Nasopharyngeal Cancer Workshop EBV Dormancy and Relationship with Carcinogenesis

25 – 26 January 2019 Prof Lawrence S Young

EBV dormancy and relationship with carcinogenesis
Nasopharyngeal Carcinoma Workshop
25-26 January 2019, Singapore
NASOPHARYNGEAL CARCINOMA
1. Patients show elevated anti-EBV antibodies and circulating
EBV DNA. Plasma EBV DNA as a primary screen.
2. Consistently EBV genome positive - monoclonal episomes.

3. Restricted EBV latent gene expression - EBNA1, LMPs,

BARTS, BARF1 but also some lytic gene expression.

4. Presence of EBV in high grade pre-invasive lesions. EBERs

Key Questions
Relevance of epithelial infection to EBV’s natural history?
Role of EBV strain variation?
Precise contribution of EBV latent and lytic genes?
Professor Lawrence S. Young
Contribution of the microenvironment?
EBNA1
Pro-Dean, Warwick Medical School
University of Warwick
Targeting EBV for therapeutic/prophylactic intervention?
UK

EBV latent gene expression in NPC

EBERs EBNA1

LMP1 LMP2A

Latent membrane protein 1 (LMP1)

NH2
PI3-K
CTAR1 TRAF
Cell transformation
ERK-MAPK
Cell motility
NF-B2
Cell survival

TRADD
CTAR2 BS69 NF-B1
COOH
TRAF Cytokine induction
JNK/p38 Cell survival

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Nasopharyngeal Cancer Workshop EBV Dormancy and Relationship with Carcinogenesis
25 – 26 January 2019 Prof Lawrence S Young

LMP2A/B localises to endosomes and lysosomes

LMP2A/B CD63 Merge

Late endosomes/lysosomes

NPC GC HL

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Nasopharyngeal Cancer Workshop EBV Dormancy and Relationship with Carcinogenesis
25 – 26 January 2019 Prof Lawrence S Young

Expressed in all forms of EBV latency

Maintenance and segregation of EBV
episome.
EBNA1
Other functions: disrupts PML nuclear
bodies, genomic instability,
cell signalling.

Glandular Squamous

LCL Hela Ad/AH SCC12F SVK

EBNA1

Degradation
products

G2M arrest

Fan et al., J. Cancer

9:2852-2864, 2018

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Nasopharyngeal Cancer Workshop EBV Dormancy and Relationship with Carcinogenesis
25 – 26 January 2019 Prof Lawrence S Young

What’s special about the NPC cell and its progenitor?

EBV Nasopharyngeal epithelium
What’s special about the type of EBV in NPC cells?
Latent infection of B lymphocyte pool
Genetic predisposition
Why can’t we detect more premalignant disease? Immune
Chronic malaria ? Co-factors
Dietary carcinogens
suppression

When does EBV infection occur in the carcinogenic process? Cellular genetic changes
Where does EBV replicate in vivo? Continued growth Cellular
in absence of genetic
Chromosomal
immune control changes
How important is tumour heterogeneity and what are the translocation. Establishment of
latent infection
C-myc activation
clinical implications?

Heterogeneity – EBV and virus gene expression, genetics and

epigenetics, immune microenvironment
PTL BL HL NPC

Institute of Cancer & Genomic Sciences Division of Biomedical Sciences

College of Medical and Dental Sciences Warwick Medical School FUTURE PERSPECTIVES AND PRIORITIES
University of Birmingham University of Warwick
1. Contribution of EBV strain variation and virus-encoded genes (lytic)
NPC and HL project Data Analytics Collaborators
EBV Sequencing
Chris Dawson Jean Crabtree
Anne Palser Nasir Rajpoot 2. Role of cancer stem cells and tumour microenvironment.
Paul Murray Ingemar Ernberg
Paul Kellam Sascha Ott
Graham Taylor Lori Frappier
Nigel Dyer
John Arrand Lindsey Hutt-Fletcher 3. Other co-factors? Other viruses, microbiome, chemical carcinogens.
Martina Vockerodt Maria Lung
Wenbin Wei Gerald Niedobitek
Rob White 4. More detailed characterization of early and metastatic disease.
Chunfang Hu Kenzo Takada
Jia Junying Martin Allday Angela Lo
Sim Sihota Paul Farrell KW Lo 5. Development of model systems - in vitro and in vivo.
Yuk Ting Ma George Tsao
Kaisheng Wen Lee Fah Yap
6. Patient stratification - predictive biomarkers of response and metastases.
Ciaran Woodman Ian Paterson
Musheng Zeng
Yi-Xin Zeng 7. Identification and therapeutic targeting of driver signalling pathways.

8. Targeted therapy – EBV latent proteins, epigenetic, gene and immunotherapy.

9. Prevention - prophylactic vaccination, diet.

T cell responses to EBV lytic and latent antigens

From Taylor et al. Ann Rev Immunol 33:787-821, 2015

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