Department of Mathematics and Computer Science, National University of Lesotho, Roma, Maseru, Lesotho.
The College of Saint Rose, Albany, NY, USA.
Bull Math Biol. 2021 May 18;83(7):75. doi: 10.1007/s11538-021-00903-6.
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.
本文研究了自然杀伤 (NK) 细胞向肿瘤微环境 (TME) 的募集如何影响溶瘤病毒治疗。NK 细胞在对抗病毒感染方面发挥着重要作用。然而，它们也被认为会导致溶瘤病毒的早期清除，从而阻碍溶瘤病毒治疗的整体效果。在这里，我们使用目前可用的临床前信息，构建并分析了肿瘤、OV 和 NK 细胞动态的简单数学模型。本研究的目的是确定在何种条件下，OV 诱导的 NK 反应与所需病毒细胞病变之间的协同平衡可能或不可能导致成功的治疗。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治疗的早期（部分原因是 NK 细胞对病毒感染或抗原的快速反应）或晚期（部分原因是 NK 细胞的抗肿瘤能力）最为重要。该模型还预测：(a) 只有当病毒细胞病变较弱时，NK 细胞反应才会增强溶瘤病毒治疗；(b) NK 细胞的募集调节肿瘤生长；(c) TME 中激活的 NK 细胞耗竭会增加溶瘤病毒治疗中肿瘤逃逸的可能性。总之，我们的模型结果表明，OV 感染不仅对于减少肿瘤负担至关重要，而且对于诱导必要的更强的 NK 细胞反应以实现完全或至少部分肿瘤缓解也至关重要。此外，我们的建模框架支持包括 NK 细胞和 OV 的联合治疗，目前用于溶瘤免疫病毒治疗几种癌症类型。
