Search

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 theMHC 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. [ABSTRACT FROM AUTHOR]

Diffuse large B cell lymphomas (DLBCLs) often express BCL6, a transcriptional repressor required for the formation of normal germinal centers. In a subset of DLBCLs, BCL6 is deregulated by chromosomal translocations or aberrant somatic hypermutation; in other tumors, BCL6 expression may simply reflect germinal center lineage. DLBCLs dependent on BCL6-regulated pathways should exhibit differential regulation of BCL6 target genes. Genomic array ChIP-on-chip was used to identify the cohort of direct BCL6 target genes. This set of genes was enriched in modulators of transcription, chromatin structure, protein ubiquitylation, cell cycle, and DNA damage responses. In primary DLBCLs classified on the basis of gene expression profiles, these BCL6 target genes were clearly differentially regulated in "BCR" tumors, a subset of DLBCLs with increased BCL6 expression and more frequent BCL6 translocations. In a panel of DLBCL cell lines analyzed by expression arrays and classified according to their gene expression profiles, only BCR tumors were highly sensitive to the BCL6 peptide inhibitor, BPI. These studies identify a discrete subset of DLBCLs that are reliant on BCL6 signaling and uniquely sensitive to BCL6 inhibitors. More broadly, these data show how genome-wide identification of direct target genes can identify tumors dependent on oncogenic transcription factors and amenable to targeted therapeutics. [ABSTRACT FROM AUTHOR]