STAT3 is over-activated within CD163^pos bone marrow macrophages in both Multiple Myeloma and the benign pre-condition MGUS

TY - JOUR

T1 - STAT3 is over-activated within CD163pos bone marrow macrophages in both Multiple Myeloma and the benign pre-condition MGUS

AU - Andersen, Morten N

AU - Andersen, Niels F

AU - Lauridsen, Kristina L

AU - Etzerodt, Anders

AU - Sorensen, Boe S

AU - Abildgaard, Niels

AU - Plesner, Trine

AU - Hokland, Marianne

AU - Møller, Holger J

PY - 2022/1

Y1 - 2022/1

N2 - Tumour-associated macrophages (TAMs) support cancer cell survival and suppress anti-tumour immunity. Tumour infiltration by CD163pos TAMs is associated with poor outcome in several human malignancies, including multiple myeloma (MM). Signal transducer and activator of transcription 3 (STAT3) is over-activated in human cancers, and specifically within TAMs activation of STAT3 may induce an immunosuppressive (M2-like) phenotype. Therefore, STAT3-inhibition in TAMs may be a future therapeutic strategy.We investigated TAM markers CD163, CD206, and activated STAT3 (pSTAT3) in patients with MGUS (n = 32) and MM (n = 45), as well as healthy controls (HCs, n = 13).Blood levels of the macrophage biomarkers sCD163 and sCD206, and circulating cytokines, as well as bone marrow mRNA expression of CD163 and CD206, were generally increased in MGUS and MM patients, compared to HCs, but to highly similar levels. By immunohistochemistry, bone marrow levels of pSTAT3 were increased specifically within CD163pos cells in both MGUS and MM patients.In conclusion, macrophage-related inflammatory changes, including activation of STAT3, were present already at the MGUS stage, at similar levels as in MM. Specific increase in pSTAT3 levels within CD163pos cells supports that the CD163 scavenger receptor may be a useful target for future delivery of STAT3-inhibitory drugs to TAMs in MM patients.

AB - Tumour-associated macrophages (TAMs) support cancer cell survival and suppress anti-tumour immunity. Tumour infiltration by CD163pos TAMs is associated with poor outcome in several human malignancies, including multiple myeloma (MM). Signal transducer and activator of transcription 3 (STAT3) is over-activated in human cancers, and specifically within TAMs activation of STAT3 may induce an immunosuppressive (M2-like) phenotype. Therefore, STAT3-inhibition in TAMs may be a future therapeutic strategy.We investigated TAM markers CD163, CD206, and activated STAT3 (pSTAT3) in patients with MGUS (n = 32) and MM (n = 45), as well as healthy controls (HCs, n = 13).Blood levels of the macrophage biomarkers sCD163 and sCD206, and circulating cytokines, as well as bone marrow mRNA expression of CD163 and CD206, were generally increased in MGUS and MM patients, compared to HCs, but to highly similar levels. By immunohistochemistry, bone marrow levels of pSTAT3 were increased specifically within CD163pos cells in both MGUS and MM patients.In conclusion, macrophage-related inflammatory changes, including activation of STAT3, were present already at the MGUS stage, at similar levels as in MM. Specific increase in pSTAT3 levels within CD163pos cells supports that the CD163 scavenger receptor may be a useful target for future delivery of STAT3-inhibitory drugs to TAMs in MM patients.

KW - BIOMARKER

KW - Bone marrow microenvironment

KW - CANCER

KW - CD163

KW - EXPRESSION

KW - MECHANISMS

KW - MGUS

KW - MODEL

KW - MONOCLONAL GAMMOPATHY

KW - Macrophage

KW - Multiple myeloma

KW - PROGNOSIS

KW - PROGRESSION

KW - STAT3

KW - TUMOR-ASSOCIATED MACROPHAGES

KW - UNDETERMINED SIGNIFICANCE

U2 - 10.1007/s00262-021-02952-1

DO - 10.1007/s00262-021-02952-1

M3 - Journal article

C2 - 34061243

SN - 0340-7004

VL - 71

SP - 177

EP - 187

JO - Cancer Immunology, Immunotherapy

JF - Cancer Immunology, Immunotherapy

IS - 1

ER -