1. 5-Aza-2'-deoxycytidin (Decitabine) increases cancer-testis antigen expression in head and neck squamous cell carcinoma and modifies immune checkpoint expression, especially in CD39-positive CD8 and CD4 T cells.
- Author
-
Fehn A, von Witzleben A, Grages A, Kors TA, Ezić J, Betzler AC, Brunner C, Schuler PJ, Theodoraki MN, Hoffmann TK, and Laban S
- Subjects
- Humans, Cell Line, Tumor, Immune Checkpoint Proteins metabolism, Immune Checkpoint Proteins genetics, Apyrase metabolism, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms metabolism, Head and Neck Neoplasms immunology, Head and Neck Neoplasms pathology, Antigens, Neoplasm metabolism, Antigens, Neoplasm immunology, Gene Expression Regulation, Neoplastic drug effects, Male, Cell Proliferation drug effects, Female, Antigens, CD metabolism, Antimetabolites, Antineoplastic pharmacology, Squamous Cell Carcinoma of Head and Neck drug therapy, Squamous Cell Carcinoma of Head and Neck metabolism, Squamous Cell Carcinoma of Head and Neck immunology, Squamous Cell Carcinoma of Head and Neck pathology, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes drug effects, Decitabine pharmacology, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes drug effects
- Abstract
Failure of immunotherapy in head and neck squamous cell carcinoma (HNSCC) patients represents an unmet need to augment leverage of adaptive immunity. Immunogenic cancer-testis antigen (CTA) expression as well as lymphocyte differentiation and function are regulated by DNA methylation. Therefore, epigenetic therapy via inhibition of DNA-Methyltransferases by 5-Aza-2'-deoxycytidine (DAC) serves a promising adjuvant in immunotherapy. We investigated the effects of DAC on CTA expression and proliferative capacity in HNSCC cell lines and on the expression of 12 immune checkpoint molecules (ICM) on lymphocytes of oropharyngeal squamous cell carcinoma (OPSCC) patients and healthy donors. In all cell lines CTA were upregulated accompanied by decreased proliferation. In lymphocytes pronounced alterations of the ICM repertoire were observed, influenced by donor type and subpopulation. On CD39+ CD4 and CD8 T cells, the expression of co-stimulatory ICM GITR and OX40 increased dose dependently, whereas expression decreased on CD39- CD4 T cells. PD1 expression increased primarily on CD39+ CD8 T cells and decreased on CD39- CD4 T cells. CD27 expression decreased primarily in CD8 T cells, but increased in CD39- CD4 T cells, whereas ICOS expression was lowered in both CD39+ and CD39- subsets of CD4 as well as CD8 T cells. DAC treatment increased immunogenicity and decreased proliferation in HNSCC cells while enhancing expression of co-stimulatory ICM GITR and OX40. We propose low dose DAC treatment as a adjuvant to immunotherapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Simon Laban: Advisory Boards: Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Sanofi Genzyme, Astra Zeneca (AZ). Honoraria: MSD, BMS. Travel reimbursement: Merck Serono, Astra Zeneca. Thomas K Hoffmann: Advisory Boards: Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Sanofi Genzyme., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2025
- Full Text
- View/download PDF