TY - JOUR
T1 - NLRC5/MHC class I transactivator is a target for immune evasion in cancer
AU - Yoshihama, Sayuri
AU - Roszik, Jason
AU - Downs, Isaac
AU - Meissner, Torsten B.
AU - Vijayan, Saptha
AU - Chapuy, Bjoern
AU - Sidiq, Tabasum
AU - Shipp, Margaret A.
AU - Lizee, Gregory A.
AU - Kobayashi, Koichi S.
N1 - Funding Information:
We thank Drs. Christian Combs and Daniela Malide [Light Microscopy Core Facility, National Heart, Lung, and Blood Institute (NHLBI)] for their much appreciated assistance with confocal microscopy and Dr. Michael A. Frohman for expert advice on PLD inhibitors. This work was supported by the Intramural Research Program, NIH, NHLBI, and in part by the Taiwan Ministry of Science and Technology (Grants MOST 103-2320-B- 006-039-MY3 and MOST 104-2320-B-006-032-MY3) (to C.-C.L.).
PY - 2016/5/24
Y1 - 2016/5/24
N2 - 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.
AB - 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.
KW - CITA
KW - Cancer
KW - Immune evasion
KW - Mhc class I
KW - NLRC5
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U2 - 10.1073/pnas.1602069113
DO - 10.1073/pnas.1602069113
M3 - Article
C2 - 27162338
AN - SCOPUS:84969790506
SN - 0027-8424
VL - 113
SP - 5999
EP - 6004
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 21
ER -