title: Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome.
abstract: The immunoproteasome plays a key role in generation of HLA peptides for T cell-mediated immunity. Integrative genomic and proteomic analysis of non-small cell lung carcinoma (NSCLC) cell lines revealed significantly reduced expression of immunoproteasome components and their regulators associated with epithelial to mesenchymal transition. Low expression of immunoproteasome subunits in early stage NSCLC patients was associated with recurrence and metastasis. Depleted repertoire of HLA class I-bound peptides in mesenchymal cells deficient in immunoproteasome components was restored with either IFNγ or 5-aza-2'-deoxycytidine (5-aza-dC) treatment. Our findings point to a mechanism of immune evasion of cells with a mesenchymal phenotype and suggest a strategy to overcome immune evasion through induction of the immunoproteasome to increase the cellular repertoire of HLA class I-bound peptides.
authors.affiliation: Department of Clinical Cancer Prevention, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Satyendra C
authors.initials: SC
authors.lastname: Tripathi
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Haley L
authors.initials: HL
authors.lastname: Peters
authors.affiliation: Department of Translational Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Ayumu
authors.initials: A
authors.lastname: Taguchi
authors.affiliation: Department of Clinical Cancer Prevention, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Katayama
authors.affiliation: Department of Clinical Cancer Prevention, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Clinical Cancer Prevention, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Amin
authors.initials: A
authors.lastname: Momin
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX;
authors.forename: Mohit Kumar
authors.initials: MK
authors.lastname: Jolly
authors.affiliation: Department of Clinical Cancer Prevention, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Muge
authors.initials: M
authors.lastname: Celiktas
authors.affiliation: Department of Translational Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Jaime
authors.initials: J
authors.lastname: Rodriguez-Canales
authors.affiliation: Department of Translational Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Translational Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.affiliation: Department of Translational Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX;
authors.forename: Eshel
authors.initials: E
authors.lastname: Ben-Jacob
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX; herbert.levine@rice.edu EJOstrin@mdanderson.org.
authors.forename: Herbert
authors.initials: H
authors.lastname: Levine
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Molldrem
authors.affiliation: Department of Clinical Cancer Prevention, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Samir M
authors.initials: SM
authors.lastname: Hanash
authors.affiliation: Department of Pulmonary Medicine, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030 herbert.levine@rice.edu EJOstrin@mdanderson.org.
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Ostrin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D015820:Cadherins / Q000276:immunology / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology* / Q000401:mortality* / Q000473:pathology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; C050361:CDH2 protein, human; D015820:Cadherins; D006680:HLA Antigens; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex
keywords: EMT; NSCLC; immunoproteasome; immunotherapy