El-Jawhari, JJ, El-Sherbiny, YM, Scott, GB et al. (8 more authors) (2014) Blocking oncogenic RAS enhances tumour cell surface MHC class I expression but does not alter susceptibility to cytotoxic lymphocytes. Molecular Immunology, 58 (2). 160 - 168. ISSN 0161-5890
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2014, Elsevier. NOTICE: this is the author’s version of a work that was accepted for publication in Molecular Immunology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Molecular Immunology, 58, 2, 2014. 10.1016/j.molimm.2013.11.020 |
Keywords: | Antigen presentation; MHC class I; Natural killer cells; RAS oncogene; Tumour immune evasion; Tumour immunology; Antibodies; Antigens, Surface; Cell Line, Tumor; Gene Deletion; HCT116 Cells; Histocompatibility Antigens Class I; Humans; Killer Cells, Natural; Lymphocyte Activation; Neoplasms; Proto-Oncogene Proteins; T-Lymphocytes, Cytotoxic; ras Proteins |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Oncology and Clinical Research (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 23 Apr 2014 11:45 |
Last Modified: | 24 Nov 2014 01:38 |
Published Version: | http://dx.doi.org/10.1016/j.molimm.2013.11.020 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.molimm.2013.11.020 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:77565 |