TRIM29 promotes antitumor immunity through enhancing IGF2BP1 ubiquitination and subsequent PD-L1 downregulation in gastric cancer

• Published in: Cancer letters 2024-01, Vol.581, p.216510-216510, Article 216510
• Main Authors: Jiang, Tianlu, Xia, Yiwen, Li, Ying, Lu, Chen, Lin, Jie, Shen, Yikai, Lv, Jialun, Xie, Li, Gu, Chao, Xu, Zekuan, Wang, Linjun
• Format: Article
• Language: English
• Subjects: Antitumor immunity; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation; Gastric cancer; Humans; PD-L1; Stomach Neoplasms - pathology; T-Lymphocytes - metabolism; Transcription Factors - genetics; TRIM29; Tumor Microenvironment
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2023.216510

Tripartite motif-containing protein 29 (TRIM29) is a member of TRIM family protein which has been reported to play a role in the progress of inflammatory and cancer diseases. However, its specific role in gastric cancer (GC) has yet to be fully understood. Here, we investigated the expression of TRIM29 in gastric cancer and its functions in the antitumor immunity. TRIM29 expression was lower in tumor tissues than that in paired normal tissues. Lower expression of TRIM29 was related to aberrant hypermethylation of CpG islands in TRIM29 gene. Comprehensive proteomics and immunoprecipitation analyses identified IGF2BP1 as TRIM29 interactors. TRIM29 interacted with IGF2BP1 and induced its ubiquitination at Lys440 and Lys450 site by K48-mediated linkage for protein degradation. IGF2BP1 promoted PD-L1 mRNA stability and expression in a 3′UTR and m6A-dependent manner. Functionally, TRIM29 enhanced antitumor T-cell immunity in gastric cancer dependent on the IGF2BP1/PD-L1 axis in vivo and in vitro. Clinical correlation analysis revealed that TRIM29 expression in patient samples was associated with CD8+ immune cell infiltration in the GC microenvironment and the overall survival rates of GC patients. Our findings revealed a crucial role of TRIM29 in regulating the antitumor T-cell immunity in GC. We also suggested that the TRIM29/IGF2BP1/PD-L1 axis could be used as a diagnostic and prognostic marker of gastric cancer and a promising target for GC immunotherapy. In the study, “TRIM29 promotes antitumor immunity through enhancing IGF2BP1 ubiquitination and subsequent PD-L1 downregulation in gastric cancer,” we explored for the first time the role of the E3 ubiquitin ligase TRIM29 in antitumor T-cell immunity and showed that this role is dependent on the IGF2BP1/PD-L1 signaling axis.•Through a gastric cancer cell-T cell co-culture model, we found that TRIM29 enhanced anti-tumor T cell immunity. Further exploring its molecular mechanism, we confirmed that TRIM29 induces K48-linked ubiquitination degradation of the IGF2BP1 K440 and K450 sites through its C-terminal structural domain binding to the KH3/4 structural domain of IGF2BP1, which further mediates the effect of IGF2BP1 in a 3′UTR- and m6A-dependent manner on the PD-L1 mRNA stability and expression.•In animal models with different immune systems, we also found that specific antagonism of TRIM29 could synergize with PD-1 monoclonal antibody to exert anti-tumor effects, and clinical samples also verified that the e