Details

Autor(en) / Beteiligte

• Ma, Xiaoxiao
• Jia, Shuqin
• Wang, Gangjian
• Liang, Min
• Guo, Ting
• Du, Hong
• Li, Sisi
• Li, Xiaomei
• Huangfu, Longtao
• Guo, Jianping
• Xing, Xiaofang
• Ji, Jiafu

Titel

TRIM28 promotes the escape of gastric cancer cells from immune surveillance by increasing PD-L1 abundance

Ist Teil von

• Signal transduction and targeted therapy, 2023-06, Vol.8 (1), p.246-246, Article 246

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• Immune checkpoint blockade (ICB) offers a new opportunity for treatment for gastric cancer (G.C.). Understanding the upstream regulation of immune checkpoints is crucial to further improve the efficacy of ICB therapy. Herein, using the CRISPR-Cas9-based genome-wide screening, we identified TRIM28 as one of the most significant regulators of PD-L1, a checkpoint protein, in G.C. cells. Mechanistically, TRIM28 directly binds to and stabilizes PD-L1 by inhibiting PD-L1 ubiquitination and promoting PD-L1 SUMOylation. Furthermore, TRIM28 facilitates K63 polyubiquitination of TBK1, activating TBK1-IRF1 and TBK1-mTOR pathways, resulting in enhanced PD-L1 transcription. It was found that TRIM28 was positively correlated with PD-L1 in G.C. cells. Moreover, high TRIM28 expression suggests poor survival in a cohort of 466 patients with G.C., and this observation is consistent while analyzing data from publicly available databases. Ectopic TRIM28 expression facilitated tumor growth, increased PD-L1 expression, and suppressed T cell activation in mice. Administration of the PD-L1 or TBK1 inhibitor significantly alleviated the TRIM28-induced tumor progression. Furthermore, combining the TBK1 inhibitor with CTLA4 immune checkpoint blockade has synergistic effects on G.C., and provides a novel strategy for G.C. therapy.