Søren Kragh Moestrup

STAT3 inhibition specifically in human monocytes and macrophages by CD163-targeted corosolic acid-containing liposomes

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STAT3 inhibition specifically in human monocytes and macrophages by CD163-targeted corosolic acid-containing liposomes. / Andersen, Morten Nørgaard; Etzerodt, Anders; Graversen, Jonas H.; Holthof, Lisa C.; Moestrup, Søren K.; Hokland, Marianne; Møller, Holger J.

In: Cancer Immunology, Immunotherapy, Vol. 68, No. 3, 03.2019, p. 489-502.

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@article{3c1c0cd9af984fc08f56cbbee19edfde,
title = "STAT3 inhibition specifically in human monocytes and macrophages by CD163-targeted corosolic acid-containing liposomes",
abstract = " Tumor-associated macrophages (TAMs) are of major importance in cancer-related immune suppression, and tumor infiltration by CD163 pos 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 CD163 pos cells, with minor effect on CD163 neg 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. ",
keywords = "Cancer, CD163, Drug delivery, Signal transducer and activator of transcription 3 (STAT3), Tumor-associated macrophage (TAM), IMMUNE-RESPONSE, ACTIVATION, STRATEGY, EPR, MECHANISMS, CANCER, NANOPARTICLES, GROWTH, TUMOR-ASSOCIATED MACROPHAGES, POLARIZATION",
author = "Andersen, {Morten N{\o}rgaard} and Anders Etzerodt and Graversen, {Jonas H.} and Holthof, {Lisa C.} and Moestrup, {S{\o}ren K.} and Marianne Hokland and M{\o}ller, {Holger J.}",
year = "2019",
month = mar,
doi = "10.1007/s00262-019-02301-3",
language = "English",
volume = "68",
pages = "489--502",
journal = "Cancer Immunology, Immunotherapy",
issn = "0340-7004",
publisher = "Springer",
number = "3",

}

RIS

TY - JOUR

T1 - STAT3 inhibition specifically in human monocytes and macrophages by CD163-targeted corosolic acid-containing liposomes

AU - Andersen, Morten Nørgaard

AU - Etzerodt, Anders

AU - Graversen, Jonas H.

AU - Holthof, Lisa C.

AU - Moestrup, Søren K.

AU - Hokland, Marianne

AU - Møller, Holger J.

PY - 2019/3

Y1 - 2019/3

N2 - Tumor-associated macrophages (TAMs) are of major importance in cancer-related immune suppression, and tumor infiltration by CD163 pos 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 CD163 pos cells, with minor effect on CD163 neg 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.

AB - Tumor-associated macrophages (TAMs) are of major importance in cancer-related immune suppression, and tumor infiltration by CD163 pos 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 CD163 pos cells, with minor effect on CD163 neg 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.

KW - Cancer

KW - CD163

KW - Drug delivery

KW - Signal transducer and activator of transcription 3 (STAT3)

KW - Tumor-associated macrophage (TAM)

KW - IMMUNE-RESPONSE

KW - ACTIVATION

KW - STRATEGY

KW - EPR

KW - MECHANISMS

KW - CANCER

KW - NANOPARTICLES

KW - GROWTH

KW - TUMOR-ASSOCIATED MACROPHAGES

KW - POLARIZATION

UR - http://www.scopus.com/inward/record.url?scp=85059945576&partnerID=8YFLogxK

U2 - 10.1007/s00262-019-02301-3

DO - 10.1007/s00262-019-02301-3

M3 - Journal article

C2 - 30637473

AN - SCOPUS:85059945576

VL - 68

SP - 489

EP - 502

JO - Cancer Immunology, Immunotherapy

JF - Cancer Immunology, Immunotherapy

SN - 0340-7004

IS - 3

ER -