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

Journal article

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: El-Jawhari, J; El-Sherbiny, Y; Scott, G; Morgan, R; Prestwich, R

• Journal: Molecular immunology
• Volume: 58
• Issue: 2
• Pages: 160-168
• Publication date: 2014-04-01
• DOI: 10.1016/j.molimm.2013.11.020
• EISSN: 1872-9142
• ISSN: 0161-5890
• Language: English
• Keywords: Proto-Oncogene Proteins; Cell Line, Tumor; ras Proteins; Gene Deletion; Lymphocyte Activation; T-Lymphocytes, Cytotoxic; Antigens, Surface; Antibodies; Histocompatibility Antigens Class I; Killer Cells, Natural; Neoplasms; HCT116 Cells; Humans