Lawrence Young (University of Warwick, United Kingdom)
“The Future of NPC Research: Opportunities and Challenges”
- Key questions
- relevance of epithelial infection to EBV’s natural history
- Role of EBV strain variation
- Precise contribution of EBV latent and lytic genes
- Contribution of the microenvironment
- Targeting EBV for …
- What’s special about the NPC cell and its progenitor?
- lymphoma-epithelium
- The fossa on rose muller: transformation zone
- Transitional zone veteran ciliated columnar respiratory epithelium and stratified squamous epithelium
- Only active during fetal development to 10 years of age -> EBV infection?
- Cancer stem cell. NPC Timor’s are enriched for cells expressing stem cell/early progenitor cell “markers”
- EBV strains (SNPs in NPC, China vs Indonesia (27)
- M81 stein (EBNA1 form NPC compromised for episomal maintenance, more lytic, ZpV3)
What’s special about the type of EBV in NPC cells
Comprehensive profiling of BILF1 expression in a subset of primneary NPC target MHC-I presentation biz executives and enjoy tic pathways 6/0ut of 28 primary NOC cases are BILF1-positive (21.4%) with a mean H-score of 100 by RNAscope
– what if the prevalent form of EBV in NOC and in CHina/Southe-East Asia is a more replication-competent virus
– Coul this explain
– 1. Elevate antibody titles to late viral antigens have diagnostic and prognostic value in NPC
– Elevated virus load is frequently observed before the onset of NOC
– virus and host interactions
Why can;t we detect more premalingnant disease?
– difficulty in establishing EBV-positive NPC cell lines in vitro and in Vito
– Los
2. Loss of EBV from cultured NPC cells -HONE 1
3. Loss of EBV from in vitro infected epithelial cells lines
4. Heterogenous cell morphology and EBV status of NPC cells (the round cells are positive for the EBV markers EBNA1, LMP1, and EBERs and the EBNA1-induced TFIIIC-102
5. Replication EBV infection in differentiating layers of tongue epithelium (Frangou et al,., J INfect Dis (191), 238-242 (2205). —> EBV replicaiton in 1.3% normal samples (217 samples)
6. Efficient replication of EBV instratified epithelim in vitro (PNAS 111, 11544 2014. Clare Sample’s Lang)underfferentiated epithelials (stem cell, Bcl12, deltaNP63,
How important is tumor heterogeneity and what are the clinical implications?
-Lin et al Nature Genetics 46: 866-871, 2014
ARID1(10%)
Hypermethylation
Mutation number is smaller
APONBEC
-COSMIC catalogue of somatic mutation in cancer (nasopharyngeal carcinoma signatures 1, 2, 5, 6, 13
-Feature 2 —> good for immunotherapy
-TP53 mutationsin NPC.
Heterogeneity -EBV and virus gene expression, genetics and epigenetic s, immune microenvironment
-intratumor heterogeneity and clinical
– Kippers R. JCI 122: 3439, 2012
– HD: TME full of storm cells —> support fem tumor cells!
Blood 2011; 117(1) :1654
PNAS 2012 (109) CD80, Cd28, CXCR3
Told of storm all cells in supporting the growth and survival of NCP cells
Immune Context
ImmunoScore CD3/CD8 T cell density
Crucial importance of early detection
Therapeutic developments
Cancer Therapuy in Evolution
The emperor of all maladies: a biography of cancer