title: Blocking oncogenic RAS enhances tumour cell surface MHC class I expression but does not alter susceptibility to cytotoxic lymphocytes.
abstract: Mutations in the RAS family of oncogenes are highly prevalent in human cancer and, amongst its manifold effects, oncogenic RAS impairs the expression of components of the antigen presentation pathway. This allows evasion of cytotoxic T lymphocytes (CTL). CTL and natural killer (NK) cells are reciprocally regulated by MHC class I molecules and any gain in CTL recognition obtained by therapeutic inactivation of oncogenic RAS may be offset by reduced NK cell activation. We have investigated the consequences of targeted inactivation of oncogenic RAS on the recognition by both CTL and NK cells. Inactivation of oncogenic RAS, either by genetic deletion or inactivation with an inducible intracellular domain antibody (iDAb), increased MHC class I expression in human colorectal cell lines. The common RAS mutations, at codons 12, 13 and 61, all inhibited antigen presentation. Although MHC class I modulates the activity of both CTL and NK cells, the enhanced MHC class I expression resulting from inactivation of mutant KRAS did not significantly affect the in vitro recognition of these cell lines by either class of cytotoxic lymphocyte. These results show that oncogenic RAS and its downstream signalling pathways modulate the antigen presentation pathway and that this inhibition is reversible. However, the magnitude of these effects was not sufficient to alter the in vitro recognition of tumour cell lines by either CTL or NK cells.
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, Wellcome Brenner Building, St. James's University Hospital, Leeds LS9 7TF, UK; Affiliated with the Clinical Pathology Department, Faculty of Medicine, Mansoura University, Egypt.
authors.forename: Jehan J
authors.initials: JJ
authors.lastname: El-Jawhari
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, Wellcome Brenner Building, St. James's University Hospital, Leeds LS9 7TF, UK; Affiliated with the Clinical Pathology Department, Faculty of Medicine, Mansoura University, Egypt.
authors.forename: Yasser M
authors.initials: YM
authors.lastname: El-Sherbiny
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, Wellcome Brenner Building, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Gina B
authors.initials: GB
authors.lastname: Scott
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, Wellcome Brenner Building, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Ruth S M
authors.initials: RS
authors.lastname: Morgan
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, Wellcome Brenner Building, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Prestwich
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, Wellcome Brenner Building, St. James's University Hospital, Leeds LS9 7TF, UK; Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bowles
authors.affiliation: Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: G Eric
authors.initials: GE
authors.lastname: Blair
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, Wellcome Brenner Building, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, Wellcome Brenner Building, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Terence H
authors.initials: TH
authors.lastname: Rabbitts
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, Wellcome Brenner Building, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Josephine L
authors.initials: JL
authors.lastname: Meade
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, Wellcome Brenner Building, St. James's University Hospital, Leeds LS9 7TF, UK. Electronic address: g.p.cook@leeds.ac.uk.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Cook
mesh_terms: D000906:Antibodies / Q000494:pharmacology*; D000954:Antigens, Surface / Q000378:metabolism; D045744:Cell Line, Tumor; D017353:Gene Deletion; D045325:HCT116 Cells; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D016283:Proto-Oncogene Proteins p21(ras); D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: D000906:Antibodies; D000954:Antigens, Surface; D015395:Histocompatibility Antigens Class I; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: Antigen presentation; MHC class I; Natural killer cells; RAS oncogene; Tumour immune evasion; Tumour immunology