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Blockade of Stat3 oncogene addiction induces cellular senescence and reveals a cell-nonautonomous activity suitable

Mara De Martino1, Mercedes Tkach2, Sofía Bruni1

  • 1Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología Y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina.

Oncoimmunology
|February 18, 2020
PubMed

Insights

Targeting Signal transducer and activator of transcription 3 (Stat3) in cancer cells induces senescence and triggers an immune response. This Stat3-silencing immunotherapy, combined with checkpoint inhibitors, shows promise for treating Stat3-addicted tumors.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Biology

Background:

  • Signal transducer and activator of transcription 3 (Stat3) is constitutively activated in many cancers, promoting tumor growth and immune suppression.
  • Understanding Stat3's role in both cancer cells and the tumor microenvironment is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the consequences of inhibiting Stat3 constitutive activation in cancer cells.
  • To develop and evaluate a novel immunotherapy based on Stat3 silencing and its associated secretory phenotype.
  • To explore the potential of combining this immunotherapy with immune checkpoint inhibitors.

Main Methods:

  • Cancer cell lines were treated to induce Stat3 silencing, leading to senescence and the senescence-associated secretory phenotype (SASP-siStat3).
  • The efficacy of SASP-siStat3 immunotherapy was assessed in preclinical models of triple-negative breast cancer and melanoma.
  • Immunotherapies were combined with anti-PD-1 antibodies, and immune cell activation (CD4+ T and NK cells) was analyzed.
  • Components of the SASP were characterized, focusing on type I IFN-related mediators and the cyclic GMP-AMP synthase (cGAS) DNA sensing pathway.

Main Results:

  • Stat3 inhibition induced senescence in various cancer cell types, confirming their dependence on Stat3.
  • SASP-siStat3 immunotherapy significantly inhibited tumor growth in triple-negative breast cancer and melanoma models.
  • Treatment activated CD4+ T and NK cells, enhancing the anti-tumor immune response.
  • Combination therapy with anti-PD-1 antibodies improved survival in melanoma-bearing mice.
  • Type I IFN-related mediators, activated via the cGAS pathway, were identified as key contributors to the immunosurveillance activity of SASP-siStat3.

Conclusions:

  • Stat3 addiction is a vulnerability in many cancers that can be exploited therapeutically.
  • SASP-siStat3 immunotherapy effectively triggers anti-tumor immunity and suppresses tumor growth.
  • Combining Stat3-targeting strategies with immune checkpoint inhibitors may enhance treatment outcomes for patients with Stat3-addicted cancers.
Keywords:
Stat3immune checkpoint blockadeimmunotherapyoncogene addictionsenescence

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