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

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, Shuo Zhang, Chuntong Yin, Dan-Dan Wei, Masaharu Hazawa, Huaguang Pan, Zhihao Lu, Wen-Qiang Wei, Ming-Rong Wang, H. Phillip Koeffler, Lin De-Chen () and Yan-Yi Jiang ()
Additional contact information
Yuan Jiang: Chinese Academy of Sciences
Yueyuan Zheng: The Seventh Affiliated Hospital of Sun Yat-sen University
Yuan-Wei Zhang: Chinese Academy of Sciences
Shuai Kong: Chinese Academy of Sciences
Jinxiu Dong: Chinese Academy of Sciences
Fei Wang: Chinese Academy of Sciences
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
Jianian Zhou: Chinese Academy of Sciences
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
Chuntong Yin: Chinese Academy of Sciences
Dan-Dan Wei: 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
Lin De-Chen: University of Southern California
Yan-Yi Jiang: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46785-9

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