NLRC5/MHC class I transactivator is a target for immune evasion in cancer
| Autor: | Isaac Downs, Bjoern Chapuy, Saptha Vijayan, Sayuri Yoshihama, Margaret A. Shipp, Gregory Lizée, Jason Roszik, Koichi Kobayashi, Tabasum Sidiq, Torsten B. Meissner |
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| Rok vydání: | 2016 |
| Předmět: |
Male
Transcriptional Activation 0301 basic medicine Proteasome Endopeptidase Complex chemical and pharmacologic phenomena C-C chemokine receptor type 7 CD8-Positive T-Lymphocytes 03 medical and health sciences Immune system Neoplasms NLRC5 MHC class I Biomarkers Tumor Humans Cytotoxic T cell ATP Binding Cassette Transporter Subfamily B Member 2 Antigen Presentation Multidisciplinary biology Antigen processing Histocompatibility Antigens Class I MHC Class I Gene Intracellular Signaling Peptides and Proteins Biological Sciences Neoplasm Proteins Gene Expression Regulation Neoplastic Cysteine Endopeptidases 030104 developmental biology Immunology Trans-Activators biology.protein Female Tumor Escape beta 2-Microglobulin CD8 |
| Zdroj: | Proceedings of the National Academy of Sciences. 113:5999-6004 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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