Poster Presentation 29th Lorne Cancer Conference 2017

The contribution of Epstein-Barr virus towards apoptotic resistance in extra-nodal NK/T cell lymphoma (#266)

Nenad Sejic 1 2 , Rosemary Tierney 3 , Heather Long 1 , Andreas Strasser 2 , Gemma Kelly 2 , Claire Shannon-Lowe 1
  1. Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, UK
  2. The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  3. Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, UK

Epstein-Barr virus (EBV) is a human gamma herpesvirus that persists asymptomatically in ~90% of adults. Despite its prevalence in healthy people, EBV is associated with a number of malignancies that contribute to 2% of the global cancer burden. One such malignancy is extra-nodal NK/T cell lymphoma (ENKTL). These tumours exhibit high chemoresistance, with patients accordingly having extremely poor prognosis. The rarity of these cancers has limited understanding of the contribution of EBV to pathogenesis, and the mechanisms behind evasion of conventional treatments.

A panel of ENKTL cell lines have been previously established from human tumours to be used as in vitro models of this disease. We have assayed the expression of EBV proteins and of members of the intrinsic apoptotic pathway in these cell lines. Furthermore, we have investigated the chemosensitivity of the tumour cell lines to conventional chemotherapeutics and to BH3-mimetic drugs, that can trigger the intrinsic apoptotic pathway, either as single agents or in combination with one another.

Transcriptional analysis confirmed the expected latency II pattern of viral gene expression associated with ENKTL, but also revealed great diversity in levels of the major viral transformation genes: latent membrane protein 1 (LMP1), LMP2A and LMP2B. Diverse expression levels were also observed across the cell line panel with regards to the BCL-2 family proteins. High LMP1 levels were not associated with increased BCL-2 expression as reported in non-T and NK cell tumours, but did show an inverse correlation with expression of the BH3-only proteins, BIM and BID. Conventional DNA damaging drugs such as etoposide and methotrexate did not induce apoptosis in ENKTL cell lines. However apoptosis could be induced to varying degrees with BH3-mimetics drugs that target BCL-XL and MCL-1. Expression levels of viral proteins and cellular BCL-2 family proteins were not indicative of the response to BH3-mimetic drugs.

Taken together, these data suggest that BH3-mimetics drugs could be a therapeutic avenue for ENKTL.