In this paper, we investigate how natural killer (NK) cell recruitment to the tumor microenvironment (TME) affects oncolytic virotherapy. NK cells play a major role against viral infections. They are, however, known to induce early viral clearance of oncolytic viruses, which hinders the overall efficacy of oncolytic virotherapy. Here, we formulate and analyze a simple mathematical model of the dynamics of the tumor, OV and NK cells using currently available preclinical information. The aim of this study is to characterize conditions under which the synergistic balance between OV-induced NK responses and required viral cytopathicity may or may not result in a successful treatment. In this study, we found that NK cell recruitment to the TME must take place neither too early nor too late in the course of OV infection so that treatment will be successful. NK cell responses are most influential at either early (partly because of rapid response of NK cells to viral infections or antigens) or later (partly because of antitumoral ability of NK cells) stages of oncolytic virotherapy. The model also predicts that: (a) an NK cell response augments oncolytic virotherapy only if viral cytopathicity is weak; (b) the recruitment of NK cells modulates tumor growth; and (c) the depletion of activated NK cells within the TME enhances the probability of tumor escape in oncolytic virotherapy. Taken together, our model results demonstrate that OV infection is crucial, not just to cytoreduce tumor burden, but also to induce the stronger NK cell response necessary to achieve complete or at least partial tumor remission. Furthermore, our modeling framework supports combination therapies involving NK cells and OV which are currently used in oncolytic immunovirotherapy to treat several cancer types.

在本文中，我们研究了自然杀伤 (NK) 细胞向肿瘤微环境 (TME) 的募集如何影响溶瘤病毒疗法。NK 细胞在对抗病毒感染方面发挥着重要作用。然而，已知它们会诱导溶瘤病毒的早期病毒清除，这阻碍了溶瘤病毒疗法的整体功效。在这里，我们使用当前可用的临床前信息来制定和分析肿瘤、OV 和 NK 细胞动力学的简单数学模型。本研究的目的是描述 OV 诱导的 NK 反应和所需的病毒细胞病变之间的协同平衡可能会或可能不会导致成功治疗的条件。在这项研究中，我们发现 NK 细胞向 TME 的募集必须在 OV 感染过程中既不能太早也不能太晚，以便治疗成功。NK 细胞反应在溶瘤病毒疗法的早期（部分因为 NK 细胞对病毒感染或抗原的快速反应）或后期（部分因为 NK 细胞的抗肿瘤能力）最具影响力。该模型还预测：（a）仅当病毒致细胞病变较弱时，NK 细胞反应才会增强溶瘤病毒疗法；(b) NK 细胞的募集调节肿瘤生长；(c) TME 内活化 NK 细胞的消耗增加了溶瘤病毒治疗中肿瘤逃逸的可能性。综上所述，我们的模型结果表明 OV 感染至关重要，不仅仅是为了减少肿瘤负荷，还可以诱导更强的 NK 细胞反应，以实现完全或至少部分肿瘤缓解。此外，我们的建模框架支持涉及 NK 细胞和 OV 的联合疗法，这些疗法目前用于溶瘤免疫病毒疗法来治疗多种癌症类型。