Downregulation of AT‐rich interaction domain 2 underlies natural killer cell dysfunction in oral squamous cell carcinoma

• Published in: Immunology and cell biology 2023-01, Vol.101 (1), p.78-90
• Main Authors: Li, Wei, An, Ning, Wang, Mingwei, Liu, Xiguo, Mei, Zhidan
• Format: Article
• Language: English
• Subjects: Animals; Antitumor activity; Apoptosis; AT‐rich interaction domain 2; Cell activation; Cell death; Cytotoxicity; Down-Regulation; Granzyme B; Granzymes - metabolism; Immune system; Interferon; Interferon-gamma - metabolism; Killer Cells, Natural; Lymphocytes; Mice; Mouth Neoplasms - metabolism; Natural killer cells; Oral cancer; Oral carcinoma; Oral squamous cell carcinoma; PD-1 protein; Perforin; Perforin - metabolism; Phenotypes; Programmed Cell Death 1 Receptor - metabolism; programmed death‐1; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - metabolism; Transcription Factors - metabolism; Tumor Microenvironment; Tumor necrosis factor; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1111/imcb.12602

The immune system plays a significant role in controlling oral squamous cell carcinoma (OSCC) initiation and progression. Natural killer (NK) cells actively participate in antitumor immunity but become dysfunctional or exhausted in the tumor microenvironment. To explore the mechanisms of NK cell dysfunction in OSCC, we characterized the expression and function of AT‐rich interaction domain 2 (ARID2) in NK cells in a murine OSCC model. ARID2 was downregulated in tongue NK cells compared with splenic NK cells. Notably, ARID2 was significantly decreased in NK cells with an exhausted phenotype and weakened antitumor function. ARID2 knockdown resulted in the upregulation of programmed cell death protein 1 (PD‐1) and downregulation of interferon‐gamma (IFN‐γ), tumor necrosis factor (TNF), granzyme B and perforin in NK cells. As a result, ARID2 knockdown impaired NK cell cytotoxicity. Besides, ARID2 overexpression suppressed the expression of PD‐1 and lymphocyte‐activation gene 3, and promoted the expression of IFN‐γ, TNF, granzyme B and perforin in NK cells which were adoptively transferred into OSCC‐bearing mice. Taken together, our study implies that the OSCC microenvironment triggers ARID2 downregulation in intratumoral NK cells. In turn, ARID2 downregulation results in PD‐1 upregulation on NK cells and subsequently impairs NK cell cytotoxicity. Therefore, we uncovered a novel mechanism of NK cell dysfunction in OSCC. In oral squamous cell carcinoma (OSCC), AT‐rich interaction domain 2 (ARID2) is downregulated in natural killer (NK) cells with an exhausted phenotype in the tongue. ARID2 knockdown suppresses the production of interferon‐gamma (IFN‐γ), tumor necrosis factor (TNF), granzyme B and perforin in NK cells, subsequently impairing NK cell cytotoxicity. By contrast, ARID2 overexpression promotes the production of IFN‐γ, TNF, granzyme B and perforin in NK cells in OSCC, likely by inhibiting programmed cell death protein 1 expression.