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.MHC class I | CITA | cancer | immune evasion | NLRC5
Cancer cells need to escape immune surveillance for successful tumor growth. Loss of MHC class I has been described as a major immune evasion strategy in many cancers. MHC class I transactivator (CITA), NLRC5, has found to be a key transcription coactivator of MHC class I genes. Recent genetic studies revealed that NLRC5 is a major target for cancer immune evasion mechanism. The reduced expression or activity of NLRC5 caused by promoter methylation, copy number loss, or somatic mutations is associated with defective MHC class I expression, impaired cytotoxic T cell activation and poor patient prognosis. Here we review the role of NLRC5 in cancer immune evasion and the future prospects for cancer research.
CITA (MHC class I transactivator)/ NLRC5 is a transcriptional co‐activator of MHC class I and related genes. NLRC5 plays critical roles in defense against viral infection and cancer through activation of CD8 T cells. The genetic and epigenetic changes in NLRC5 serve as immune evasion mechanisms in multiple cancer types.
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