Erlach Katja C, Böhm Verena, Seckert Christof K, Reddehase Matthias J, Podlech Jürgen
Institute for Virology, Johannes Gutenberg-University, Mainz, Germany.
J Virol. 2006 May;80(10):4801-19. doi: 10.1128/JVI.80.10.4801-4819.2006.
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.
巨细胞病毒（CMV）对造血干细胞移植治疗造血系统恶性肿瘤构成威胁，但抗病毒免疫的有效重建可预防CMV器官疾病。源自微小残留白血病的肿瘤复发构成了另一个威胁。尽管多种危险因素的组合被认为会增加移植相关疾病的发生率和严重程度，但先前一种肝脏适应性B细胞淋巴瘤的小鼠模型显示，通过非致死性皮下感染鼠CMV可带来生存益处并抑制肿瘤生长。在此我们研究了潜在的抗肿瘤机制。事实证明病毒复制是必需的，因为灭活的病毒粒子或高度减毒的无增强子突变体mCMV-ΔMIEenh对肝脏中的淋巴瘤没有影响。令人惊讶的是，传播缺陷型突变体mCMV-ΔM36抑制了肿瘤生长，尽管这种病毒无法感染肝脏。另一方面，各种单纯疱疹病毒株始终无法控制淋巴瘤，尽管它们可感染肝脏。对肿瘤生长动力学的定量分析确定，通过凋亡导致的短暂肿瘤缓解是抗肿瘤效应机制。即使在存在严重组织感染的情况下，具有在CMV诱导的“凋亡危机”中存活下来的细胞的肿瘤细胞集落也会导致肿瘤复发。存活肿瘤细胞的连续传代并未表明选择了抗凋亡的遗传变体。表达CD49b的细胞的NK细胞活性在过继转移后无法控制淋巴瘤。我们提出存在一种先天性抗肿瘤机制，该机制由CMV感染触发，涉及在肿瘤生长远处有效的凋亡信号。
