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Published on: November 12, 2019
Different mechanisms of CD200-CD200R induce diverse outcomes in cancer treatment
Kang-Ling Liao1, Kenton D Watt1, Tom Protin2
1Department of Mathematics, University of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada.
Abstract:
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.
Insights
The CD200-CD200R immune checkpoint has opposing roles in different cancers. Mathematical models reveal distinct mechanisms driving CD200 blockade efficacy, impacting combination cancer immunotherapies.
Area of Science:
- Immunology
- Oncology
- Computational Biology
Background:
- The CD200-CD200R axis, involving a cell membrane protein on tumor cells and its receptor on immune cells, acts as an immune checkpoint.
- CD200-CD200R interaction typically inhibits immune cell function, making its blockade a potential cancer therapeutic strategy.
- However, CD200 blockade exhibits varied outcomes across different cancer types, suggesting context-dependent mechanisms.
Purpose of the Study:
- To investigate the hypothesis that differing CD200-CD200R mechanisms within the tumor microenvironment explain diverse CD200 blockade treatment outcomes.
- To develop and utilize Ordinary Differential Equations (ODEs) models to simulate CD200-CD200R's role in melanoma and pancreatic ductal adenocarcinoma (PDAC)/head and neck squamous cell carcinoma (HNSCC).
- To evaluate the efficacy of combined CD200-CD200R blockade and anti-PD-1 immunotherapy across different cancer models.
Main Methods:
- Construction of two distinct ODE models: one for melanoma (incorporating CCL8 inhibition, regulatory T cells, and M2-to-M1 macrophage switching) and another for PDAC/HNSCC (focusing on M2 macrophage polarization and suppressive activity promotion).
- Simulation of CD200-CD200R blockade and anti-PD-1 combination therapies using the developed ODE models.
- Analysis of the impact of CD200-CD200R on specific immune cell populations (M1/M2 macrophages, dendritic cells, regulatory T cells) in different cancer contexts.
Main Results:
- The CD200-CD200R blockade effectively reduced tumor load in melanoma by inhibiting M1 macrophages and dendritic cells, not M2 macrophages.
- In PDAC and HNSCC, CD200-CD200R signaling promoted tumor growth; combination therapy with anti-PD-1 and CD200 knockout decreased tumor load.
- Distinct ODE models demonstrated that the differential mechanisms of CD200-CD200R signaling lead to varied responses in combination immunotherapies.
Conclusions:
- The context-dependent mechanisms of CD200-CD200R signaling in the tumor microenvironment are critical determinants of CD200 blockade efficacy.
- Mathematical modeling provides a powerful tool for dissecting complex immune interactions and predicting therapeutic outcomes in cancer.
- Tailoring combination immunotherapies based on the specific roles of immune checkpoints like CD200-CD200R is essential for optimizing treatment strategies.
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