HSV amplicon-mediated delivery of LIGHT enhances the antigen-presenting capacity of chronic lymphocytic leukemia.
Chronic lymphocytic leukemia (CLL) is a B lymphocyte malignancy that remains a largely incurable disease. CLL B cells possess the ability to process and present tumor antigens but lack expression of costimulatory molecules, rendering them inefficient effectors of T-cell activation. We previously demonstrated that helper virus-free preparations of herpes simplex virus (HSV) amplicon vectors encoding CD40L efficiently transduce CLL B cells and render them capable of eliciting specific anti-tumor T-cell responses. LIGHT (TNFSF14), a member of the tumor necrosis factor (TNF) superfamily, efficiently activates both T cells and antigen-presenting cells (APCs). We employed an HSV amplicon vector expressing human LIGHT (hf-HSV-LIGHT) to transduce CLL B cells and compared the immunomodulatory function and T-cell activation induced by hf-HSV-LIGHT transduction to that observed with a CD40L-expressing HSV amplicon (hf-HSV-CD40L). hf-HSV-LIGHT transduction induced expression of endogenous B7.1, B7.2, and ICAM.1 on CLL cells, albeit to a lesser degree than that observed in response to transduction with hf-HSV-CD40L. hf-HSV-LIGHT enhanced the antigen-presenting capacity of CLL B cells, as measured by induction of T-cell proliferation in an allogeneic mixed lymphocyte tumor reaction. Finally, hf-HSV-LIGHT-transduced CLL B cells successfully stimulated the outgrowth of autologous cytotoxic T-lymphocytes in vitro. In aggregate, these data suggest that hf-HSV-LIGHT transduction may be useful for induction of immune responses to CLL and other B-cell lymphoid malignancies.
Tolba
Khaled A
KA
James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA. ktolba@mac.com
Bowers
William J
WJ
Eling
David J
DJ
Casey
Ann E
AE
Kipps
Thomas J
TJ
Federoff
Howard J
HJ
Rosenblatt
Joseph D
JD
D017951:Antigen Presentation / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology; D002460:Cell Line; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology*; D018139:Simplexvirus; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology*
D019013:CD40 Antigens; D008565:Membrane Proteins; C505914:TNFSF14 protein, human; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha