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NAT10-mediated upregulation of GAS5 facilitates immune cell infiltration in non-small cell lung cancer via the MYBBP1A-p53/IRF1/type I interferon signaling axis

Zimu WangDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, ChinaJing LuoDepartment of Cardiothoracic Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, ChinaHairong HuangDepartment of Cardiothoracic Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, ChinaLi WangNanjing Medical University, Nanjing, 211166, ChinaTangfeng LvDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, ChinaZhaofeng WangDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, ChinaChuling LiDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Nanjing Medical University, Nanjing, 210002, ChinaYimin WangDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Nanjing Medical University, Nanjing, 210002, ChinaJiaxin LiuDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, ChinaQinpei ChengDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, ChinaXueying ZuoDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, ChinaLiwen HuDepartment of Cardiothoracic Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, ChinaMingxiang YeDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, ChinaHongbing LiuDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China. [email protected]Yong SongDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China. [email protected]

2024en

ABI

Annotatsiya

Interactions of tumor cells with immune cells in the tumor microenvironment play an important role during malignancy progression. We previously identified that GAS5 inhibited tumor development by suppressing proliferation of tumor cells in non-small cell lung cancer (NSCLC). Herein, we discovered a tumor-suppressing role for tumor cell-derived GAS5 in regulating tumor microenvironment. GAS5 positively coordinated with the infiltration of macrophages and T cells in NSCLC clinically, and overexpression of GAS5 promoted macrophages and T cells recruitment both in vitro and in vivo. Mechanistically, GAS5 stabilized p53 by directly binding to MYBBP1A and facilitating MYBBP1A-p53 interaction, and enhanced p53-mediated transcription of IRF1, which activated type I interferon signaling and increased the production of downstream CXCL10 and CCL5. We also found that activation of type I interferon signaling was associated with better immunotherapy efficacy in NSCLC. Furthermore, the stability of GAS5 was regulated by NAT10, the key enzyme responsible for N4-acetylcytidine (ac4C) modification, which bound to GAS5 and mediated its ac4C modification. Collectively, tumor cell-derived GAS5 could activate type I interferon signaling via the MYBBP1A-p53/IRF1 axis, promoting immune cell infiltration and potentially correlating with immunotherapy efficacy, which suppressed NSCLC progression. Our results suggested GAS5 as a promising predictive marker and potential therapeutic target for combination therapy in NSCLC. A schematic diagram demonstrating the regulatory effect of GAS5 on immune cell infiltration by activating type I interferon signaling via MYBBP1A-p53/IRF1 axis in non-small cell lung cancer. IFN, interferon.

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DOI: 10.1038/s41420-024-01997-2

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