Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
Cancer Res. 2019 Jul 1;79(13):3406-3416. doi: 10.1158/0008-5472.CAN-18-3147. Epub 2019 Apr 30.
Immunotherapies are an emerging strategy for treatment of solid tumors. Improved understanding of the mechanisms employed by cytotoxic T lymphocytes (CTL) to control tumors will aid in the development of immunotherapies. CTLs can directly kill tumor cells in a contact-dependent manner or may exert indirect effects on tumor cells via secretion of cytokines. Here, we aim to quantify the importance of these mechanisms in murine thymoma EL4/EG7 cells. We developed an agent-based model (ABM) and an ordinary differential equation model of tumor regression after adoptive transfer of a population of CTLs. Models were parameterized based on measurements of CTL infiltration and killing rates applied to EL4/EG7 tumors and OTI T cells. We quantified whether infiltrating CTLs are capable of controlling tumors through only direct, contact-dependent killing. Both models agreed that the low measured killing rate of CTLs was insufficient to cause tumor regression. In our ABM, we also simulated CTL production of the cytokine IFNγ in order to explore how an antiproliferative effect of IFNγ might aid CTLs in tumor control. In this model, IFNγ substantially reduced tumor growth compared with direct killing alone. Collectively, these data demonstrate that contact-dependent killing is insufficient for EL4 regression and highlight the potential importance of cytokine-induced antiproliferative effects in T-cell-mediated tumor control. SIGNIFICANCE: Computational modeling highlights the importance of cytokine-induced antiproliferative effects in T-cell-mediated control of tumor progression.
免疫疗法是治疗实体瘤的一种新兴策略。深入了解细胞毒性 T 淋巴细胞（CTL）控制肿瘤所采用的机制将有助于免疫疗法的发展。CTL 可以通过直接杀伤肿瘤细胞（在接触依赖性方式下）或通过分泌细胞因子对肿瘤细胞产生间接作用。在这里，我们旨在量化这些机制在小鼠胸腺瘤 EL4/EG7 细胞中的重要性。我们开发了一种基于代理的模型（ABM）和细胞毒性 T 细胞过继转移后肿瘤消退的常微分方程模型。根据 CTL 浸润和杀伤率的测量值对 EL4/EG7 肿瘤和 OTI T 细胞进行参数化。我们量化了浸润 CTL 是否能够仅通过直接的、接触依赖性的杀伤来控制肿瘤。两种模型都认为，测量到的 CTL 杀伤率很低，不足以导致肿瘤消退。在我们的 ABM 中，我们还模拟了 CTL 产生细胞因子 IFNγ，以探索 IFNγ 的抗增殖作用如何帮助 CTL 控制肿瘤。在这个模型中，IFNγ 与单独的直接杀伤相比，大大降低了肿瘤的生长。总的来说，这些数据表明，接触依赖性杀伤不足以使 EL4 消退，并强调了细胞因子诱导的抗增殖效应对 T 细胞介导的肿瘤控制的潜在重要性。意义：计算模型突出了细胞因子诱导的抗增殖效应对 T 细胞介导的肿瘤进展控制的重要性。
