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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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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
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author 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.
author_facet 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.
author_sort Cruz Cruz, Joselyn
collection PubMed
description 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.
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spelling pubmed-100277042023-03-22 Inhibiting efferocytosis reverses macrophage-mediated immunosuppression in the leukemia microenvironment 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. Front Immunol Immunology 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. Frontiers Media S.A. 2023-03-07 /pmc/articles/PMC10027704/ /pubmed/36960055 http://dx.doi.org/10.3389/fimmu.2023.1146721 Text en Copyright © 2023 Cruz Cruz, Allison, Page, Jenkins, Wang, Earp, Frye, Graham, Verneris and Lee-Sherick https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
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.
Inhibiting efferocytosis reverses macrophage-mediated immunosuppression in the leukemia microenvironment
title Inhibiting efferocytosis reverses macrophage-mediated immunosuppression in the leukemia microenvironment
title_full Inhibiting efferocytosis reverses macrophage-mediated immunosuppression in the leukemia microenvironment
title_fullStr Inhibiting efferocytosis reverses macrophage-mediated immunosuppression in the leukemia microenvironment
title_full_unstemmed Inhibiting efferocytosis reverses macrophage-mediated immunosuppression in the leukemia microenvironment
title_short Inhibiting efferocytosis reverses macrophage-mediated immunosuppression in the leukemia microenvironment
title_sort inhibiting efferocytosis reverses macrophage-mediated immunosuppression in the leukemia microenvironment
topic Immunology
url 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
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