Department of Mathematics, University of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada.
Department of Mathematics, University of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada.
Math Biosci. 2023 Nov;365:109072. doi: 10.1016/j.mbs.2023.109072. Epub 2023 Sep 19.
The CD200 is a cell membrane protein expressed by tumor cells, and its receptor CD200 receptor (CD200R) is expressed by immune cells including macrophages and dendritic cells. The formation of CD200-CD200R inhibits the cellular functions of the targeted immune cells, so CD200 is one type of the immune checkpoint and blockade CD200-CD200R formation is a potential cancer treatment. However, the CD200 blockade has opposite treatment outcomes in different types of cancers. For instance, the CD200R deficient mice have a higher tumor load than the wild type (WT) mice in melanoma suggesting that CD200-CD200R inhibits melanoma. On the other hand, the antibody anti-CD200 treatment in pancreatic ductal adenocarcinoma (PDAC) and head and neck squamous cell carcinoma (HNSCC) significantly reduces the tumor load indicating that CD200-CD200R promotes PDAC and HNSCC. In this work, we hypothesize that different mechanisms of CD200-CD200R in tumor microenvironment could be one of the reasons for the diverse treatment outcomes of CD200 blockade in different types of cancers. We create one Ordinary Differential Equations (ODEs) model for melanoma including the inhibition of CCL8 and regulatory T cells and the switching from M2 to M1 macrophages by CD200-CD200R to capture the tumor inhibition by CD200-CD200R. We also create another ODEs model for PDAC and HNSCC including the promotion of the polarization and suppressive activities of M2 macrophages by CD200-CD200R to generate the tumor promotion by CD200-CD200R. Furthermore, we use these two models to investigate the treatment efficacy of the combination treatment between the CD200-CD200R blockade and the other immune checkpoint inhibitor, anti-PD-1. Our result shows that different mechanisms of CD200-CD200R can induce different treatment outcomes in combination treatments, namely, only the CD200-CD200R blockade reduces tumor load in melanoma and only the anti-PD-1 and CD200 knockout decrease tumor load in PDAC and HNSCC. Moreover, in melanoma, the CD200-CD200R mainly utilizes the inhibitions on M1 macrophages and dendritic cells to inhibit tumor growth, instead of M2 macrophages.
CD200 是一种肿瘤细胞表面蛋白，其受体 CD200 受体 (CD200R) 则表达于包括巨噬细胞和树突状细胞在内的免疫细胞表面。CD200-CD200R 的形成抑制了靶向免疫细胞的细胞功能，因此 CD200 是一种免疫检查点，阻断 CD200-CD200R 的形成是一种潜在的癌症治疗方法。然而，CD200 阻断在不同类型的癌症中具有相反的治疗效果。例如，在黑色素瘤中，CD200R 缺陷型小鼠的肿瘤负荷高于野生型 (WT) 小鼠，这表明 CD200-CD200R 抑制了黑色素瘤。另一方面，抗 CD200 抗体在胰腺导管腺癌 (PDAC) 和头颈部鳞状细胞癌 (HNSCC) 中的治疗显著降低了肿瘤负荷，表明 CD200-CD200R 促进了 PDAC 和 HNSCC。在这项工作中，我们假设 CD200-CD200R 在肿瘤微环境中的不同作用机制可能是 CD200 阻断在不同类型癌症中治疗效果不同的原因之一。我们为黑色素瘤创建了一个常微分方程 (ODE) 模型，其中包括 CD200-CD200R 抑制 CCL8 和调节性 T 细胞以及从 M2 向 M1 巨噬细胞的转换，以捕获 CD200-CD200R 对肿瘤的抑制作用。我们还为 PDAC 和 HNSCC 创建了另一个 ODE 模型，其中包括 CD200-CD200R 促进 M2 巨噬细胞的极化和抑制活性，以产生 CD200-CD200R 对肿瘤的促进作用。此外，我们使用这两个模型来研究 CD200-CD200R 阻断与其他免疫检查点抑制剂抗 PD-1 联合治疗的治疗效果。我们的结果表明，CD200-CD200R 的不同作用机制会在联合治疗中引起不同的治疗效果，即只有 CD200-CD200R 阻断会降低黑色素瘤中的肿瘤负荷，只有抗 PD-1 和 CD200 敲除会降低 PDAC 和 HNSCC 中的肿瘤负荷。此外，在黑色素瘤中，CD200-CD200R 主要通过抑制 M1 巨噬细胞和树突状细胞来抑制肿瘤生长，而不是 M2 巨噬细胞。
