Storey Kathleen M, Lawler Sean E, Jackson Trachette L
Department of Mathematics, University of Michigan, Ann Arbor, MI, United States.
Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, United States.
Front Physiol. 2020 Mar 3;11:151. doi: 10.3389/fphys.2020.00151. eCollection 2020.
Oncolytic viruses are of growing interest to cancer researchers and clinicians, due to their selectivity for tumor cells over healthy cells and their immunostimulatory properties. The immune response to an oncolytic virus plays a critical role in treatment efficacy. However, uncertainty remains regarding the circumstances under which the immune system either assists in eliminating tumor cells or inhibits treatment via rapid viral clearance, leading to the cessation of the immune response. In this work, we develop an ordinary differential equation model of treatment for a lethal brain tumor, glioblastoma, using an oncolytic Herpes Simplex Virus. We use a mechanistic approach to model the interactions between distinct populations of immune cells, incorporating both innate and adaptive immune responses to oncolytic viral therapy (OVT), and including a mechanism of adaptive immune suppression via the PD-1/PD-L1 checkpoint pathway. We focus on the tradeoff between viral clearance by innate immune cells and the innate immune cell-mediated recruitment of antiviral and antitumor adaptive immune cells. Our model suggests that when a tumor is treated with OVT alone, the innate immune cells' ability to clear the virus quickly after administration has a much larger impact on the treatment outcome than the adaptive immune cells' antitumor activity. Even in a highly antigenic tumor with a strong innate immune response, the faster recruitment of antitumor adaptive immune cells is not sufficient to offset the rapid viral clearance. This motivates our subsequent incorporation of an immunotherapy that inhibits the PD-1/PD-L1 checkpoint pathway by blocking PD-1, which we combine with OVT within the model. The combination therapy is most effective for a highly antigenic tumor or for intermediate levels of innate immune localization. Extreme levels of innate immune cell activity either clear the virus too quickly or fail to activate a sufficiently strong adaptive response, yielding ineffective combination therapy of GBM. Hence, we show that the innate and adaptive immune interactions significantly influence treatment response and that combining OVT with an immune checkpoint inhibitor expands the range of immune conditions that allow for tumor size reduction or clearance.
由于溶瘤病毒对肿瘤细胞比对健康细胞具有选择性以及其免疫刺激特性，癌症研究人员和临床医生对其兴趣日益浓厚。对溶瘤病毒的免疫反应在治疗效果中起着关键作用。然而，免疫系统在何种情况下协助消除肿瘤细胞或通过快速清除病毒抑制治疗从而导致免疫反应停止，仍存在不确定性。在这项工作中，我们使用溶瘤单纯疱疹病毒开发了一种针对致命性脑肿瘤胶质母细胞瘤的治疗常微分方程模型。我们采用一种机制方法来模拟不同免疫细胞群体之间的相互作用，纳入对溶瘤病毒疗法（OVT）的先天和适应性免疫反应，并包括通过PD-1/PD-L1检查点途径进行适应性免疫抑制的机制。我们关注先天免疫细胞清除病毒与先天免疫细胞介导的抗病毒和抗肿瘤适应性免疫细胞募集之间的权衡。我们的模型表明，当仅用OVT治疗肿瘤时，给药后先天免疫细胞快速清除病毒的能力对治疗结果的影响比适应性免疫细胞的抗肿瘤活性大得多。即使在具有强烈先天免疫反应的高抗原性肿瘤中，抗肿瘤适应性免疫细胞的更快募集也不足以抵消病毒的快速清除。这促使我们随后纳入一种通过阻断PD-1抑制PD-1/PD-L1检查点途径的免疫疗法，并在模型中将其与OVT联合使用。联合疗法对高抗原性肿瘤或先天免疫定位处于中等水平时最为有效。先天免疫细胞活性的极端水平要么使病毒清除过快，要么无法激活足够强的适应性反应，导致GBM联合治疗无效。因此，我们表明先天和适应性免疫相互作用显著影响治疗反应，并且将OVT与免疫检查点抑制剂联合使用扩大了允许肿瘤缩小或清除的免疫条件范围。
