CD200是一种由肿瘤细胞表达的细胞膜蛋白，而其受体CD200受体（CD200R）则由包括巨噬细胞和树突状细胞在内的免疫细胞表达。CD200-CD200R的形成抑制了目标免疫细胞的细胞功能，因此CD200是一种免疫检查点，并且阻断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结果。例如，CD200R缺乏的小鼠在黑色素瘤中具有比野生型小鼠更高的肿瘤负荷，这表明CD200-CD200R抑制了黑色素瘤的发展。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）中的治疗明显减少了肿瘤负荷，表明CD200-CD200R促进了PDAC和HNSCC的发展。在这项工作中，我们假设CD200-CD200R在肿瘤微环境中的不同机制可能是不同类型癌症中CD200阻断治疗结果多样性的原因之一。我们为黑色素瘤创建了一个包括抑制CCL8和调节性T细胞以及通过CD200-CD200R从M2到M1巨噬细胞的转化来捕捉CD200-CD200R抑制肿瘤的常微分方程（ODEs）模型。我们还为PDAC和HNSCC创建了另一个包括通过CD200-CD200R促进M2巨噬细胞的极化和抑制活性来产生CD200-CD200R促进肿瘤的ODEs模型。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如抗PD-1的组合治疗的治疗效果。我们的结果显示，CD200-CD200R的不同机制可以在组合治疗中引起不同的治疗结果，即只有CD200-CD200R阻断能减少黑色素瘤的肿瘤负荷，只有抗PD-1和CD200敲除能减少PDAC和HNSCC的肿瘤负荷。此外，在黑色素瘤中，CD200-CD200R主要利用对M1巨噬细胞和树突状细胞的抑制来抑制肿瘤生长，而不是对M2巨噬细胞的抑制。 版权所有 © 2023 Elsevier Inc. 保留所有权利。

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 inhibits tumor growth, instead of M2 macrophages.Copyright © 2023 Elsevier Inc. All rights reserved.