title: Myxoma virus suppresses proliferation of activated T lymphocytes yet permits oncolytic virus transfer to cancer cells.
abstract: Allogeneic hematopoietic cell transplant (allo-HCT) can be curative for certain hematologic malignancies, but the risk of graft-versus-host disease (GVHD) is a major limitation for wider application. Ideally, strategies to improve allo-HCT would involve suppression of T lymphocytes that drive GVHD while sparing those that mediate graft-versus-malignancy (GVM). Recently, using a xenograft model, we serendipitously discovered that myxoma virus (MYXV) prevented GVHD while permitting GVM. In this study, we show that MYXV binds to resting, primary human T lymphocytes but will only proceed into active virus infection after the T cells receive activation signals. MYXV-infected T lymphocytes exhibited impaired proliferation after activation with reduced expression of interferon-γ, interleukin-2 (IL-2), and soluble IL-2Rα, but did not affect expression of IL-4 and IL-10. MYXV suppressed T-cell proliferation in 2 patterns (full vs partial) depending on the donor. In terms of GVM, we show that MYXV-infected activated human T lymphocytes effectively deliver live oncolytic virus to human multiple myeloma cells, thus augmenting GVM by transfer of active oncolytic virus to residual cancer cells. Given this dual capacity of reducing GVHD plus increasing the antineoplastic effectiveness of GVM, ex vivo virotherapy with MYXV may be a promising clinical adjunct to allo-HCT regimens.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine.
authors.forename: Nancy Y
authors.initials: NY
authors.lastname: Villa
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, and.
authors.forename: Clive H
authors.initials: CH
authors.lastname: Wasserfall
authors.affiliation: Division of Hematology and Oncology, Department of Medicine.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Meacham
authors.affiliation: Division of Hematology and Oncology, Department of Medicine.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wise
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL.
authors.forename: Winnie
authors.initials: W
authors.lastname: Chan
authors.affiliation: Division of Hematology and Oncology, Department of Medicine.
authors.forename: John R
authors.initials: JR
authors.lastname: Wingard
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL.
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
authors.affiliation: Division of Hematology and Oncology, Department of Medicine.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Cogle
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D006086:Graft vs Host Disease / Q000276:immunology / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008213:Lymphocyte Activation; D009101:Multiple Myeloma / Q000628:therapy*; D009233:Myxoma virus / Q000276:immunology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000276:immunology*; D011213:Poxviridae Infections / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D014412:Tumor Virus Infections / Q000276:immunology