Tumour inflammasome-derived IL-1b recruits neutrophils and improves local recurrence-free survival in EBV-induced nasopharyngeal carcinoma (original) (raw)
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EMBO Molecular Medicine, 2012
Inflammasomes sense infection and cellular damage and are critical for triggering inflammation through IL-1b production. In carcinogenesis, inflammasomes may have contradictory roles through facilitating antitumour immunity and inducing oncogenic factors. Their function in cancer remains poorly characterized. Here we show that the NLRP3, AIM2 and RIG-I inflammasomes are overexpressed in Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC), and expression levels correlate with patient survival. In tumour cells, AIM2 and RIG-I are required for IL-1b induction by EBV genomic DNA and EBV-encoded small RNAs, respectively, while NLRP3 responds to extracellular ATP and reactive oxygen species. Irradiation and chemotherapy can further activate AIM2 and NLRP3, respectively. In mice, tumour-derived IL-1b inhibits tumour growth and enhances survival through host responses. Mechanistically, IL-1b-mediated anti-tumour effects depend on infiltrated immunostimulatory neutrophils. We show further that presence of tumour-associated neutrophils is significantly associated with better survival in NPC patients. Thus, tumour inflammasomes play a key role in tumour control by recruiting neutrophils, and their expression levels are favourable prognostic markers and promising therapeutic targets in patients.
Nature Communications
Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro-inflammatory phenotype. Additionally, genomic changes impairing TGFBR2 promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of CDKN2A/CDKN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work ...
Nature Microbiology, 2019
The Epstein-Barr virus M81 strain, isolated from a nasopharyngeal carcinoma, induces potent spontaneous virus production in infected B cells. We found that the M81 non-coding Epstein-Barr-encoded RNA EBER2, which carries polymorphisms that are mainly restricted to viruses found in endemic nasopharyngeal carcinomas, markedly stimulated this process. M81 EBER2 increased CXCL8 expression, and this chemokine enhanced spontaneous lytic replication levels in M81-infected B cells. Both events resulted from the endocytosis of extracellular vesicles containing EBER2 that were generated by neighbouring M81infected B cells, thereby generating a paracrine loop. These effects were strictly dependent on a functional Toll-like receptor 7 (TLR7), a sensor of single-stranded RNA located in the endosome of these cells. These unique properties of M81 EBER2 could be ascribed to its unusually high expression level and to the ability of its single-stranded region to activate TLR7; both of these properties were dependent on M81-specific polymorphisms. Thus, M81 induced chronic inflammation in its target cells and this resulted in increased virus production. These observations provide a mechanistic molecular link between M81 virus replication-a central viral function and a cancer risk factor-and the production of a chemokine involved in inflammation and carcinogenesis.
Proceedings of the National Academy of Sciences, 1987
Nasopharyngeal carcinoma (NPC) is a human epithelial cancer that is constantly associated with the Epstein-Barr virus (EBV). Investigations on this tumor have been limited so far by the difficulty of culturing NPC cells for long periods. C15 is an NPC tumor that has been successfully carried in nude mice for >2 yr. C15 cells isolated from the animal were shown to produce a soluble factor with interleukin 1 (IL-1) activity. Its biochemical (Mr, -17,000; pI -5) and immunological properties are identical to those of IL-la. RNA gel blot analysis showed IL-la, but not IL-1,, transcripts in C15 cells, in sharp contrast to monocytes that express IL-1f8 predominantly. Media from short-term cultures of fresh NPC biopsies also contained a strong IL-1 activity. Several lymphoblastoid cell lines obtained by EBV infection of normal B lymphocytes have been shown to produce IL-1 and use it as an autocrine growth factor.
Journal of General Virology, 2008
The Epstein–Barr virus (EBV)-encoded EBNA1 protein is expressed in all virus-associated tumours, including nasopharyngeal carcinoma (NPC), where it plays an essential role in EBV genome maintenance, replication and transcription. Previous studies suggest that EBNA1 may have additional effects relevant to oncogenesis, including enhancement of cell survival, raising the possibility that EBNA1 may influence cellular gene expression. We have recently demonstrated by gene expression microarray profiling in an NPC cell model that EBNA1 influences the expression of a range of cellular genes, including those involved in transcription, translation and cell signalling. Here, we report for the first time that EBNA1 enhances activity of the AP-1 transcription factor in NPC cells and demonstrate that this is achieved by EBNA1 binding to the promoters of c-Jun and ATF2, enhancing their expression. In addition, we demonstrate elevated expression of the AP-1 targets interleukin 8, vascular endothel...
Cancer Biology & Therapy, 2007
To understand the role of Epstein-Barr virus (EBV) and viral products in associated with immunophenotype and clinical outcome of primary nasopharyngeal carcinoma (NPC), the expression levels of chemokines IFN-g-induced protein 10 (IP-10, CXCL10), stromal-derived factor-1 (SDF-1, CXCL12) and its receptor CXCR4 was investigated in 56 primary NPC biopsy specimens from Chinese NPC patients in parallels with LMP1 antigen and EBER1 by immunohistochemisty (IHC) and in situ hybridization (ISH). Moreover, the expression levels of HLA class I (b-microglobulin) and II antigen (HLA-DR), and co-stimulatory molecule CD54 were also evaluated in 31 out of these 56 patients using immunohistochemisty (IHC). Our results showed that (a) the elevated expression levels of IP10, SDF-1, CXCR4, b-microglobulin, HLA-DR and CD54 in NPC lesions was 66%, 36%, 30%, 42%, 55% and 69%, respectively. (b) High expression of SDF-1 was observed in advanced NPC (N stage, p < 0.05). (c) LMP1 expression correlated with upregulation of CXCR4 and translocation of CXCR4 to the nucleus of the tumor cells. This role of LMP1 in regulating the expression of CXCR4 was confirmed in the EBV positive NPC cell line C666 by inhibition of LMP1 expression with small interfering RNA (siRNA). Our findings provide new insights on the immune status of the malignant cells which may affect the outcome of immunotherapy in NPC. The differentiated nonkeratinizing and undifferentiated types of nasopharyngeal carcinoma (NPC) are associated with Epstein-Barr virus (EBV) in South China, which has the highest incidence rate in the world. 1 The EBV latent type II antigens include nuclear antigen 1 (EBNA1), and latent membrane protein 1 (LMP1, in approximately 50%, seen in ref. 2) and protein 2 (LMP2), in addition small non-polyadenylated viral RNAs non-coding nuclear RNAs (EBERs) and BamHI-A rightward transcripts (BARTs) expressed in NPC tumor cells. The expressions of EBV antigens in NPC tumor cells provide the targets for adoptive immunotherapy. 3-6 However, the poorly differentiated NPC is always characterized by the presence of a highly cellular lymphoid stroma admixed with tumor cells. 7 However, the role of local immunity surrounding NPC cells and the role EBV and viral products expressed in tumor cell remain unclear, which is associated with the expression of immune-related molecules including chemokines and receptors, HLA class I and II antigens, and co-stimulatory molecules and the role of EBV and viral products to alter the expression of immune-related molecules on tumor cells. It has been reported that the expression pattern of immune related-molecules on tumor cells will affect the outcome of T-cell-based adoptive immunotherapy for NPC. 8-10
Molecular Cancer, 2011
Background: The importance of the malignant cell environment to its growth and survival is becoming increasingly apparent, with dynamic cross talk between the neoplastic cell, the leukocyte infiltrate and the stroma. Most cancers are accompanied by leukocyte infiltration which, contrary to an anticipated immuno-protective role, could be contributing to tumour development and cancer progression. Epstein-Barr virus (EBV) associated cancers, including nasopharyngeal carcinoma and Hodgkin's Disease, show a considerable leukocyte infiltration which surrounds the neoplastic cells, raising the questions as to what role these cells play in either restricting or supporting the tumour and what draws the cells into the tumour. In order to begin to address this we have studied a transgenic model of multistage carcinogenesis with epithelial expression of the EBV primary oncoprotein, latent membrane protein 1 (LMP1). LMP1 is expressed particularly in the skin, which develops a hyperplastic pathology soon after birth.