表皮间质转化（EMT）以及通过程序性死亡配体1（PD-L1）上调介导的免疫抵抗，是肿瘤进展的确立驱动因素。它们之间的双向互作据称能够促进肿瘤免疫逃逸，然而免疫抑制和空间异质性对于这些过程之间相互作用的影响仍需进一步研究。在本文中，我们使用数学模型和空间模型来研究这些因素的作用。首先，我们设计了模型，将通过PD-L1介导的PD-L1（T细胞）的免疫抑制效应和诱导EMT的细胞因子转化生长因子β（TGFβ）纳入其中。我们的模型预测，PD-L1介导的免疫抑制仅仅减少了EMT状态下PD-L1水平的差异，而TGFβ介导的抑制还导致PD-L1表达在每个EMT表型中与TGFβ呈负相关。随后，我们将这些模型嵌入多尺度空间模拟中，以明确描述细胞因子水平和肿瘤内异质性之间的差异。我们的多尺度模型表明，干扰素γ（IFNγ）诱导的肿瘤细胞亚群的部分EMT可以为旁观者提供一些有限的保护。此外，我们的模拟结果显示，在人群水平上，EMT状态和PD-L1表达之间的真实关系可能被隐藏起来，强调了在单个细胞水平研究EMT和PD-L1状态的重要性。我们的研究结果深化了对EMT和免疫反应之间相互作用的理解，这对于开发癌症患者的新诊断和治疗方法至关重要。版权所有 © 2023 Lems, Burger and Beltman.

Epithelial-mesenchymal transition (EMT) and immune resistance mediated by Programmed Death-Ligand 1 (PD-L1) upregulation are established drivers of tumor progression. Their bi-directional crosstalk has been proposed to facilitate tumor immunoevasion, yet the impact of immunosuppression and spatial heterogeneity on the interplay between these processes remains to be characterized. Here we study the role of these factors using mathematical and spatial models. We first designed models incorporating immunosuppressive effects on T cells mediated via PD-L1 and the EMT-inducing cytokine Transforming Growth Factor beta (TGFβ). Our models predict that PD-L1-mediated immunosuppression merely reduces the difference in PD-L1 levels between EMT states, while TGFβ-mediated suppression also causes PD-L1 expression to correlate negatively with TGFβ within each EMT phenotype. We subsequently embedded the models in multi-scale spatial simulations to explicitly describe heterogeneity in cytokine levels and intratumoral heterogeneity. Our multi-scale models show that Interferon gamma (IFNγ)-induced partial EMT of a tumor cell subpopulation can provide some, albeit limited protection to bystander tumor cells. Moreover, our simulations show that the true relationship between EMT status and PD-L1 expression may be hidden at the population level, highlighting the importance of studying EMT and PD-L1 status at the single-cell level. Our findings deepen the understanding of the interactions between EMT and the immune response, which is crucial for developing novel diagnostics and therapeutics for cancer patients.Copyright © 2023 Lems, Burger and Beltman.