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

Author

Listed:
  • Yuan Jiang

    (Chinese Academy of Sciences
    University of Science and Technology of China)

  • Yueyuan Zheng

    (The Seventh Affiliated Hospital of Sun Yat-sen University)

  • Yuan-Wei Zhang

    (Chinese Academy of Sciences)

  • Shuai Kong

    (Chinese Academy of Sciences
    University of Science and Technology of China)

  • Jinxiu Dong

    (Chinese Academy of Sciences)

  • Fei Wang

    (Chinese Academy of Sciences
    University of Science and Technology of China)

  • Benjamin Ziman

    (University of Southern California)

  • Sigal Gery

    (Cedars-Sinai Medical Center)

  • Jia-Jie Hao

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Dan Zhou

    (Chinese Academy of Sciences
    Anhui University)

  • Jianian Zhou

    (Chinese Academy of Sciences
    University of Science and Technology of China)

  • Allen S. Ho

    (Cedars-Sinai Medical Center)

  • Uttam K. Sinha

    (University of Southern California)

  • Jian Chen

    (Chinese Academy of Sciences)

  • Shuo Zhang

    (Chinese Academy of Sciences
    University of Science and Technology of China)

  • Chuntong Yin

    (Chinese Academy of Sciences
    The First Affiliated Hospital of Anhui Medical University)

  • Dan-Dan Wei

    (Chinese Academy of Sciences
    University of Science and Technology of China
    Chinese Academy of Sciences)

  • Masaharu Hazawa

    (Kanazawa University)

  • Huaguang Pan

    (The First Affiliated Hospital of Anhui Medical University)

  • Zhihao Lu

    (Peking University Cancer Hospital and Institute)

  • Wen-Qiang Wei

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Ming-Rong Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • H. Phillip Koeffler

    (Cedars-Sinai Medical Center)

  • De-Chen Lin

    (University of Southern California)

  • Yan-Yi Jiang

    (Chinese Academy of Sciences
    University of Science and Technology of China)

Abstract

Squamous cell carcinomas (SCCs) are common and aggressive malignancies. Immune check point blockade (ICB) therapy using PD-1/PD-L1 antibodies has been approved in several types of advanced SCCs. However, low response rate and treatment resistance are common. Improving the efficacy of ICB therapy requires better understanding of the mechanism of immune evasion. Here, we identify that the SCC-master transcription factor TP63 suppresses interferon-γ (IFNγ) signaling. TP63 inhibition leads to increased CD8+ T cell infiltration and heighten tumor killing in in vivo syngeneic mouse model and ex vivo co-culture system, respectively. Moreover, expression of TP63 is negatively correlated with CD8+ T cell infiltration and activation in patients with SCC. Silencing of TP63 enhances the anti-tumor efficacy of PD-1 blockade by promoting CD8+ T cell infiltration and functionality. Mechanistically, TP63 and STAT1 mutually suppress each other to regulate the IFNγ signaling by co-occupying and co-regulating their own promoters and enhancers. Together, our findings elucidate a tumor-extrinsic function of TP63 in promoting immune evasion of SCC cells. Over-expression of TP63 may serve as a biomarker predicting the outcome of SCC patients treated with ICB therapy, and targeting TP63/STAT/IFNγ axis may enhance the efficacy of ICB therapy for this deadly cancer.

Suggested Citation

  • Yuan Jiang & Yueyuan Zheng & Yuan-Wei Zhang & Shuai Kong & Jinxiu Dong & Fei Wang & Benjamin Ziman & Sigal Gery & Jia-Jie Hao & Dan Zhou & Jianian Zhou & Allen S. Ho & Uttam K. Sinha & Jian Chen & Shu, 2024. "Reciprocal inhibition between TP63 and STAT1 regulates anti-tumor immune response through interferon-γ signaling in squamous cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46785-9
    DOI: 10.1038/s41467-024-46785-9
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