Ferroptosis Signature Shapes the Immune Profiles to Enhance the Response to Immune Checkpoint Inhibitors in Head and Neck Cancer

• Published in: Advanced science Vol. 10; no. 15; pp. e2204514 - n/a
• Main Authors: Chung, Chih‐Hung, Lin, Chun‐Yu, Chen, Chih‐Yu, Hsueh, Chun‐Wei, Chang, Yao‐Wen, Wang, Chen‐Chi, Chu, Pen‐Yuan, Tai, Shyh‐Kuan, Yang, Muh‐Hwa
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.05.2023; John Wiley and Sons Inc; Wiley
• Subjects: Animals; Apoptosis; Cancer therapies; Cells; Ferroptosis; Gene expression; Genomics; head and neck cancer; Head and Neck Neoplasms - drug therapy; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Inflammation; Interferon; Lipids; Lymphocytes; Metastasis; Mice; Papillomavirus Infections; Patients; programmed death ligand 1; Squamous Cell Carcinoma of Head and Neck - drug therapy; Tumor Microenvironment; Tumors; head and neck cancer; programmed death ligand 1; ferroptosis
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202204514

As a type of immunogenic cell death, ferroptosis participates in the creation of immunoactive tumor microenvironments. However, knowledge of spatial location of tumor cells with ferroptosis signature in tumor environments and the role of ferroptotic stress in inducing the expression of immune‐related molecules in cancer cells is limited. Here the spatial association of the transcriptomic signatures is demonstrated for ferroptosis and inflammation/immune activation located in the invasive front of head and neck squamous cell carcinoma (HNSCC). The association between ferroptosis signature and inflammation/immune activation is more prominent in HPV‐negative HNSCC compared to HPV‐positive ones. Ferroptotic stress induces PD‐L1 expression through reactive oxygen species (ROS)‐elicited NF‐κB signaling pathway and calcium influx. Priming murine HNSCC with the ferroptosis inducer sensitizes tumors to anti‐PD‐L1 antibody treatment. A positive correlation between the ferroptosis signature and the active immune cell profile is shown in the HNSCC samples. This study reveals a subgroup of ferroptotic HNSCC with immune‐active signatures and indicates the potential of priming HNSCC with ferroptosis inducers to increase the antitumor efficacy of immune checkpoint inhibitors. Ferroptosis stress elicits PD‐L1 expression in head and neck cancer cells and modulates tumor microenvironments to an immune‐active state, highlighting the potential of priming tumors with ferroptosis inducers to potentiate the antitumor efficacy of immunotherapy.