title: NLRC5/MHC class I transactivator is a target for immune evasion in cancer.
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.
authors.affiliation: Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College Station, TX 77843; Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;
authors.forename: Sayuri
authors.initials: S
authors.lastname: Yoshihama
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054;
authors.forename: Jason
authors.initials: J
authors.lastname: Roszik
authors.affiliation: Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College Station, TX 77843;
authors.forename: Isaac
authors.initials: I
authors.lastname: Downs
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115;
authors.forename: Torsten B
authors.initials: TB
authors.lastname: Meissner
authors.affiliation: Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College Station, TX 77843;
authors.forename: Saptha
authors.initials: S
authors.lastname: Vijayan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115;
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.affiliation: Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College Station, TX 77843;
authors.forename: Tabasum
authors.initials: T
authors.lastname: Sidiq
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115;
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Lizee
authors.affiliation: Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College Station, TX 77843; kobayashi@medicine.tamhsc.edu.
authors.forename: Koichi S
authors.initials: KS
authors.lastname: Kobayashi
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2 / Q000235:genetics / Q000276:immunology; D017951:Antigen Presentation; D014408:Biomarkers, Tumor / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology*; D015533:Transcriptional Activation / Q000276:immunology*; D019139:Tumor Escape; D001613:beta 2-Microglobulin / Q000235:genetics / Q000276:immunology
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D014408:Biomarkers, Tumor; D015395:Histocompatibility Antigens Class I; D047908:Intracellular Signaling Peptides and Proteins; C548042:NLRC5 protein, human; D009363:Neoplasm Proteins; C073119:TAP1 protein, human; D015534:Trans-Activators; D001613:beta 2-Microglobulin; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex
keywords: CITA; MHC class I; NLRC5; cancer; immune evasion