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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1445472
This article is part of the Research Topic Multi-omics Approaches to Identify Immune Profiles and Therapeutic Targets for Rare Cancers View all articles

TP63 transcriptionally regulates SLC7A5 to suppress ferroptosis in head and neck squamous cell carcinoma

Provisionally accepted
Zilong Chen Zilong Chen 1Haoxi Cai Haoxi Cai 2*Weiwei Ye Weiwei Ye 3*Junming Wu Junming Wu 4,5Jing Liu Jing Liu 3*Yun Xie Yun Xie 3*Shiqiang Feng Shiqiang Feng 3*Yuanpei Jin Yuanpei Jin 3*Lv Yunxia Lv Yunxia 6*Hui Ye Hui Ye 3*Chengfu Cai Chengfu Cai 3,7*Gengming Cai Gengming Cai 3,7*
  • 1 Quanzhou First Hospital, Fujian Medical University, Quanzhou, China
  • 2 Xiangya Stomatological Hospital, Xiangya School of Stomatology, Central South University, Changsha, China
  • 3 Xiamen Medical College Affiliated Haicang Hospital, The Sixth Hospital of Xiamen City, The Haicang Hospital of Xiamen, Xiamen, China
  • 4 YuanDong International Academy Of Life Sciences, Hong Kong, China
  • 5 Guangxi Academy of Sciences, Nanning, China
  • 6 Nanchang University Second Affiliated Hospital, Nanchang, China
  • 7 Fujian Medical University, Fuzhou, Fujian Province, China

The final, formatted version of the article will be published soon.

    Background: Most head and neck squamous cell carcinoma (HNSCC) patients are diagnosed at an advanced local stage. While immunotherapy has improved survival rates, only a minority of patients respond durably to targeted immunotherapies, posing substantial clinical challenges. We investigated the heterogeneity of the tumor microenvironment in HNSCC cohorts before and after immunotherapy by analyzing single-cell RNA sequencing (scRNA-seq) data and bulk RNA sequencing datasets retrieved from public databases. Methods: We constructed a single-cell transcriptome landscape of HNSCC patients before and after immunotherapy and analyzed the cellular composition, developmental trajectories, gene regulatory networks, and communication patterns of different cell type subpopulations. Additionally, we assessed the expression levels of relevant indicators in HNSCC cells via western blot, ELISA, and fluorescent probe techniques. Results: At the single-cell level, we identified a subpopulation of TP63+ SLC7A5+ HNSCC that exhibited a ferroptosis-resistant phenotype. This subpopulation suppresses ferroptosis in malignant cells through the transcriptional upregulation of SLC7A5 mediated by high TP63 expression, thereby promoting tumor growth and resistance to immunotherapy. The experimental results demonstrated that the overexpression of TP63 upregulated the expression of SLC7A5 and suppressed the concentrations of Fe2+ and ROS in HNSCC cells. By integrating bulk transcriptome data, we developed a clinical scoring model based on TP63 and SLC7A5, which are closely associated with tumor stage, revealing the significant prognostic efficacy of the TP63+ SLC7A5+ HNSCC-mediated ferroptosis mechanism in HNSCC patients. Conclusion: Our research elucidates the TME in HNSCC before and after immunotherapy, revealing a novel mechanism by which TP63+ SLC7A5+ HNSCC inhibits ferroptosis and enhances tumor resistance via TP63-induced SLC7A5 upregulation. These insights lay the foundation for the development of more effective treatments for HNSCC.

    Keywords: Head and neck squamous cell carcinoma, ferroptosis, single-cell RNA sequencing, Immunotherapy, Tumor Microenvironment

    Received: 07 Jun 2024; Accepted: 24 Jul 2024.

    Copyright: © 2024 Chen, Cai, Ye, Wu, Liu, Xie, Feng, Jin, Yunxia, Ye, Cai and Cai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Haoxi Cai, Xiangya Stomatological Hospital, Xiangya School of Stomatology, Central South University, Changsha, China
    Weiwei Ye, Xiamen Medical College Affiliated Haicang Hospital, The Sixth Hospital of Xiamen City, The Haicang Hospital of Xiamen, Xiamen, China
    Jing Liu, Xiamen Medical College Affiliated Haicang Hospital, The Sixth Hospital of Xiamen City, The Haicang Hospital of Xiamen, Xiamen, China
    Yun Xie, Xiamen Medical College Affiliated Haicang Hospital, The Sixth Hospital of Xiamen City, The Haicang Hospital of Xiamen, Xiamen, China
    Shiqiang Feng, Xiamen Medical College Affiliated Haicang Hospital, The Sixth Hospital of Xiamen City, The Haicang Hospital of Xiamen, Xiamen, China
    Yuanpei Jin, Xiamen Medical College Affiliated Haicang Hospital, The Sixth Hospital of Xiamen City, The Haicang Hospital of Xiamen, Xiamen, China
    Lv Yunxia, Nanchang University Second Affiliated Hospital, Nanchang, China
    Hui Ye, Xiamen Medical College Affiliated Haicang Hospital, The Sixth Hospital of Xiamen City, The Haicang Hospital of Xiamen, Xiamen, China
    Chengfu Cai, Xiamen Medical College Affiliated Haicang Hospital, The Sixth Hospital of Xiamen City, The Haicang Hospital of Xiamen, Xiamen, China
    Gengming Cai, Xiamen Medical College Affiliated Haicang Hospital, The Sixth Hospital of Xiamen City, The Haicang Hospital of Xiamen, Xiamen, China

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