Lymphoma cell apoptosis in the liver induced by distant murine cytomegalovirus infection.
Cytomegalovirus (CMV) poses a threat to the therapy of hematopoietic malignancies by hematopoietic stem cell transplantation, but efficient reconstitution of antiviral immunity prevents CMV organ disease. Tumor relapse originating from a minimal residual leukemia poses another threat. Although a combination of risk factors was supposed to enhance the incidence and severity of transplantation-associated disease, a murine model of a liver-adapted B-cell lymphoma has previously shown a survival benefit and tumor growth inhibition by nonlethal subcutaneous infection with murine CMV. Here we have investigated the underlying antitumoral mechanism. Virus replication proved to be required, since inactivated virions or the highly attenuated enhancerless mutant mCMV-DeltaMIEenh did not impact the lymphoma in the liver. Surprisingly, the dissemination-deficient mutant mCMV-DeltaM36 inhibited tumor growth, even though this virus fails to infect the liver. On the other hand, various strains of herpes simplex viruses consistently failed to control the lymphoma, even though they infect the liver. A quantitative analysis of the tumor growth kinetics identified a transient tumor remission by apoptosis as the antitumoral effector mechanism. Tumor cell colonies with cells surviving the CMV-induced "apoptotic crisis" lead to tumor relapse even in the presence of full-blown tissue infection. Serial transfer of surviving tumor cells did not indicate a selection of apoptosis-resistant genetic variants. NK cell activity of CD49b-expressing cells failed to control the lymphoma upon adoptive transfer. We propose the existence of an innate antitumoral mechanism that is triggered by CMV infection and involves an apoptotic signal effective at a distant site of tumor growth.
Erlach
Katja C
KC
Institute for Virology, Johannes Gutenberg-University, Mainz, Germany.
Böhm
Verena
V
Seckert
Christof K
CK
Reddehase
Matthias J
MJ
Podlech
Jürgen
J
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006566:Herpesviridae Infections / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000473:pathology* / Q000821:virology; D008223:Lymphoma / Q000473:pathology* / Q000821:virology; D016393:Lymphoma, B-Cell / Q000401:mortality / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000401:mortality / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D018146:Muromegalovirus / Q000235:genetics / Q000276:immunology*; D041681:NIH 3T3 Cells; D017354:Point Mutation