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Open AccessArticle

STAT3 Activity Promotes Programmed-Death Ligand 1 Expression and Suppresses Immune Responses in Breast Cancer

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Department of Oncology-Pathology, Karolinska Institutet, 17164 Stockholm, Sweden
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Department of Women’s and Children’s Health, Karolinska Institutet, 17177 Stockholm, Sweden
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Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17165 Stockholm, Sweden
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Breast Center, Theme Cancer, Karolinska University Hospital, 17176 Stockholm, Sweden
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Department of Pathology and Cytology, Karolinska University Hospital, 17176 Stockholm, Sweden
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(10), 1479; https://doi.org/10.3390/cancers11101479
Received: 14 August 2019 / Revised: 23 September 2019 / Accepted: 27 September 2019 / Published: 1 October 2019
(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)
Signal transducer and activator of transcription 3 (STAT3) is an oncogene and multifaceted transcription factor involved in multiple cellular functions. Its role in modifying anti-tumor immunity has been recently recognized. In this study, the biologic effects of STAT3 on immune checkpoint expression and anti-tumor responses were investigated in breast cancer (BC). A transcriptional signature of phosphorylated STAT3 was positively correlated with PD-L1 expression in two independent cohorts of early BC. Pharmacologic inhibition and gene silencing of STAT3 led to decreased Programmed Death Ligand 1 (PD-L1) expression levels in vitro, and resulted as well in reduction of tumor growth and decreased metastatic dissemination in a mammary carcinoma mouse model. The hampering of tumor progression was correlated to an anti-tumoral macrophage phenotype and accumulation of natural-killer cells, but also in reduced accrual of cytotoxic lymphocytes. In human BC, pro-tumoral macrophages correlated to PD-L1 expression, proliferation status and higher grade of malignancy, indicating a subset of patients with immunosuppressive properties. In conclusion, this study provides evidence for STAT3-mediated regulation of PD-L1 and modulation of immune microenvironment in BC. View Full-Text
Keywords: breast cancer; PD-L1; STAT3; M2 macrophages; NK cells; STAT3 inhibitor XIII breast cancer; PD-L1; STAT3; M2 macrophages; NK cells; STAT3 inhibitor XIII
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Zerdes, I.; Wallerius, M.; Sifakis, E.G.; Wallmann, T.; Betts, S.; Bartish, M.; Tsesmetzis, N.; Tobin, N.P.; Coucoravas, C.; Bergh, J.; Rassidakis, G.Z.; Rolny, C.; Foukakis, T. STAT3 Activity Promotes Programmed-Death Ligand 1 Expression and Suppresses Immune Responses in Breast Cancer. Cancers 2019, 11, 1479.

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