Tumor control in a model of bone marrow transplantation and acute liver-infiltrating B-cell lymphoma: an unpredicted novel function of cytomegalovirus.
Tumor relapse and cytomegalovirus (CMV) infection are major concerns in the therapy of hematopoietic malignancies by bone marrow transplantation (BMT). Little attention so far has been given to a possible pathogenetic interplay between CMV and lymphomas. CMV inhibits stem cell engraftment and hematopoietic reconstitution. Thus, by causing maintenance of bone marrow aplasia and immunodeficiency, CMV could promote tumor relapse. Alternatively, CMV could aid tumor remission. One might think of cytopathogenic infection of tumor cells, induction of apoptosis or inhibitory cytokines, interference with tumor cell extravasation or tumor vascularization, or bystander stimulation of an antitumoral immune response. To approach these questions, the established model of experimental BMT and murine CMV infection was extended by the introduction of liver-infiltrating, highly tumorigenic variant clone E12E of BALB/c-derived B-cell lymphoma A20. We document a remarkable retardation of lymphoma progression. First-guess explanations were ruled out: (i) lymphoma cells were not infected; (ii) lymphoma cells located next to infected hepatocytes did not express executioner caspase 3 but were viable and proliferated; (iii) an inhibitory effect of virus on the formation of tumor nodules in the liver became apparent by day 7 after BMT, long before the reconstitution of immune cells; and (iv) recombinant tumor necrosis factor alpha (TNF-alpha) did not substitute for virus; accordingly anti-TNF-alpha did not prevent the inhibition. Notably, while the antitumoral effect required replicative virus, prevention of cytopathogenic infection of the liver by antiviral CD8 T cells did not abolish lymphoma control. These findings are paradigmatic for a novel virus-associated antitumoral mechanism distinct from oncolysis.
Erlach
Katja C
KC
Institute for Virology, Johannes Gutenberg-University, 55101 Mainz, Germany.
Podlech
Jürgen
J
Rojan
Aysel
A
Reddehase
Matthias J
MJ
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D004195:Disease Models, Animal; D008099:Liver / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha