IGF2BP3 boosts lactate generation to accelerate gastric cancer immune evasion

• Published in: Apoptosis (London) 2024-12, Vol.29 (11-12), p.2147-2160
• Main Authors: Lin, Kai, Lin, Xiufeng, Luo, Fan
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - metabolism; Animals; Anticancer properties; Antitumor activity; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Care and treatment; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Biology; Cell culture; Cell Line, Tumor; Female; Gastric cancer; Gene Expression Regulation, Neoplastic; Growth factors; Health aspects; Humans; Immunity; Immunotherapy; Lactic acid; Lactic Acid - metabolism; Lymphocytes; Lymphocytes T; Male; Metastases; Mice; mRNA stability; N6-methyladenosine; Oncology; Prognosis; Protein binding; RNA; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Stomach cancer; Stomach Neoplasms - genetics; Stomach Neoplasms - immunology; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; T cells; Tumor Escape - genetics; Tumor microenvironment; Tumor Microenvironment - immunology; Tumors; Virology
• ISSN: 1360-8185; 1573-675X; 1573-675X
• DOI: 10.1007/s10495-024-02020-w

The CD8 + T cells mediated antitumor immunity plays a critical function on gastric cancer (GC) immunotherapy. However, the mechanism of N 6 -methyladenosine (m 6 A) and lactate in GC immune microenvironment are still unclear. Here, present research investigated the role of Insulin like growth factor II mRNA binding protein 3 (IGF2BP3) in GC and its in-depth mechanisms in the antitumor immunity. Data illustrated that high IGF2BP3 level was associated to GC poor prognosis and tumor infiltration. Functional assays demonstrated that IGF2BP3 overexpression could promote the lactate accumulation, and impair the CD8 + T cells’ antitumor immunity activity in co-culture system. Correspondingly, IGF2BP3 silencing enhanced the CD8 + T cells’ antitumor immunity activity towards co-cultured GC cells. Mechanistically, IGF2BP3 could bind the m 6 A site on LDHA mRNA, thereby promoting its mRNA stability. Rescue assays elucidated that IGF2BP3/LDHA axis impaired the CD8 + T cells antitumor immunity by triggering lactate excess tumor microenvironment. In conclusion, our findings demonstrate that IGF2BP3 impairs the CD8 + T cells antitumor immunity by targeting LDHA/lactate axis, providing a novel therapeutic insight for GC immunotherapy.