Dichotomous effects of cellular expression of STAT3 on tumor growth of HNSCC

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Thomas E Bickett1, Michael W Knitz1, Miles Piper1

  • 1Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|November 18, 2021
PubMed

Insights

Targeting STAT3 in head and neck cancer cells can cause treatment resistance. However, targeting STAT3 in regulatory T cells (Tregs) can overcome resistance, while targeting it in NK cells accelerates tumor growth.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Signal transducer and activator of transcription 3 (STAT3) signaling regulates immune cells and cytokine production within the tumor microenvironment (TME).
  • Previous studies in head and neck squamous cell carcinoma (HNSCC) showed that combining STAT3 inhibition with radiation therapy improved tumor growth delay.
  • STAT3 has independent regulatory roles in anti-tumor immunity, necessitating investigation into its specific functions within different cellular compartments of the HNSCC TME.

Purpose of the Study:

  • To investigate the distinct roles of STAT3 in cancer cells, regulatory T cells (Tregs), and natural killer (NK) cells in HNSCC tumor growth and therapeutic resistance.
  • To determine the impact of individually targeting STAT3 in these specific cell types on the anti-tumor immune response.

Main Methods:

  • Utilized a CRISPR-Cas9 system for genetic deletion of STAT3 in HNSCC cancer cells.
  • Generated and employed two genetic knockout mouse models: FoxP3-Cre/STAT3(fl) for Treg-specific STAT3 deletion and NKp46-Cre/STAT3(fl) for NK cell-specific STAT3 deletion.
  • Analyzed tumor growth, immune cell infiltration, and functional changes in response to STAT3 manipulation in different cell compartments.

Main Results:

  • STAT3 deletion in cancer cells led to treatment resistance, associated with altered immune cell recruitment to the TME.
  • STAT3 knockout in Tregs reversed treatment resistance, promoting Treg reprogramming, recruitment, and activation of antigen-presenting cells.
  • STAT3 knockout in NK cells resulted in NK cell inactivation and accelerated tumor growth, highlighting a pro-tumorigenic role in this context.

Conclusions:

  • STAT3 plays complex, context-dependent roles in HNSCC, influencing both cancer cell-intrinsic properties and immune cell functions within the TME.
  • Targeting STAT3 in Tregs represents a potential strategy to overcome therapeutic resistance in HNSCC.
  • Targeting STAT3 in NK cells may be detrimental and could accelerate tumor progression, underscoring the need for cell-specific therapeutic strategies.
Keywords:
NK cellsSTAT3head and neck squamous cell carcinomaradiation therapyregulatory T cells

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