Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
J Virol. 2019 Sep 30;93(20). doi: 10.1128/JVI.00533-19. Print 2019 Oct 15.
Cytomegalovirus (CMV) is a ubiquitous betaherpesvirus that infects many different cell types. Human CMV (HCMV) has been found in several solid tumors, and it has been hypothesized that it may promote cellular transformation or exacerbate tumor growth. Paradoxically, in some experimental situations, murine CMV (MCMV) infection delays tumor growth. We previously showed that wild-type MCMV delayed the growth of poorly immunogenic B16 melanomas via an undefined mechanism. Here, we show that MCMV delayed the growth of these immunologically "cold" tumors by recruiting and modulating tumor-associated macrophages. Depletion of monocytic phagocytes with clodronate completely prevented MCMV from delaying tumor growth. Mechanistically, our data suggest that MCMV recruits new macrophages to the tumor via the virus-encoded chemokine MCK2, and viruses lacking this chemokine were unable to delay tumor growth. Moreover, MCMV infection of macrophages drove them toward a proinflammatory (M1)-like state. Importantly, adaptive immune responses were also necessary for MCMV to delay tumor growth as the effect was substantially blunted in Rag-deficient animals. However, viral spread was not needed and a spread-defective MCMV strain was equally effective. In most mice, the antitumor effect of MCMV was transient. Although the recruited macrophages persisted, tumor regrowth correlated with a loss of viral activity in the tumor. However, an additional round of MCMV infection further delayed tumor growth, suggesting that tumor growth delay was dependent on active viral infection. Together, our results suggest that MCMV infection delayed the growth of an immunologically cold tumor by recruiting and modulating macrophages in order to promote anti-tumor immune responses. Cytomegalovirus (CMV) is an exciting new platform for vaccines and cancer therapy. Although CMV may delay tumor growth in some settings, there is also evidence that CMV may promote cancer development and progression. Thus, defining the impact of CMV on tumors is critical. Using a mouse model of melanoma, we previously found that murine CMV (MCMV) delayed tumor growth and activated tumor-specific immunity although the mechanism was unclear. We now show that MCMV delayed tumor growth through a mechanism that required monocytic phagocytes and a viral chemokine that recruited macrophages to the tumor. Furthermore, MCMV infection altered the functional state of macrophages. Although the effects of MCMV on tumor growth were transient, we found that repeated MCMV injections sustained the antitumor effect, suggesting that active viral infection was needed. Thus, MCMV altered tumor growth by actively recruiting macrophages to the tumor, where they were modulated to promote antitumor immunity.
巨细胞病毒（CMV）是一种普遍存在的β疱疹病毒，可感染多种不同的细胞类型。人类巨细胞病毒（HCMV）已在几种实体瘤中发现，有人假设它可能促进细胞转化或加剧肿瘤生长。矛盾的是，在某些实验情况下，鼠巨细胞病毒（MCMV）感染会延迟肿瘤生长。我们之前曾表明，野生型 MCMV 通过未定义的机制延迟了免疫原性差的 B16 黑色素瘤的生长。在这里，我们表明 MCMV 通过招募和调节肿瘤相关巨噬细胞来延迟这些免疫“冷”肿瘤的生长。用 clodronate 耗尽单核吞噬细胞完全阻止了 MCMV 延迟肿瘤生长。从机制上讲，我们的数据表明，MCMV 通过病毒编码的趋化因子 MCK2 将新的巨噬细胞募集到肿瘤中，并且缺乏这种趋化因子的病毒无法延迟肿瘤生长。此外，MCMV 感染巨噬细胞使其向促炎（M1）样状态发展。重要的是，适应性免疫反应对于 MCMV 延迟肿瘤生长也是必需的，因为在 Rag 缺陷动物中，这种作用大大减弱。然而，病毒传播不是必需的，并且传播缺陷型 MCMV 株同样有效。在大多数小鼠中，MCMV 的抗肿瘤作用是短暂的。尽管招募的巨噬细胞持续存在，但肿瘤的重新生长与肿瘤中病毒活性的丧失相关。然而，第二轮 MCMV 感染进一步延迟了肿瘤生长，这表明肿瘤生长延迟依赖于病毒的活性感染。总之，我们的结果表明，MCMV 通过招募和调节巨噬细胞来延迟免疫“冷”肿瘤的生长，以促进抗肿瘤免疫反应。巨细胞病毒（CMV）是疫苗和癌症治疗的一个令人兴奋的新平台。尽管 CMV 在某些情况下可能会延迟肿瘤生长，但也有证据表明 CMV 可能会促进癌症的发展和进展。因此，确定 CMV 对肿瘤的影响至关重要。我们之前使用黑色素瘤小鼠模型发现，鼠巨细胞病毒（MCMV）延迟了肿瘤生长并激活了肿瘤特异性免疫，尽管其机制尚不清楚。我们现在表明，MCMV 通过一种需要单核吞噬细胞和一种募集巨噬细胞到肿瘤的病毒趋化因子的机制来延迟肿瘤生长。此外，MCMV 感染改变了巨噬细胞的功能状态。尽管 MCMV 对肿瘤生长的影响是短暂的，但我们发现重复 MCMV 注射维持了抗肿瘤作用，这表明需要活跃的病毒感染。因此，MCMV 通过主动将巨噬细胞募集到肿瘤中，从而改变肿瘤生长，在肿瘤中对其进行调节以促进抗肿瘤免疫。
