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

Ioannis Zerdes1, Majken Wallerius2, Emmanouil G Sifakis3

  • 1Department of Oncology-Pathology, Karolinska Institutet, 17164 Stockholm, Sweden. ioannis.zerdes@ki.se.

Cancers
|October 5, 2019
PubMed

Insights

Signal transducer and activator of transcription 3 (STAT3) regulates anti-tumor immunity in breast cancer by controlling PD-L1 expression. Inhibiting STAT3 reduces tumor growth and metastasis by altering the immune microenvironment.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Signal transducer and activator of transcription 3 (STAT3) is a key oncogene and transcription factor with diverse cellular roles.
  • STAT3's influence on anti-tumor immunity is an emerging area of research, particularly in breast cancer (BC).
  • Immune checkpoints, such as PD-L1, play a critical role in tumor immune evasion.

Purpose of the Study:

  • To investigate the biological effects of STAT3 on immune checkpoint expression, specifically PD-L1, in breast cancer.
  • To determine the impact of STAT3 modulation on anti-tumor immune responses and tumor progression.
  • To explore the relationship between STAT3, PD-L1, and the tumor immune microenvironment in BC.

Main Methods:

  • Analysis of STAT3 transcriptional signatures and PD-L1 expression in human breast cancer cohorts.
  • In vitro experiments involving pharmacologic inhibition and gene silencing of STAT3.
  • In vivo studies using a mammary carcinoma mouse model to assess tumor growth, metastasis, and immune cell infiltration.

Main Results:

  • A STAT3 signature positively correlated with PD-L1 expression in early breast cancer.
  • STAT3 inhibition decreased PD-L1 levels in vitro and reduced tumor growth and metastasis in vivo.
  • Tumor progression was hampered by promoting anti-tumoral macrophages and natural killer cells, while reducing cytotoxic lymphocytes.
  • Pro-tumoral macrophages in human BC correlated with PD-L1, proliferation, and higher malignancy grade.

Conclusions:

  • STAT3 plays a significant role in regulating PD-L1 expression in breast cancer.
  • STAT3 inhibition modulates the tumor immune microenvironment, leading to reduced tumor progression.
  • These findings highlight STAT3 as a potential therapeutic target for enhancing anti-tumor immunity in breast cancer.
Keywords:
M2 macrophages, NK cells, STAT3 inhibitor XIIIPD-L1STAT3breast cancer

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