 2020, 12(4), 3807-3827.
[http://dx.doi.org/10.18632/aging.102847] [PMID: 32084007]
[20]
Meng, T.; Huang, R.; Zeng, Z.; Huang, Z.; Yin, H.; Jiao, C.; Yan, P.; Hu, P.; Zhu, X.; Li, Z.; Song, D.; Zhang, J.; Cheng, L. Identification of prognostic and metastatic alternative splicing signatures in kidney renal clear cell carcinoma. Front. bioeng. biotechnol., 2019, 7, 270.
[http://dx.doi.org/10.3389/fbioe.2019.00270] [PMID: 31681747]
[21]
McDermott, D.F.; Huseni, M.A.; Atkins, M.B.; Motzer, R.J.; Rini, B.I.; Escudier, B.; Fong, L.; Joseph, R.W.; Pal, S.K.; Reeves, J.A.; Sznol, M.; Hainsworth, J.; Rathmell, W.K.; Stadler, W.M.; Hutson, T.; Gore, M.E.; Ravaud, A.; Bracarda, S.; Suárez, C.; Danielli, R.; Gruenwald, V.; Choueiri, T.K.; Nickles, D.; Jhunjhunwala, S.; Piault-Louis, E.; Thobhani, A.; Qiu, J.; Chen, D.S.; Hegde, P.S.; Schiff, C.; Fine, G.D.; Powles, T. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat. Med., 2018, 24(6), 749-757.
[http://dx.doi.org/10.1038/s41591-018-0053-3] [PMID: 29867230]
[22]
Liu, X.D.; Kong, W.; Peterson, C.B.; McGrail, D.J.; Hoang, A.; Zhang, X.; Lam, T.; Pilie, P.G.; Zhu, H.; Beckermann, K.E.; Haake, S.M.; Isgandrova, S.; Martinez-Moczygemba, M.; Sahni, N.; Tannir, N.M.; Lin, S.Y.; Rathmell, W.K.; Jonasch, E. PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma. Nat. commun., 2020, 11(1), 2135.
[http://dx.doi.org/10.1038/s41467-020-15959-6] [PMID: 32358509]
[23]
Braun, D.A.; Ishii, Y.; Walsh, A.M.; Van Allen, E.M.; Wu, C.J.; Shukla, S.A.; Choueiri, T.K. Clinical validation of PBRM1 alterations as a marker of immune checkpoint inhibitor response in renal cell carcinoma. JAMA Oncol., 2019, 5(11), 1631-1633.
[http://dx.doi.org/10.1001/jamaoncol.2019.3158] [PMID: 31486842]
[24]
Yang, Y.; Huang, Y.; Wang, Z.; Wang, H-T.; Duan, B.; Ye, D.; Wang, C.; Jing, R.; Leng, Y.; Xi, J.; Chen, W.; Wang, G.; Jia, W.; Zhu, S.; Kang, J. HDAC10 promotes lung cancer proliferation via AKT phosphorylation. Oncotarget, 2016, 7(37), 59388-59401.
[http://dx.doi.org/10.18632/oncotarget.10673] [PMID: 27449083]
[25]
Nakata, D.; Nakao, S.; Nakayama, K.; Araki, S.; Nakayama, Y.; Aparicio, S.; Hara, T.; Nakanishi, A. The RNA helicase DDX39B and its paralog DDX39A regulate androgen receptor splice variant AR-V7 generation. Biochem. biophys. res. commun., 2017, 483(1), 271-276.
[http://dx.doi.org/10.1016/j.bbrc.2016.12.153] [PMID: 28025139]
[26]
Galarza-Muñoz, G.; Briggs, F.B.S.; Evsyukova, I.; Schott-Lerner, G.; Kennedy, E.M.; Nyanhete, T.; Wang, L.; Bergamaschi, L.; Widen, S.G.; Tomaras, G.D.; Ko, D.C.; Bradrick, S.S.; Barcellos, L.F.; Gregory, S.G.; Garcia-Blanco, M.A. Human epistatic interaction controls IL7R splicing and increases multiple sclerosis risk. Cell, 2017, 169(1), 72-84.e13.
[http://dx.doi.org/10.1016/j.cell.2017.03.007] [PMID: 28340352]
[27]
Wang, L.; Wang, Y.; Su, B.; Yu, P.; He, J.; Meng, L.; Xiao, Q.; Sun, J.; Zhou, K.; Xue, Y.; Tan, J. Transcriptome-wide analysis and modelling of prognostic alternative splicing signatures in invasive breast cancer: A prospective clinical study. Sci. Rep., 2020, 10(1), 16504.
[http://dx.doi.org/10.1038/s41598-020-73700-1] [PMID: 33020551]
[28]
Booth, L.; Roberts, J.L.; Poklepovic, A.; Kirkwood, J.; Dent, P. HDAC inhibitors enhance the immunotherapy response of melanoma cells. Oncotarget, 2017, 8(47), 83155-83170.
[http://dx.doi.org/10.18632/oncotarget.17950] [PMID: 29137331]
[29]
Liu, X.; Wang, Y.; Zhang, R.; Jin, T.; Qu, L.; Jin, Q.; Zheng, J.; Sun, J.; Wu, Z.; Wang, L.; Liu, T.; Zhang, Y.; Meng, X.; Wang, Y.; Wei, N. HDAC10 Is positively associated with PD-L1 expression and poor prognosis in patients with NSCLC. Front. oncol., 2020, 10, 485.
[http://dx.doi.org/10.3389/fonc.2020.00485] [PMID: 32373519]