Dataset Information

Yu2019 - A mathematical model of tumor-immune interactions with an immune checkpoint inhibitor

ABSTRACT: This is a mathematical model investigating interactions among malignant tumor cells, CD4+ T cells, anti-tumor cytokines (specifically IFN-gamma), and the immune checkpoint inhibitor CTLA-4 to assess the importance of immune checkpoints in mediating tumor regression.

SUBMITTER: Johannes Meyer

PROVIDER: MODEL1911270002 | BioModels | 2024-12-09

REPOSITORIES: BioModels

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	MODEL1911270002?filename=Yu2019.cps	Other
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Publications

Modeling anti-tumor Th1 and Th2 immunity in the rejection of melanoma.

Eftimie Raluca R Bramson Jonathan L JL Earn David J D DJ

Journal of theoretical biology 20100505 3

Recent experiments indicate that CD4(+) Th2 cells can reject skin tumors in mice, while CD4(+) Th1 cells cannot (Mattes et al., 2003; Zhang et al., 2009). These results are surprising because CD4(+) Th1 cells are typically considered to be capable of tumor rejection. We used mathematical models to investigate this unexpected outcome. We found that neither CD4(+) Th1 nor CD4(+) Th2 cells could eliminate the cancer cells when acting alone, but that tumor elimination could be induced by recruitment ...[more]

PMID: 20450922

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Project description:Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1/PD-L1 or CTLA4 have revolutionized cancer management but are associated with devastating immune-related adverse events (irAEs) including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI-myocarditis is often fulminant and is pathophysiologically characterized by myocardial infiltration of T lymphocytes and macrophages. While much has been learned regarding the role of T-cells in ICI-myocarditis, little is understood regarding the identity, transcriptional diversity, and functions of infiltrating macrophages. We employed an established murine ICI myocarditis model (Ctla4+/-Pdcd1-/- mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, and molecular imaging. We observed marked increases in CCR2+ monocyte-derived macrophages and CD8+ T-cells in this model. The macrophage compartment was heterogeneous and displayed marked enrichment in an inflammatory CCR2+ subpopulation expressing Cxcl9, Cxcl10, Gbp2b, and Fcgr4 that originated from CCR2+ monocytes. Importantly, a similar macrophage population expressing CXCL9, CXCL10, and CD16α (human homologue of mouse FcgR4) were found selectively in patients with ICI myocarditis compared to other forms of heart failure and myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and Cxcl9+Cxcl10+ macrophages via IFN-γ and CXCR3 signaling pathways. Depleting CD8+T-cells and blockade of IFN-γ signaling blunted the emergence of Cxcl9+Cxcl10+ macrophages in the heart and attenuated myocarditis suggesting that this interaction was necessary for disease pathogenesis. Collectively, these data demonstrate that ICI-myocarditis is associated with the emergence of a specific population of inflammatory macrophages and suggest the possibility that IFN-γ blockade may serve as an effective treatment for this devastating condition.