STAT3 inhibition specifically in human monocytes and macrophages by CD163-targeted corosolic acid-containing liposomes
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Tumor-associated macrophages (TAMs) are of major importance in cancer-related immune suppression, and tumor infiltration by CD163pos TAMs is associated with poor outcome in most human cancers. Therefore, therapeutic strategies for reprogramming TAMs from a tumor-supporting (M2-like) phenotype towards a tumoricidal (M1-like) phenotype are of great interest. Activation of the transcription factor STAT3 within the tumor microenvironment is associated with worse prognosis, and STAT3 activation promotes the immunosuppressive phenotype of TAMs. Therefore, we aimed to develop a drug for inhibition of STAT3 specifically within human TAMs by targeting the endocytic CD163 scavenger receptor, which is highly expressed on TAMs. Here, we report the first data on a CD163-targeted STAT3-inhibitory drug consisting of corosolic acid (CA) packaged within long-circulating liposomes (LCLs), which are CD163-targeted by modification with monoclonal anti-CD163 antibodies (αCD163)—CA-LCL-αCD163. We show, that activation of STAT3 (by phosphorylation) was inhibited by CA-LCL-αCD163 specifically within CD163pos cells, with minor effect on CD163neg cells. Furthermore, CA-LCL-αCD163 inhibited STAT3-regulated gene expression of IL-10, and increased expression of TNFα, thus indicating a pro-inflammatory effect of the drug on human macrophages. This M1-like reprogramming at the mRNA level was confirmed by significantly elevated levels of pro-inflammatory cytokines (IFNγ, IL-12, TNFα, IL-2) in the culture medium. Since liposomes are attractive vehicles for novel anti-cancer drugs, and since direct TAM-targeting may decrease adverse effects of systemic inhibition of STAT3, the present results encourage future investigation of CA-LCL-αCD163 in the in vivo setting.
KeywordsCancer Signal transducer and activator of transcription 3 (STAT3) Tumor-associated macrophage (TAM) CD163 Drug delivery
- EPR effect
Enhanced permeability and retention effect
Median fluorescence intensity
P-(Y705)-STAT3:activated STAT3 by Tyr-705-phosphorylation
Signal transducer and activator of transcription 3
All flow cytometry experiments were performed using the LSR Fortessa flow cytometer at the FACS Core Facility, Aarhus University, Denmark. The authors wish to thank Zane Binate, Lene Dabelstein, Helle Ryom, and Christina Sønderskov for excellent technical assistance.
Conception and design: MNA, AE, JHG, SKM, MH, HJM. Acquisition of data: MNA, AE, LCH. Analysis and interpretation of data: MNA, AE, MH, HJM. Drafting the article: MNA. All authors revised the manuscript critically, and approved the version to be published.
Institutional funding: Department of Clinical Biochemistry, Aarhus University Hospital, Denmark; and the Faculty of Health, Aarhus University, Denmark. Funding of Morten N Andersen: The Danish Cancer Research Foundation; The Cancer Foundation (Denmark); The Memorial Foundation of Eva and Henry Frænkel; and The Memorial Foundation of Max and Inger Wørzner. Funding of Anders Etzerodt: The Novo Nordisk Foundation.
Compliance with ethical standards
Conflict of interest
Jonas H. Graversen, Søren K. Moestrup, and Holger J. Møller are minority shareholders in Affinicon ApS, which holds IP protecting the use of CD163 drug targeting. The other authors declare no conflict of interest.
Ethical approval and ethical standards
Buffy coats (residual product from blood processing) were collected anonymously from volunteer donors during routine blood donation at the blood bank, Department of Clinical Immunology, Aarhus University Hospital, Denmark (project number 0094). Volunteers gave informed written consent before blood donation. According to Danish law, this use of anonymized buffy coats does not require separate ethical approval.
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