Blocking oncogenic RAS enhances tumour cell surface MHC class I expression but does not alter susceptibility to cytotoxic lymphocytes

被引:42
作者
El-Jawhari, Jehan [1 ,3 ]
El-Sherbiny, Yasser M. [1 ,3 ]
Scott, Gina B. [1 ]
Morgan, Ruth S. M. [1 ]
Prestwich, Robin [1 ]
Bowles, Paul A. [1 ,2 ]
Blair, G. Eric [2 ]
Tanaka, Tomoyuki [1 ]
Rabbitts, Terence H. [1 ]
Meade, Josephine L. [1 ]
Cook, Graham P. [1 ]
机构
[1] Univ Leeds, Leeds Inst Mol Med, St Jamess Univ Hosp, Leeds LS9 7TF, W Yorkshire, England
[2] Univ Leeds, Fac Biol Sci, Inst Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire, England
[3] Mansoura Univ, Fac Med, Dept Clin Pathol, Mansoura, Egypt
基金
英国惠康基金; 英国医学研究理事会;
关键词
Tumour immunology; Antigen presentation; MHC class I; Tumour immune evasion; Natural killer cells; RAS oncogene; HLA CLASS-I; DOWN-REGULATION; COLORECTAL-CANCER; SOMATIC MUTATIONS; ADAPTIVE IMMUNITY; INTERFERON-GAMMA; NKG2D LIGANDS; ANTIGEN; PATHWAY; ACTIVATION;
D O I
10.1016/j.molimm.2013.11.020
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. (C) 2013 Elsevier Ltd. All rights reserved.
引用
收藏
页码:160 / 168
页数:9
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