Reactive oxygen species reprogram macrophages to suppress antitumor immune response through the exosomal miR-155-5p/PD-L1 pathway

dc.contributor.authorLi, Xiang
dc.contributor.authorWang, Shaomin
dc.contributor.authorMu, Wei
dc.contributor.authorBarry, Jennifer
dc.contributor.authorHan, Anna
dc.contributor.authorCarpenter, Richard L.
dc.contributor.authorJiang, Bing‑Hua
dc.contributor.authorPeiper, Stephen C.
dc.contributor.authorMahoney, Mỹ G.
dc.contributor.authorAplin, Andrew E.
dc.contributor.authorRen, Hong
dc.contributor.authorHe, Jun
dc.contributor.departmentBiochemistry and Molecular Biology, School of Medicine
dc.date.accessioned2023-05-15T10:40:53Z
dc.date.available2023-05-15T10:40:53Z
dc.date.issued2022-01-27
dc.description.abstractBackground: Cancer cells have an imbalance in oxidation-reduction (redox) homeostasis. Understanding the precise mechanisms and the impact of the altered redox microenvironment on the immunologic reaction to tumors is limited. Methods: We isolated exosomes from ovarian cancer cells through ultracentrifuge and characterized by Western-blots and Nanoparticle Tracking Analysis. 2D, 3D-coculture tumor model, and 3D live cell imaging were used to study the interactions between tumor cells, macrophages and CD3 T cells in vitro. The role of exosomal miR-155-5p in tumor growth was evaluated in xenograft nude mice models and immune-competent mice models. Flow cytometry and flow sorting were used to determine the expression levels of miR-155-5p and PD-L1 in ascites and splenic macrophages, and the percentages of CD3 T cells subpopulations. Results: The elevation of reactive oxygen species (ROS) greatly downregulated exosomal miR-155-5p expression in tumor cells. Neutralization of ROS with N-acetyl-L-cysteine (NAC) increased the levels of miR-155-5p in tumor exosomes that were taken up by macrophages, leading to reduction of macrophage migration and tumor spheroid infiltration. We further found that programmed death ligand 1 (PD-L1) is a functional target of miR-155-5p. Co-culture of macrophages pre-treated with NAC-derived tumor exosomes or exosomal miR-155-5p with T-lymphocytes leading to an increased percentage of CD8+ T-lymphocyte and a decreased CD3+ T cell apoptosis through PD-L1 downregulation. Tumor growth in nude mice was delayed by treatment with NAC-derived tumor exosomes. Delivery of tumor exo-miR-155-5p in immune-intact mice suppressed ovarian cancer progression and macrophage infiltration, and activated CD8+ T cell function. It is of note that exo-miR-155-5p inhibited tumor growth more potently than the PD-L1 antibody, suggesting that in addition to PD-L1, other pathways may also be targeted by this approach. Conclusions: Our findings demonstrate a novel mechanism, ROS-induced down-regulation of miR-155-5p, by which tumors modulate the microenvironment that favors tumor growth. Understanding of the negative impact of ROS on the tumor immune response will improve current therapeutic strategies. Targeting miR-155-5p can be an alternative approach to prevent formation of an immunosuppressive TME through downregulation of PD-L1 and other immunosuppressive factors.en_US
dc.eprint.versionFinal published versionen_US
dc.identifier.citationLi X, Wang S, Mu W, et al. Reactive oxygen species reprogram macrophages to suppress antitumor immune response through the exosomal miR-155-5p/PD-L1 pathway. J Exp Clin Cancer Res. 2022;41(1):41. Published 2022 Jan 27. doi:10.1186/s13046-022-02244-1en_US
dc.identifier.urihttps://hdl.handle.net/1805/32953
dc.language.isoen_USen_US
dc.publisherBMCen_US
dc.relation.isversionof10.1186/s13046-022-02244-1en_US
dc.relation.journalJournal of Experimental & Clinical Cancer Researchen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0*
dc.sourcePMCen_US
dc.subjectReactive oxygen speciesen_US
dc.subjectTumor immune responseen_US
dc.subjectOvarian canceren_US
dc.subjectTumor-associated macrophagesen_US
dc.subjectTumor exosomesen_US
dc.subjectmiR-155-5pen_US
dc.titleReactive oxygen species reprogram macrophages to suppress antitumor immune response through the exosomal miR-155-5p/PD-L1 pathwayen_US
dc.typeArticleen_US
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