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Inhibiting efferocytosis reverses macrophage-mediated immunosuppression in the leukemia microenvironment

BACKGROUND: Previous studies show that the spleen and bone marrow can serve as leukemia microenvironments in which macrophages play a significant role in immune evasion and chemoresistance. We hypothesized that the macrophage driven tolerogenic process of efferocytosis is a major contributor to the...

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Detalles Bibliográficos
Autores principales: Cruz Cruz, Joselyn, Allison, Kristen C., Page, Lauren S., Jenkins, Alexis J., Wang, Xiaodong, Earp, H. Shelton, Frye, Stephen V., Graham, Douglas K., Verneris, Michael R., Lee-Sherick, Alisa B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10027704/
https://www.ncbi.nlm.nih.gov/pubmed/36960055
http://dx.doi.org/10.3389/fimmu.2023.1146721
Descripción
Sumario:BACKGROUND: Previous studies show that the spleen and bone marrow can serve as leukemia microenvironments in which macrophages play a significant role in immune evasion and chemoresistance. We hypothesized that the macrophage driven tolerogenic process of efferocytosis is a major contributor to the immunosuppressive leukemia microenvironment and that this was driven by aberrant phosphatidylserine expression from cell turnover and cell membrane dysregulation. METHODS: Since MerTK is the prototypic efferocytosis receptor, we assessed whether the MerTK inhibitor MRX2843, which is currently in clinical trials, would reverse immune evasion and enhance immune-mediated clearance of leukemia cells. RESULTS: We found that inhibition of MerTK decreased leukemia-associated macrophage expression of M2 markers PD-L1, PD-L2, Tim-3, CD163 and Arginase-1 compared to vehicle-treated controls. Additionally, MerTK inhibition led to M1 macrophage repolarization including elevated CD86 and HLA-DR expression, and increased production of T cell activating cytokines, including IFN-β, IL-18, and IL-1β through activation of NF-κB. Collectively, this macrophage repolarization had downstream effects on T cells within the leukemia microenvironment, including decreased PD-1(+)Tim-3(+) and LAG3(+) checkpoint expression, and increased CD69(+)CD107a(+) expression. DISCUSSION: These results demonstrate that MerTK inhibition using MRX2843 altered the leukemia microenvironment from tumor-permissive toward immune responsiveness to leukemia and culminated in improved immune-mediated clearance of AML.