Abstract
Cancer cells develop under immune surveillance, thus necessitating immune escape for successful growth. Loss of MHC class I expression provides a key immune evasion strategy in many cancers, although the molecular mechanisms remain elusive. MHC class I transactivator (CITA), known as "NLRC5" [NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5], has recently been identified as a critical transcriptional coactivator of MHC class I gene expression. Here we show that the MHC class I transactivation pathway mediated by CITA/NLRC5 constitutes a target for cancer immune evasion. In all the 21 tumor types we examined, NLRC5 expression was highly correlated with the expression of MHC class I, with cytotoxic T-cell markers, and with genes in the MHC class I antigen-presentation pathway, including LMP2/LMP7, TAP1, and β2-microglobulin. Epigenetic and genetic alterations in cancers, including promoter methylation, copy number loss, and somatic mutations, were most prevalent in NLRC5 among all MHC class I-related genes and were associated with the impaired expression of components of the MHC class I pathway. Strikingly, NLRC5 expression was significantly associated with the activation of CD8(+) cytotoxic T cells and patient survival in multiple cancer types. Thus, NLRC5 constitutes a novel prognostic biomarker and potential therapeutic target of cancers.
Keywords:
CITA; MHC class I; NLRC5; cancer; immune evasion.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 2 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 2 / immunology
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Antigen Presentation*
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / immunology*
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / pathology
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Cysteine Endopeptidases / genetics
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Cysteine Endopeptidases / immunology
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Female
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Gene Expression Regulation, Neoplastic / immunology*
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Histocompatibility Antigens Class I / genetics
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Histocompatibility Antigens Class I / immunology*
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / immunology*
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Male
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Neoplasm Proteins / genetics
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Neoplasm Proteins / immunology*
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Neoplasms / genetics
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Neoplasms / immunology*
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Neoplasms / mortality
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Neoplasms / pathology
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / immunology
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Trans-Activators / genetics
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Trans-Activators / immunology*
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Transcriptional Activation / immunology*
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Tumor Escape*
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beta 2-Microglobulin / genetics
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beta 2-Microglobulin / immunology
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 2
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Biomarkers, Tumor
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Histocompatibility Antigens Class I
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Intracellular Signaling Peptides and Proteins
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NLRC5 protein, human
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Neoplasm Proteins
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TAP1 protein, human
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Trans-Activators
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beta 2-Microglobulin
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LMP-2 protein
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Cysteine Endopeptidases
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LMP7 protein
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Proteasome Endopeptidase Complex