EBV Conference 2008 Guangzhou - Baylor College of Medicine

45 (RegID: 1495)
Kimberley Jones
Institution: Queensland Institute of Medical Research
e-mail: Kimberley.Jones@qimr.edu.au
MECHANISMS UNDERLYING THE SELECTIVE IMPAIRMENT OF EBNA1-SPECIFIC
EFFECTOR T-CELLS OBSERVED IN PTLD.
K. Jones, J. Nourse,S. Yekollu, L. Morrison, D. Moss, MK Gandhi.
Oralabstract:
Immunosurveillance by cytotoxic T lymphocytes (CTL) plays a critical role in the detection and killing of
lymphoma. The ability to evade CTL recognition promotes cancer survival. In EBV-driven PTLD, evasion
was believed to be simply the result of iatrogenic immunosuppression leading to an absence of
EBV-specific cellular surveillance. If this were true, EBV-specific immunity would be “globally”
depressed. Conversely if lymphoma-driven mechanisms operate this would result in selective impairment
against only those EBV-antigens expressed within the diseased lymph node. Although EBV-latent antigen
expression in PTLD is variable, EBV-nuclear antigen 1 (EBNA1) is universally expressed. EBNA1 may
offer a viable antigenic target for the treatment of PTLD. A deeper understanding of the mechanisms
utilized by the lymphoma cell to evade EBNA1 is needed to optimize immunotherapeutic strategies.
CTL capable of proliferation and interferon-gamma (IFN-gamma) and/or CD107 granule release were
studied in 12 PTLD patients. Blood was taken prior to therapy and results compared with 19 healthy
EBV-seropositive controls. T-cells were expanded using peptide-pools directed against the EBV-antigens
EBNA1 or the lytic protein BZLF1 (the latter is not expressed in PTLD) in a 14-day culture and assayed
by flow cytometry.
Strikingly, we observed a four-to-five fold reduction in both IFN-gamma and CD107 releasing
EBNA1-specific CTL in PTLD patients as compared to controls. By contrast, BZLF1-specific CTL were
unimpaired relative to controls, consistent with a lymphoma-specific inhibition mediated within the
tumour microenvironment. Class I pentamer EBNA1-peptide-specific T-cell lines showed strong
expression of the T-cell inhibitory receptor PD1 and concomitant expression of its ligands PDL1/2 on
EBV-transformed cell-lines and 16 spontaneously outgrown primary patient samples.
We demonstrate a selective impairment of immunity against a highly-relevant tumour-associated antigen
and suggest that EBNA1-specific CTL are under the inhibitory influence of PDL1/2 expressed by
malignant B-cells. Our finding provides a new potential strategy for the treatment and prevention of
PTLD.
EBV Conference 2008 Guangzhou
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