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Reciprocal inhibition between TP63 and STAT1 regulates anti-tumor immune response through interferon-γ signaling in

Yuan Jiang1,2, Yueyuan Zheng3, Yuan-Wei Zhang1

  • 1Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.

Nature Communications
|March 21, 2024
PubMed

Insights

TP63, a key factor in squamous cell carcinomas (SCCs), hinders anti-tumor immunity by suppressing interferon-gamma (IFNγ) signaling. Inhibiting TP63 boosts T cell responses, enhancing immunotherapy efficacy in SCC.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Squamous cell carcinomas (SCCs) are aggressive cancers with limited treatment options.
  • Immune checkpoint blockade (ICB) therapy shows promise but faces challenges like low response rates and resistance.
  • Understanding immune evasion mechanisms is crucial for improving ICB efficacy in SCC.

Purpose of the Study:

  • To investigate the role of the transcription factor TP63 in SCC immune evasion.
  • To explore TP63's impact on interferon-gamma (IFNγ) signaling and T cell responses.
  • To assess TP63 as a potential biomarker and therapeutic target for enhancing ICB therapy in SCC.

Main Methods:

  • In vivo syngeneic mouse models and ex vivo co-culture systems were used to study TP63 inhibition.
  • Analysis of TP63 expression and CD8+ T cell infiltration/activation in patient-derived SCC samples.
  • Investigated the molecular mechanism of TP63 and STAT1 interaction in regulating IFNγ signaling.

Main Results:

  • TP63 was identified as a suppressor of IFNγ signaling in SCC.
  • TP63 inhibition increased CD8+ T cell infiltration and tumor cell killing.
  • TP63 expression negatively correlated with CD8+ T cell infiltration and activation in SCC patients.
  • Silencing TP63 enhanced PD-1 blockade efficacy by improving T cell function.
  • TP63 and STAT1 mutually regulate IFNγ signaling.

Conclusions:

  • TP63 plays a tumor-extrinsic role in promoting immune evasion in SCC.
  • TP63 overexpression may predict poor outcomes for ICB therapy in SCC patients.
  • Targeting the TP63/STAT/IFNγ axis presents a potential strategy to enhance ICB therapy for SCC.

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