COMPLICATIONS - MALIGNANCY

O. Hatton¹, S.L. Lambert¹, M. Vaysberg¹, S.M. Krams², C.O. Esquivel³, O.M. Martinez^1
1Department Of Surgery/division Of Transplantation And Program In Immunology, Stanford University School of Medicine, Stanford/UNITED STATES OF AMERICA, ²Department Of Surgery/division Of Transplantation And Program In Immunology, Stanford University, Stanford/CA/UNITED STATES OF AMERICA, ³Department Of Surgery/division Of Transplantation, Stanford University School of Medicine, Stanford/UNITED STATES OF AMERICA

Body: PTLD-associated EBV+ B cell lymphomas are a serious, often fatal, complication of solid organ and bone marrow transplantation. These lymphomas express several viral genes including latent membraneprotein 2A (LMP2A). LMP2A mimics a constitutively active B cell receptor and provides survival signals to latently infected host cells in part by the recruitment of the Syk tyrosine kinase. We haveshown that inhibition of Syk by R406, an orally available Syk inhibitor, significantly decreases proliferation and increases apoptosis, in vitro, of EBV+ B cell lymphoma lines derived from patientswith PTLD. Based on these results, we hypothesized that inhibition of Syk activity would diminish the growth of EBV+ B cell lymphomas in vivo, in a xenotransplantation model of PTLD. In this model,PTLD tumor lines (AB5, ZD3, JB7) or an EBV- B cell lymphoma line (BL41) and BL41 infected with the B95 lab strain of EBV (BL41.B95), are injected subcutaneously over the right flank of NOD-SCID mice.R406 is delivered as the prodrug (R788) in mouse chow (3g/kg). We observed no difference in time to tumor formation or tumor size between treatment and control groups, even though R406 was present inthe serum and the tumor site at levels above the in vitro determined IC50 values. Unexpectedly, we observed lymph node (LN) growths exclusively in the R406-treated animals; these growths wereobserved regardless of in vitro sensitivity to R406 or EBV infection. Histological analysis showed that these LN growths consisted primarily of hCD20+EBER+ tumor cells. Additionally, no differencesin tumor necrosis or proliferation were seen between treated and control groups, and very few cells other than the hCD20+EBER+ cells were observed within the tumor microenvironment. Microarrayanalysis was performed comparing control tumor, R406-treated tumor and LN tissues. No differences were observed in expression of chemokines or receptors involved in LN metastasis (ex, CCR7, CCL21) orin the expression of genes involved in lymph/angiogenesis (eg VEGF-C, Tie2). Taken together, these data suggest that Syk plays multiple roles in the growth, survival, and migration of EBV+ B celllymphomas in PTLD and provides novel insights into mechanisms of tumor dissemination in PTLD.

Disclosure: All authors have declared no conflicts of interest.