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Cell death & disease
10 23, 2021;12 (11): 993.

Targeting LSD1 suppresses stem cell-like properties and sensitizes head and neck squamous cell carcinoma to PD-1 blockade.

Yong Han, Shengming Xu, Weimin Ye, Yang Wang, Xiangkai Zhang, Jiong Deng, Zhiyuan Zhang, Liu Liu, Shuli Liu
Author Information
  1. Yong Han: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  2. Shengming Xu: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  3. Weimin Ye: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  4. Yang Wang: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  5. Xiangkai Zhang: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  6. Jiong Deng: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  7. Zhiyuan Zhang: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  8. Liu Liu: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. cycstal2002@126.com.
  9. Shuli Liu: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. liushuli@shsmu.edu.cn. ORCID
PMID: 34689153 DOI: 10.1038/s41419-021-04297-0

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive tumor with poor clinical outcomes due to recurrence, metastasis, and treatment resistance. Cancer stem cells (CSCs), a small population among tumor cells, are proposed to be responsible for tumor initiation, progression, metastasis, drug resistance, and recurrence. Here we show that high LSD1 expression was a predictor of poor prognosis for HNSCC patients. We found that high expression of LSD1 is essential for the maintenance of the CSC properties by regulating Bmi-1 expression. Moreover, tumor LSD1 ablation suppresses CSC-like characteristics in vitro and inhibits tumorigenicity in vivo in immune-deficient xenografts. However, this deletion induces the upregulation of PDL1 levels, which compromises antitumor immunity and reduces antitumor efficacy in an immune-competent mouse model. Functionally, the combination of LSD1 inhibitor and anti-PD-1 monoclonal antibody can overcome tumor immune evasion and greatly inhibit tumor growth, which was associated with reduced Ki-67 level and augmented CD8 T cell infiltration in immunocompetent tumor-bearing mouse models. In summary, these findings provide a novel and promising combined strategy for the treatment of HNSCC using a combination of LSD1 inhibition and PD-1 blockade.

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Grants

  1. 81802696/National Natural Science Foundation of China (National Science Foundation of China)

MeSH Term

Aged
Animals
Cell Line, Tumor
Female
Histone Demethylases
Humans
Immune Checkpoint Inhibitors
Mice
Mice, Nude
Middle Aged
Neoplastic Stem Cells
Squamous Cell Carcinoma of Head and Neck

Chemicals

Immune Checkpoint Inhibitors
Histone Demethylases
KDM1a protein, mouse
Journal Article Research Support, Non-U.S. Gov't

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