Reactive oxygen species reprogram macrophages to suppress antitumor immune response through the exosomal miR-155-5p/PD-L1 pathway
dc.contributor.author | Li, Xiang | |
dc.contributor.author | Wang, Shaomin | |
dc.contributor.author | Mu, Wei | |
dc.contributor.author | Barry, Jennifer | |
dc.contributor.author | Han, Anna | |
dc.contributor.author | Carpenter, Richard L. | |
dc.contributor.author | Jiang, Bing‑Hua | |
dc.contributor.author | Peiper, Stephen C. | |
dc.contributor.author | Mahoney, Mỹ G. | |
dc.contributor.author | Aplin, Andrew E. | |
dc.contributor.author | Ren, Hong | |
dc.contributor.author | He, Jun | |
dc.contributor.department | Biochemistry and Molecular Biology, School of Medicine | |
dc.date.accessioned | 2023-05-15T10:40:53Z | |
dc.date.available | 2023-05-15T10:40:53Z | |
dc.date.issued | 2022-01-27 | |
dc.description.abstract | Background: 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.version | Final published version | en_US |
dc.identifier.citation | Li 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/s13046-022-02244-1 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/32953 | |
dc.language.iso | en_US | en_US |
dc.publisher | BMC | en_US |
dc.relation.isversionof | 10.1186/s13046-022-02244-1 | en_US |
dc.relation.journal | Journal of Experimental & Clinical Cancer Research | en_US |
dc.rights | Attribution 4.0 International | * |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | * |
dc.source | PMC | en_US |
dc.subject | Reactive oxygen species | en_US |
dc.subject | Tumor immune response | en_US |
dc.subject | Ovarian cancer | en_US |
dc.subject | Tumor-associated macrophages | en_US |
dc.subject | Tumor exosomes | en_US |
dc.subject | miR-155-5p | en_US |
dc.title | Reactive oxygen species reprogram macrophages to suppress antitumor immune response through the exosomal miR-155-5p/PD-L1 pathway | en_US |
dc.type | Article | en_US |