ΔNp63-restricted viral mimicry response impedes cancer cell viability and remodels tumor microenvironment in esophageal squamous cell carcinoma

肿瘤微环境 癌症 癌症研究 癌变 生物 癌细胞 细胞 干扰素 肿瘤进展 转录因子 肿瘤细胞 免疫学 遗传学 生物化学 基因
作者
Valen Zhuoyou Yu,Shan Shan So,Bryan Chee-chad Lung,George Zhaozheng Hou,Carissa Wing-Yan Wong,Larry Ka-Yue Chow,M.-K. Chung,Ian Yu-hong Wong,Claudia Lai-yin Wong,Desmond Kwan-kit Chan,Fion Siu‐Yin Chan,Betty Tsz-ting Law,Kaiyan Xu,Zack Zhen Tan,Ka-On Lam,Anthony W.I. Lo,Alfred K. Lam,Dora Lai‐Wan Kwong,Josephine Mun Yee Ko,Wei Dai,Simon Law,Maria Li Lung
出处
期刊:Cancer Letters [Elsevier]
卷期号:595: 216999-216999 被引量:1
标识
DOI:10.1016/j.canlet.2024.216999
摘要

Tumor protein p63 isoform ΔNp63 plays roles in the squamous epithelium and squamous cell carcinomas (SCCs), including esophageal SCC (ESCC). By integrating data from cell lines and our latest patient-derived organoid cultures, derived xenograft models, and clinical sample transcriptomic analyses, we identified a novel and robust oncogenic role of ΔNp63 in ESCC. We showed that ΔNp63 maintains the repression of cancer cell endogenous retrotransposon expression and cellular double-stranded RNA sensing. These subsequently lead to a restricted cancer cell viral mimicry response and suppressed induction of tumor-suppressive type I interferon (IFN-I) signaling through the regulations of Signal transducer and activator of transcription 1, Interferon regulatory factor 1, and cGAS-STING pathway. The cancer cell ΔNp63-IFN-I signaling axis affects both the cancer cell and tumor-infiltrating immune cell (TIIC) compartments. In cancer cells, depletion of ΔNp63 resulted in reduced cell viability. ΔNp63 expression is negatively associated with the anticancer responses to viral mimicry booster treatments targeting cancer cells. In the tumor microenvironment, cancer cell TP63 expression negatively correlates with multiple TIIC signatures in ESCC clinical samples. ΔNp63 depletion leads to increased cancer cell antigen presentation molecule expression and enhanced recruitment and reprogramming of tumor-infiltrating myeloid cells. Similar IFN-I signaling and TIIC signature association with ΔNp63 were also observed in lung SCC. These results support the potential application of ΔNp63 as a therapeutic target and a biomarker to guide candidate anticancer treatments exploring viral mimicry responses.
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