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Proc Natl Acad Sci U S A. 2016 May 24;113(21):5999-6004. doi: 10.1073/pnas.1602069113. Epub 2016 May 9.

NLRC5/MHC class I transactivator is a target for immune evasion in cancer.

Author information

1
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;
2
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054;
3
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College Station, TX 77843;
4
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115;
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115;
6
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.
7
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College Station, TX 77843; kobayashi@medicine.tamhsc.edu.

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

PMID:
27162338
PMCID:
PMC4889388
DOI:
10.1073/pnas.1602069113
[Indexed for MEDLINE]
Free PMC Article

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